CIRCULATION IN HUMAN AND VETERINARY PHYSIOLOGY

I Dr.E.Muralinath providing information regarding humoral and nervous regulation of BP and Fetal circulation.

1. Circulation Dr. E. Muralinath Associate Professor, College of Veterinary Science, Proddatur, Andhra Pradesh

2. Microcirculation Circulation in the tissues I ncludes arterioles, capillaries, venules & lymph channels E xchange of gases & nutrients S mall arterioles and metarterioles control blood flow to each tissue S mall arterioles are controlled by tissue needs E ach tissue controls its own blood flow - autoregulation 10 billion capillaries with a total surface area estimated at 500 - 700 m 2

3. Structure of M icrocirculation Arterioles: small arteries branches 6 - 8 times to form arterioles (D = 10 -15 μ m), muscular, capable of vasomotion branch 2-5 times - metarterioles (5-10 μ m) m etarterioles & precapillary sphincters vary near to tissues served d irectly affected by t issue conditions (e.g., nutrient & metabolic end product conc. Venules: Significantly larger than arterioles, have weaker muscular walls p ressure in venules < arterioles Veins contract despite weak walls f unctional cells are within 20 to 30 μ m from the nearest capillary

4. Capillaries are 0.5 -1 μ m thick, and 5-9 μ m long Capillary Pores: intercellular clefts 6-7 nm, 20X > H 2 0 molecules) and p lasmalemmal vesicles Brain: tight junctions allow only gases & water Liver: clefts are wide open, allow plasma proteins to move in & out GIT: midway to Liver & muscles Kidneys: fenestrae allows large amounts of molecules & electrolytes to pass through Structure of Microcirculation

5. Blood flows intermittently in capillaries due to smooth muscle activity in metarterioles & precapillary sphincter, ‘ vasomotion ’ Cause of vasomotion: Oxygen utilization in tissues ↑ oxygen utilization by the tissue , ↓ conc. of oxygen in capillaries,↑ the frequency & duration of intermittent blood flow Average function of capillary system: an average rate of blood flow, an average capillary pressure, an average rate of transfer of substances between the capillary bed & interstitial fluid Mode of transfer − Diffusion, Filtration ( S lit pores) & Pinocytoses (Vesicles) – Diffusion is quantitatively more important hydrophilic substances: H 2 O,Na + Cl − glucose & urea (D) lipophilic substances: trans-endothelial movement, CO 2 & O 2 Microcirculation − Vasomotion

6. Microcirculation – Capillary Permeability Net rate of diffusion (NRD): NRD ∞ to the concentration difference between the two sides of the membrane NRD ∞ Concentration gradient x permeability Slight concentration gradient causes a net diffusion of large quantities

7. Frank - Starling Forces Interstitial fluid: 1/6 th of total volume of the body is intercellular spaces filled with fluid Hydrostatic & Colloid Osmotic Forces (four) determine NRD , referred to as ‘ Starling forces ‘ or Filtration pressure Capillary pressure (Pc ) : force fluid out of capillary wall into the interstitial spaces Interstitial fluid pressure (P if ) : force fluid into the capillary when P if is positive, and outside when P if is negative Capillary plasma colloid osmotic pressure (Pp): cause osmosis of fluid inward through the capillary membrane from interstitial spaces Interstitial fluid colloid osmotic pressure ( P if ): cause osmosis of fluid outward through the capillary membrane into interstitial spaces

8. Frank − Starling Forces

9. Negative ISF pressure is due to pumping of fluid out by the Lymphatics COP of plasma and ISF is due to Proteins, Albumin, Globulin and others Considerable amounts of proteins leak into ISF from capillaries Absolute quantity of proteins in ISF > plasma Volume of ISF is 4 times more than plasma volume Concentration of proteins in ISF < plasma COP of plasma, ISF and negative ISF pressure is same at the venous end & arterial end Frank - Starling Forces

10. The sum of all these forces is called net filtration pressure NFP = P c − P if + π if − π p If net filtration pressure is positive: fluid forced outward If net filtration pressure is negative: fluid forced inward NFP is slightly positive in normal conditions, resulting in a net filtration of fluid out into the interstitial space in most organs Starling Forces – ∆P at A rterial End NFP = P c − P if + π if − π p NFP = 30 − ( − 3 )+ 8 -28 = 13

11. Starling Forces – ∆P at Venous E nd NFP = P c − P if + π if − π p NFP = 10 − ( − 3 )+21 − 28 = 7

12. Starling Forces –Average ∆ P in Capillaries NFP = P c − P if + π if − π p NFP = 17.3 − ( − 3 )+ 8 -28

13. Amount filtered out = Amount reabsorbed Net filtration pressure outward is 28.3 – 28.0 = 0.3 mm Hg Net filtration rate throughout body = 2ml/min Average net filtration pressure = 0.3 mm Hg W hole body capillary filtration coefficient? = = 6.67ml. min -1 . mm. Hg -1 If filtration forces ↑, oedema occurs If reabsorption forces ↑, dehydration occurs Filtration coefficient /100g of tissue = 0.01 ml. min -1 . mm Hg -1   W hole body capillary filtration coefficient

14. Lymphatic System Lymphatic vessels are thin walled Lymph is formed from interstitial fluid (ISF) Lymphatics remove excess fluid from interstitium In superficial skin, CNS, muscle endomysium and bones, prelymphatics connect to Lymphatics Lymphatics empty into right and left subclavian veins at their junction with internal jugular veins Protein conc. o f lymph is different in different tissues

15. Anchoring elements attach endothelial cells to surrounding tissues E ndothelial cells edges overlap to form valves Valves opens only into the lymphatic capillary Smooth muscles walls of lymph capillaries help in moving lymph ISF push these valves open & allow flow directly into lymph vessels Lymphatic C apillaries 1/10 of the fluid that passes through capillaries returns to circulation via. the lymphatics ( 2 to 3 litres/day )

16. Contraction of Lymphatics Intrinsic contraction Fluid accrual stretches walls causing reflex contraction of smooth muscles Intra vessel pressure increases and valves open ( up to 50mm Hg) Successive segments operate independently Extrinsic contraction Contraction of muscles, movement of body parts, arterial pulsations, compression of tissue by objects outside body, all increase lymph flow Exercise increases lymph flow by 10-30X, While rest reduces lymph flow

17. L ymph flow changes with ISF pressure changes If negative ISF pressure > 0, lymph flow increases to 20X Factors that increase ISF volume, pressure and lymph flow ↑capillary pressure ↑plasma COP ↑ conc. Of protein in ISF ↑permeability of capillaries ↑ in ISF pressure >2-3 mm Hg Rate of lymph flow lymph flow↓ if lymph vessels collapse lymph flow ∞ degree of lymph pump activity

18. Hydraulic Conductivity of Lymphatics

19. Higher ISF & Edema

20. Lymphatics function Fluids are moved from ISF into blood circulation Brings in proteins from ISF to circulation Blood capillaries cannot reabsorb proteins If proteins are not removed from ISF on regular basis, an animal would die within 24h Regulate ISF volume, conc. & pressure R emove bacteria from tissues & lymph glands eliminate them Major route of absorption in GIT the rate of lymph flow ∞ I nterstitial fluid pressure X Activity of the lymphatic pump

21. Basic T heories O f Circulation

22. Blood F low C ontrol Importance of circulation delivery of oxygen & nutrients to the tissues r emoval of CO 2 & H 2 maintain optimal concentrations of ions transport of hormones & other factors other needs - thermoregulation, glomerular filtration Tissues control local blood flow according to their own metabolic & oxygen demands Intrinsic, independent of neural & hormonal effects WHY is it important to have a controlled blood flow to tissues? takes lot more blood than the heart can pump maintain minimal supply required to meet the tissue needs

23. Blood F low C ontrol

24. Blood Flow C ontrol T wo phases of local flow control: A cute vs. L ong term Rapid vs. slow Seconds/minutes vs. days , weeks or months vasodilatation/constriction of vessels vs. altered physical size/number of supplying blood vessels Acute control rapidly restores normal flow to local tissues Metabolism Oxygen sat.

25. Acute control of local blood flow in response to changes in tissue metabolism and oxygen supply modulates contractility of resistance vessels--------- vasoconstriction or vasodilation (arterioles, metarterioles, pre-capillary sphincters) Two theories of local blood flow in response to changing metabolic needs of the tissue Vasodilator theory Oxygen-lack theory/nutrient lack theory

26. Vasodilator Theory release of vasodilator substances High metabolic rate ( exercise ), lower blood flow ( higher BP ), short O 2 supply ( high altitudes ), nutrients shortage ( starvation ) and decreased quantities of available oxygen (hypoxia) act on smooth musculature of arterioles, metarterioles and pre-capillary sphincters increases blood flow and oxygen supply cause relaxation/dilatation of blood vessels

27. Oxygen/Nutrient Lack Theory deficient supply causes vasodilatation decreased oxygen, glucose, amino acids, vitamins (B-complex) required for optimal smooth muscle contraction in blood vessels opens pre-capillary sphincters of large number of capillaries high tissue levels/ precapillary sphincters closed till nutrients utilized activating more tissue units low tissue levels/Precapillary sphincters kept opened until restored

28. Both vasodilator & oxygen lack theory work together, in varying ratios, in different conditions Active hyperemia higher blood flow in a highly active tissue more vasodilator substances released E .g., thinking brain, exercising muscle or secreting GIT glands flow may increase to as high as 20X normal Reactive hyperemia increased blood flow after infarction, embolism etc. flow may continue from sec to hours, u ntil tissue oxygen debt repaid mainly an effect of metabolic blood flow regulation Metabolic C ontrol

29. Myogenic theory contractile properties of smooth muscle fibers stretching due to suddenly ↑Blood Pressure(BP) - ↑cytosolic calcium in smooth muscles → vasoconstriction & ↓ blood flow relaxation due to ↓BP - ↓cytosol calcium levels in smooth muscles → vasodilation & ↑ blood flow Metabolic theory autoregulation is by metabolic end products blood carries metabolic end products away from tissues ↓flow → ↑end products in tissue → vasodilation → ↑flow ↑flow → ↓end products → vasoconstriction → ↓flow Autoregulation - arterial pressure changes Acute changes in BP alter local blood flow to tissues “autoregulation” is explained by two theories

30. Special Cases of Acute Flow Control Kidneys tubuloglomerular feedback mechanism m ediated by macula densa f iltered excess fluid in distal tubules sensed by macula densa leads to afferent arteriole constriction, decreased blood flow and decreased glomerular fluid filtration Brain concentrations of CO 2 and hydrogen ions in brain tissue increased concentrations causes cerebral blood vessel dilatation washout of excess CO 2 and hydrogen ions restores normalcy Skin blood flow increases to skin capillaries in hot environments to dissipate excess heat

31. Dilatation of Upstream blood vessels l ocal mechanisms can only dilate small arterioles and capillaries, not arteries v asodilators cannot reach beyond vessels of a tissue unit increased blood flow through microcirculation is possible only by dilatation of upstream arteries in response to local tissue needs i n response to shear stress induced by rapid blood flow, endothelium of small vessels secrets endothelial derived relaxing factor (EDRF ) p rincipal component of EDRF is Nitric oxide (NO, gas) which is a short lived vasodilator (half life of 6 sec) NO causes vasodilatation of upstream arteries and facilitates increased local tissue blood flow

32. Flow, P ressure and Resistance

33. Flow, P ressure and Resistance Blood flows from high pressure to low, pressure areas Pressure difference (P1−P2), Units of resistance, R = dynes x s/cm 5 E.g., Perfusion pressure = 90 mm. Hg; Vent. output= 90 mL/s = 1 R unit Blood flow measured by Doppler flow meter, plethysmograph  

34. Factors Determining B lood F low Pressure gradient flow Resistance Viscosity (RBC count, plasma proteins) Diameter flow (Aorta – elasticity/recoiling effect, arterioles – sympathetic tone, CSA) Velocity flow (Cardiac output, CSA, Viscosity)  

35. Blood flow Blood flow: laminar (streamline) vs. turbulent (noisy) Probability of turbulence , Re= Reynolds number: the critical velocity at which flow becomes turbulent Re =Reynolds number, ρ (Rho) = fluid density, D = diameter , V = flow velocity and η (eta) = fluid viscosity Re < 2000 – linear flow; Re > 3000 – turbulent flow  

36. Blood flow & velocity Flow vs. Velocity: volume per unit time (cm 3 /s ) vs. linear displacement per unit time (eg, cm/s) Mean blood flow ( ) = volume of blood that flows into a region of circulatory system in a given unit of time Flow, = x A Mean blood velocity (V): Distance travelled by a volume of blood in a unit time through a specific blood vessel Mean velocity aorta> smaller vessels>capillaries The peak velocity occurs during maximal ventricular ejection  

37. Viscosity Plasma is 1.8 times more viscous than water whole blood is 3–4 times more viscous than water, e.g., immunoglobilinemia, hereditary spherocytosis In large vessels, ↑ haematocrit ↑ viscosity In arterioles, capillaries , and venules viscosity change /unit haematocrit change is smaller vs. large vessels In polycythaemia (haematocrit is 60 or 70), the blood viscosity can be 10 times more vs. water, and flow through blood vessels is greatly retarded

38. Hagen- Poiseuille equation : Flow (Q ) is directly proportional to pressure gradient ( P A – P B ), fourth power of radius (r 4 ), but inversely proportional to the length of the tube ( L) & viscosity ( η) . Therefore, flow rate F = ( P A – P B ) × ( π/8 ) × ( 1/η ) × ( r 4 /L) Arterioles change their radius between 8-30 μ m, so blood flow could change ~256 times Windkessel ( elastic reservoir) effect: recoiling effect of blood vessels that converts the pulsatile flow into continuous flow M ean velocity in aorta is ≥ 50 cm/second s ystole: up to 120 cm/s vs. diastole: zero or negative ( Pulsatile ) flow through other blood vessels is continuous Windkessel vessels maintains continuous flow of blood through the circulatory tree by acting as a second pump  

39. Conductance It is the blood flow through a vessel at a given pressure gradient, ml/S/mm Hg Conductance = When the blood flow is laminar, small diameter changes causes tremendous changes in conductance Conductance ∞ (diameter) 4  

40. Shear S tress F orce applied by the flowing blood on the endothelium in the direction of flow/parallel to the long axis of the blood vessel Due to viscous drag of blood against vascular walls Shear stress (γ), viscosity ( η, eta) and rate ( dy/ dr ) This stress releases NO from endothelial cells NO relaxes blood vessels, ↑diameter of the upstream arterial blood vessels in response to ↑micro-vascular blood flow downstream Effectiveness of local blood flow control is enhanced  

41. Vascular distensibility & Compliance Vascular distensibility: fractional increase in blood volume in a blood vessel for each mm. of Hg. pressure rise arteries are 8X less distensible than veins & pulmonary arteries are 6X more distensible than systemic arteries Vascular compliance/ Capacitance: total volume of blood that can be stored in a given portion of the circulation for each mm. of Hg. (pressure) rise C Veins are called capacitance vessels  

42. C ompliance = distensibility x original volume a highly distensible vessel that has a slight original volume may have less compliance compared to a much less distensible vessel that has a large original volume E .g., a highly distensible bld. Vessel with a original volume of 100 mL, new volume is 120 mL, distensibility = x 100 = 0.2 and c ompliance = 0.2 x 20 = 4 E.g., a less distensible bld. Vessel with a original volume of 1000 mL, new volume is 1020 mL, then the distensibility = = 0.002, compliance = 0.002 x 200 = 0.4   Vascular distensibility & Compliance

43. Flow & Cross-Sectional A rea As same volume of blood must flow through each segment of the circulation every minute, the velocity of blood flow is inversely proportional to vascular cross-sectional area.

44. The cross-sectional area of aorta is 0.8 cm 2 , large arteries is 3.0 cm 2 and capillaries is 600 cm 2 Parts Velocity of blood flow (cm/sec) Aorta 13 Large arteries 6 Arterioles 0.3 Capillaries 0.05 Venules 0.1 Veins 1.0 Vena cava 9 Velocity of Blood Flow in Dogs

45. Total Peripheral Vascular Resistance The resistance to blood flow of the entire systemic circulation is called the total peripheral resistance Measured in peripheral resistance units (PRU) If  P = 1mm Hg and F = 1ml/s, then R = 1 PRU Ex: In an average adult, F = 100ml/s (Cardiac output) and  P = 100 mm Hg (between systemic arteries and systemic veins), then the resistance is 1 PRU Powerful vasoconstriction: Resistance to ↑4X (4 PRU) Extreme Vasodilatation: Resistance to ↓5X (0.2PRU)

46. Total P ulmonary V ascular R esistance The resistance to blood flow in the pulmonary circulation is called the total pulmonary vascular resistance Mean pulmonary arterial pressure = 16 mm Hg Mean left atrial pressure = 2 mm Hg N et pressure difference = 14 mm Hg cardiac output = 100 ml/sec the total pulmonary vascular resistance = 14/100= 0.14 PRU , about one seventh that in the systemic circulation)

47. Circulation T ime T ime taken by blood to travel through one part or entire circulatory system Pulmonary circulation time: transit time from a major vein to lungs. E .g., injecting a substance ( histamine) and measure the time taken to see flushing of face circulation time from arm vein to face: 24 seconds Number of heartbeat/total circulation time , is same for most mammalian species, ≈ 30 beats/total circulation time Circulation time ↓, if velocity of blood flow ↑ & vice versa Prolonged circulation time: Polycythaemia, heart failure Decreased circulation time: Exercise, adrenaline rush, anemia

48. Blood Pressure

49. Blood pressure L ateral pressure exerted by a circulating column of blood against any unit area of the arterial wall ( Stephen Hales (1730) ) Expressed in four different parameters Systolic blood pressure Diastolic blood pressure Pulse pressure Mean arterial blood pressure Systolic pressure: maximum pressure exerted during cardiac systole ( increased blood volume & distension of arterial walls ) Diastolic pressure : minimum pressure exerted during cardiac diastole (less distension & lower blood volume in arteries) Pulse pressure : systolic pressure − diastolic pressure (120 − 80 = 40 mm. Hg.) Mean arterial pressure : average pressure that exists in arteries throughout one cardiac cycle, systole, and diastole .

50. Blood P ressure Systolic pressure: indicates the total kinetic energy imparted to the blood by the heart. Diastolic pressure: reflects the state of peripheral vessels and load on vascular wall Pulse pressure: ventricular output and measure the variations of kinetic energy of heart. Values increases and decreases with increase and decrease of stroke volume Mean arterial pressure (MAP): useful to find out pressure in major arteries distal to aorta but not in aorta because the pattern of arterial pressure pulsation change as the pulse moves away from the heart

51. Mean A rterial P ressure (MAP) MAP = 60% of Diastolic Pressure + 40% of Systolic Pressure Arterial pressure = Cardiac output x Total Peripheral Resistance MAP is measured millisecond by milliseconds over a time period As the arterial pressure is closure to diastolic pressure than to systolic pressure during greater part of the cardiac cycle (also diastole period is longer than systole period (almost twice), MAP is closer to diastolic pressure value Mean arterial blood pressure = Diastolic + = 80 + = 93.3 mm Hg  

52. Standard Units of Pressure Arterial Blood Pressure: Expressed in millimeters of mercury (mm Hg), as the mercury manometer has been used since its invention Millimeters of Mercury (mm. of Hg.): if pressure in a vessel is 50 mm Hg, means that the force exerted is sufficient to push a column of mercury against gravity up to a level of 50 mm high, and at 100 mm Hg, it will push the column of mercury up to height of 100 mm Centimeters of Water (cm H 2 O): a pressure of 10 cm H 2 O means a pressure sufficient to raise a column of water against gravity to a height of 10 centimeters One mm Hg P ressure = 1.36 cm H 2 O pressure , because the specific gravity of mercury is 13.6 times of water’s, and 1 cm =10 mm One millimetre of Mercury = 0.133 kPa (kilo pascal), so in SI units this value is 16.0/9.3 kPa

53. Pulse P ressure D rives B lood F low BP is highest in aorta (98 mm Hg), moderate in capillaries and lowest in the vena cava (3 mm Hg ) Maximal pressure gradient is 95 mm. Hg . (98 – 3 mm. Hg.) that drives blood flow to aorta to vena cava RV LV RV LV

54. Heart pumps blood into aorta in a pulsatile manner Arterial pressure alternates between a systolic pressure (120 mm Hg) and a diastolic pressure level (80 mm Hg) , averaging about 100 mm Hg As the blood flows through the systemic circulation - mean pressure falls progressively – at the termination of the vena cava (0 mm Hg) The pressure in the systemic capillaries arteriolar ends: 35 mm Hg venous ends: 10 mm Hg average “functional” pressure in vascular beds: 17 mm Hg , ( a pressure low enough that little of the plasma leaks through the minute pores of the capillary walls ) nutrients can diffuse easily to the outlying tissue cells Systemic Circulation LV RV

55. In the pulmonary arteries, t he pressure is also p ulsatile - but the pressure level is far less than that in systemic arteries Pulmonary artery systolic pressure: 25 mm Hg P ulmonary artery diastolic pressure: 8 mm Hg A verage: 16 mm Hg The mean pulmonary capillary pressure is around 7 mm of Hg E ach minute, Flow , lungs = systemic circulation = heart = Cardiac output The low pressures of the pulmonary system – ensures adequate time of exposure of the blood in the pulmonary capillaries to oxygen and other gases while traversing alveolar walls   Pulmonary Circulation LV RV

56. Parts Velocity of blood flow (cm/sec) Aorta 13 Large arteries 6 Arterioles 0.3 Capillaries 0.05 Venules 0.1 Veins 1.0 Vena cava 9 Blood Pressure, Flow & Velocity Systole Diastole Systole

57. Pressure − volume (P-V) relation in arterial system blood 700 mL– AP 100 mm. Hg 400 mL of blood – AP 0 mm. Hg Veins have high capacitance even with 2−3 L blood, changes in pressure are trivial (3 − 5 mm. Hg, < 20 mm Hg) Sympathetics alter P-V relations increases cardiac function circulation works normally even when 25% of total blood is lost, e.g., traumas Pressure Volume − Arteries & V eins

58. Delayed Compliance ↑ blood volume at first ↑ pressure , but delayed compliance ↓ pressure back to normal within a minute to an hour – delayed compliance d ue to immediate elastic distention, stress relaxation o pposite in case of blood loss c onverts pulsatile blood flow into continuous Pulse pressure: SP − DP = e.g., 120 – 80 = 40 mm. of Hg stroke volume & c ompliance (distensibility)

59. Arteriosclerosis ↑ Pulse pressure Aortic stenosis ↓Pulse pressure Patent ductus arteriosus Aorta – Pulmonary artery shunt ↓ Diastolic pressure Aortic regurgitation Incompetent or absence of aortic valve ↓Pulse pressure Pulse P ressure Pulse pressure ↑ & ↓ with ↑ & ↓ of stroke volume (SV) When SV constant, Pulse pressure =  

60. Pressure Pulse T ransmission & D amping Greater compliance → lesser velocity, low rate of pulse pressure transmission In aorta, pressure pulse transmission velocity is 15-20 times > flow velocity Intensity of pulsation is lowest in the capillaries (damping) because of high resistance and less compliance Damping α  

61. Auscultatory method : BP is measured using stethoscope P alpatory method: pulse is used to find systolic pressure only Ultrasound Method : In this method, the Korotkoff’s sounds are amplified using piezoelectric microphones mounted within or below the cuff. The electric signal obtained is amplified to increase the audibility Microphone Method : In this method ultrasound is used to detect arterial wall movement as pressure is decreased with the blood pressure cuff Methods of BP Measurement

62. Direct Method Animal should be anesthetized Carotid artery can be connected to any of: the mercury manometer, membrane manometer, optical manometer, to record BP Mercury manometer is a `U' glass tube containing mercury in one limb and 10% sodium citrate in the opposite limb to balance the mercury. The limb with sodium citrate is connected to carotid artery through a tube with a cannula at its end. The float over the mercury column will record the BP over the kymograph

63. Measurement of BP - Indirect M ethod Clinically auscultation, pressure pulsation in major arteries heard with a stethoscope. E.g., human(brachial artery) , dog (femoral artery), cattle (middle coccygeal artery) M easured when external pressure > systolic pressure, is applied to a major artery u ntil blood flow through that artery is stopped and no sounds are heard ( KOROTOKOFF sounds) When the external pressure is slowly released blood flow resumes and sounds begin to be heard – Phase I: Clear tapping sound for two successive beats, systolic pressure Phase II: Softening of tapping sound & addition of swishing sound Phase III: Return of tapping sounds with more intensity & sharpness Phase IV: Abrupt of muffling of sounds, exhibiting a soft blowing quality Phase V : Complete disappearance of all sounds, diastolic pressure These sounds are called KOROTOKOFF sounds ( Nikolai Korotkoff Auscultatory method )

64. Representative Adult Blood P ressures

65. Mean Circulatory F illing P ressure The pressure in the entire ( systemic & pulmonary ) static circulatory system ( no blood motion ), and no pressure difference between the aorta and the vena cava, is called mean circulatory filling pressure (7 mm Hg) Circulatory f illing pressure is caused by the static blood distending the blood vessels; the vessels being elastic, they recoil and this recoiling accounts for the pressure in the static circulation

66. Basic Theory of Circulatory Function The rate of blood flow to each tissue of the body is almost always precisely controlled in relation to the tissue needs Active tissue demands more nutrients Heart can increase its cardiac output 4 −7 times over resting levels The micro-vessels of each tissue continuously monitor tissue needs - dilation or constriction - to control local blood flow Nervous control of the circulation from the central nervous system provides additional help in controlling tissue blood flow

67. Cardiac output regulated by sum of all the local tissue flows A rterial pressure is independent of either local blood flow control or c ardiac o utput c ontrol When pressure falls markedly below normal , nervous signals increase the force of heart pumping cause contraction of the large venous reservoirs to provide more blood to the heart cause generalized constriction of most of the arterioles throughout the body - more blood accumulates in the large arteries to increase the arterial pressure When pressure falls markedly for p rolonged periods, Kidneys Secrete pressure controlling hormones Blood volume regulating factors

68. Long term Blood flow regulation Acute blood flow regulation acts within seconds to minutes , once local tissue conditions change Caveat: Can adjust blood only to 75% of exact requirements E.g., When AP increases from 100 to 175 mm Hg Blood flow increased very little A cute control (within in 30sec to 3 min) brings back blood to ~ 15% above normal Therefore acute control is rapid BUT INCOMPLETE L ong term control regulates the blood flow to exact previous levels E.g., If AP remains at 150 mm Hg for several days/weeks Therefore long term control is delayed but NEARLY COMPLETE

69. Upon change in long-term metabolic demands, tissue requires a constant increase in supply of oxygen and other nutrients. Hence, arterioles & capillaries increase both in size and number within a few weeks to match the tissue needs Long-term regulation principally changes the amount of vascularity of the tissues, albeit by actual physical reconstruction of the tissue vasculature ↑metabolism − ↑vascular growth ↓metabolism − ↓vascular growth Rapid in neonates, young animals vs. slow in Old animals Rapid in new growth tissue vs. Old, well-established tissue Long term Blood flow regulation

70. Oxygen in Long-Term Regulation Increases vascularity in animal tissues at high altitudes, where atmospheric oxygen is low F eotal chicks hatched in low oxygen have ≈ twice tissue blood vessel conductivity vs. normal chicks R etrolental fibroplasia − premature babies put into oxygen tents, leads to immediate cessation of retinal neovascularization. When infant is taken out of the oxygen tent, blood vessels overgrow to compensate for sudden decrease in oxygen concentration Deficiency of tissue oxygen or nutrients , or both, leads to formation of angiogenic factors

71. Determination of Tissue Vascularity Determined by the MAXIMUM LEVEL OF BLOOD FLOW NEED & not by the AVERAGE NEED OF A TISSUE Tissue oxygen /nutrient deficiencies provokes release of vascular growth factors, that direct angiogenesis V ascular growth factors (angiogenic factors) are Vascular endothelial growth factor ( VEGF ) Fibroblast growth factor (FGF) Angiogenin Steroid hormones inhibit angiogenesis & heavy exercise promotes angiogenesis Extra vascularity remains constricted and opens to primarily allow MAXIMUM BLOOD FLOW NEED , following local stimuli such as lack of oxygen, nutrients, nerve vasodilatory stimuli, etc .

72. Collateral Circulation Blockage of a regular blood vessel dilatation of m any existing vascular channels in first few mins. a case of metabolic relaxation of small muscle fibers Partial restoration, maybe 1/4 th of the needs Progressively, more channels open until 100% tissue needs are met Growth of collateral circulation involves increase in both number and diameter of new vessels , which continues for months By age 60, at least one smaller branch of coronary artery is blocked in humans Not detected because of collateral circulation Heart attacks occur if blocks develop rapidly without development of compensatory collateral circulation

73. Determinants of Blood pressure Systolic pressure ∞ Cardiac output (exercise, myocardial infarction) Systolic pressure ∞ CO ∞ Diastolic pressure ∞ Peripheral resistance (PR) ( resistance offered to blood flow in arterioles in peripheral circulation) BP ∞ Venous return ( increases ventricular filling and CO) BP ∞ Blood volume ( maintains BP by controlling VR & CO) BP ∞ Velocity of blood flow (∞ PR ∞ BP ∞ Viscosity of blood ( η ) (increases vasodilation, reduces resistance to flow, which at 100 mm Hg is 4X vs. 50 mm Hg) BP ∞ BP ∞ ∞  

74. Physiological variations in BP Systolic pressure is more prone to changes than diastolic pressure Increases with Age ( SP/DP - newborn - 70/95, puberty 95/40, 80 year old 180/95) Sex (5 mm. Hg higher in young women vs. similar aged males) Body build (obese > lean) Diurnal Variation (low in the morning, high at noon and lower in the evening) Nutritional Plane: high after meals vs. low in unfed state Activity: 15-20 mm Hg. l ower during s leep vs. while awake Emotional condition (high with anxiety vs. low when calm) Physical state (high after moderate exercise − SP raises by 20 to 30 mm. of Hg, and after sever exercise SP can increase by 40 to 50 mm. of Hg. vs. resting state)

75. Pathological Variations in BP Hypertension: presence of persistent high blood pressure (SP >150 & DP> 90 mm Hg). Systolic hypertension-SP is very high Primary Hypertension: ↑SP, no underlying cause Benign Hypertension: 200/100 long course, symptomless Malignant Hypertension: 250/150, fatal condition Secondary Hypertension : High BP due to underlying cause Cardiovascular hypertension: atherosclerosis Endocrine hypertension: hyper-secretory adrenaline gland Renal hypertension: Glomerulonephritis, renal artery stenosis Neurogenic hypertension : tractus solitaries lesions, ↑I/C pressure Pregnancy toxaemia: AI disorder and vasoconstrictor hormones

76. Hypotension Hypotension: persistent low blood pressure (SP < 90 mm. Hg) Primary Hypotension: ↓SP, no underlying cause Secondary Hypotension: High BP due to underlying cause Myocardial infarction Hypoactivity of pituitary gland Hypoactivity of adrenal glands Neurogenic hypotension Chronic diseases Orthostatic hypotension : sudden fall in BP due to gravity, some conditions include myasthenia gravis, tabes dorsalis, syringomyelia and diabetic neuropathy

77. Humoral regulation of Circulation Humoral regulation: control by substances that are secreted and/or absorbed into the body fluids ( Hormones, ions etc.) Secreted by remote glands or in neighboring or local tissue Agents increasing Blood Pressure Norepinephrine Epinephrine Angiotensin II Vasopressin Endothelin Serotonin Thyroxine Calcium (Ca 2+) Agents decreasing Blood pressure Vasoactive intestinal peptide Bradykinin Histamine Prostaglandin, Acetyl choline Natriuretic peptides: ANP, BNP, C-type NP Carbon dioxide Ions : K + , Mg 2+, Na + , H + , Acetate, Citrate , lactate, NO

78. Humoral regulation of Circulation

79. Vasoconstrictor Agents Norepinephrine P owerful vasoconstrictor R eleased by sympathetic stimulation (exercise/stress) in various tissues S ympathetic stimulation of adrenal medullae secretes both norepinephrine and epinephrine into the blood with same effects as above Excites heart, contracts veins & arterioles Increases TPR & AP Epinephrine L ess powerful vasoconstrictor Even mildly dilates coronary arteries during increased heart activity

80. Angiotensin II Key for normal blood pressure regulation Powerful vasoconstrictor (arterioles) Increases TPR & AP Conc. at 1 PPM , hikes AP by more than 50 mm Hg. Vasopressin (ADH ) key for AP regulation in injury via. body fluid volume regulation Secreted by neurons of hypothalamus/SON (supra optic nucleus), & stored in posterior pituitary N ot for routine regulation of vasculature function Important in hemorrhage , increase in ADH levels increase AP as much as 60 mm Hg Vasoconstrictor Agents

81. Endothelin powerful vasoconstrictor in d amaged b lood vessels Effective vasoconstrictor at nanogram quantities present in the endothelial cells of most blood vessels Severe blood vessel damage releases endothelin causes vasoconstriction to prevent excessive bleeding from arteries (5 mm) size that are damaged due to crushing injury Calcium ions Increased conc. leads to vasoconstriction Vasoconstriction is by contracting smooth muscles of blood vessels Vasoconstrictor Agents

82. Bradykinin P owerful vasodilator in blood & tissue fluids of some organs Activated by tissue damage/inflammation/chemicals alpha2-globulin converted by kallikrein to kallidin Kallidin is then processed by tissue enzymes into Bradykinin Short lived (few minutes), deactivated by carboxypeptidases Causes powerful arteriolar dilation and increases capillary permeability (mainly pore size) Even a microgram of Bradykinin can rise blood flow by 6X Smaller amounts when applied locally causes marked oedema Vasodilator Agents

83. Histamine Released in all damaged or inflamed or allergy affected tissues Source of histamine mast cells – damaged tissues basophils – blood Powerful vasodilator effect on arterioles, augments capillary porosity allows leakage of tremendous amounts of fluid and plasma proteins into the interstitial spaces of the tissues causing oedema Mediates local allergic reactions due to its vasodilatory and oedema producing effects Vasodilator Agents

84. Thyroxine Secreted by thyroid gland Increases blood volume & force of cardiac contraction Increases Cardiac Output Increased metabolism, increases metabolites in t issue that cause vasodilation & decreases in total peripheral resistance Increases SP, but not DP AP is unaltered and pulse pressure changes Vasodilator Agents

85. ↑Ca 2 + − Vasoconstriction by augmenting smooth muscle contraction ↑K + − vasodilation by inhibiting smooth muscle contraction ↑Mg 2+ − vasodilation by inhibiting smooth muscle contraction ↑H + − vasodilation , ↓H + − vasoconstriction ↑CO 2 in tissues – moderate vasodilation in peripheral circulation, but significant vasodilation in cerebral blood vessels ↑CO 2 in blood acts on vasomotor centre and stimulates powerful sympathetic stimulated vasoconstriction across various tissues in the body Acetate, Lactate & Citrate anions − Vasodilation Nitric Oxide - vasodilator , secreted by endothelial cells Ions & Chemicals in Vasomotion

86. Nervous Regulation of the Circulation

87. Exerts wide spread control Rapid & short term regulation Controls blood flow distribution, heart pump activity & BP Total peripheral vascular resistance Blood vessel capacitance ( ∆ Volume /∆P ) C ardiac output How ? VASOMOTOR CENTRE responds to peripheral sensory impulses Autonomic nervous system via. Sympathetic nervous system ( resistance vessels & veins ) Parasympathetic nervous system ( heart ) Nervous Regulation

88. Vasomotor system Sympathetic VM nerve fibers leave spinal cord through all thoracic and 1 or 2 lumbar spinal nerves, enters sympathetic chains & exits through specific sympathetic nerves, innervate V essels of viscera & heart Vessels of peripheral areas No innervation into C apillaries, Precapillary sphincters, & metarterioles I nnervation of small arteries & arterioles allows sympathetic regulation of resistance

89. Vasomotor system

90. Located in upper medulla & pons region Three components Vasomotor centre Vasoconstrictor area Vasodilator area Sensory area Vasoconstrictor fibers Vasodilator fibers Parasympathetic vasodilator fibers Sympathetic vasodilator fibers Antidromic vasodilator fibers Vasomotor system

91. Vasoconstrictor area: p ressor /cardio-accelerator area , lateral side sends impulses to vasculature & cardio-accelerator area via . sympathetic vasoconstrictor fibers u nder hypothalamus & cortex control Result: Vasoconstriction, ↑HR, ↑AP Vasodilator area: depressor area/cardio-inhibitory area, medial side inhibits vasoconstrictor area & cardioinhibitor Under cortex, hypothalamus, Chemo- & Baro -, receptors Result : Vasodilation, ↓HR, ↓AP Sensory area: NTS , posterolateral part of medulla & p ons Peripheral sensory impulses via. GP, Vagal nerves & baroreceptors Result: Controls V asoconstrictor & Vasodilator area Vasomotor centre

92. Vasoconstrictor fibers Fiber endings secrete noradrenaline A cts on α -adrenergic receptors of smooth muscle Predominant role in BP regulation than Vasodilator fibers maintenance of vasomotor tone (vasoconstrictor tone) in blood vessels (continuous impulse discharge) Result: Vasoconstriction & ↑ in BP Vasodilator fibers : three types Parasympathetic vasodilator fibers dilatation of blood vessels by releasing acetylcholine Result: ↓ in HR & a small ↓ in contractility

93. Sympathetic vasodilator fibers vasodilatation by secreting acetylcholine from sympathetic cholinergic fibers (e.g., exercise) o rigin: cerebral cortex - relayed to spinal cord via. hypothalamus, midbrain & medulla Mainly important in skeletal muscle during exercise Result: Vasodilation & ↓ in BP Antidromic vasodilator fibers impulses produced by cutaneous receptor (e.g., pain receptor) & pass through sensory nerve fibers part of these impulses pass in opposite direction & reach blood vessels & dilates blood vessels Antidromic/axon reflex, fibers are antidromic vasodilator Result: Vasodilation & ↓in BP Vasodilator fibers

94. Vasomotor centre regulated by higher centres of brain Cerebral cortex Area 13 of brain, read emotions Sends signals to vasomotor center Vasomotor tone increase & ↑ BP Hypothalamus Posterior & lateral hypothalamic nuclei activation Signals to vasomotor center causing vasoconstriction Signals to PON causes vasodilation & ↓BP Respiratory Centre – Respiratory pressure waves onset of expiration , ↑ BP by 4 - 6 mm of Hg BP↓ during inspiration & expiration - spillover signals from respiratory centre to vasomotor cent re Thoracic cavity pressure changes venous return & CO Higher brain centres

95. Carotid baroreceptors Located in Carotid sinus Afferents form Hering nerve, a branch in glossopharyngeal (IX, C) to NTS Relays BP changes in 50 − 200 mm . Hg Aortic baroreceptors Located in aortic arch adventitia Afferents form aortic nerve , a distinct branch of vagus ( X, C) to NTS Relays BP changes in 100 − 200 mm. Hg Baroreceptors/ Pressoreceptors Respond to changes in BP & relays to vasomotor center Major role in short term regulation of blood pressure Baroreceptors helps to rapidly adjust for pressure changes due to altered posture, BV, CO & TPR

96. Baroreceptors Baroreceptor stimulation (rapid increase in BP due to sympathetic α – adrenergic stimulation) reduces heart rate RR interval ∞   Heart rate as a function of increasing arterial pressure during α - adrenergic stimulation Within 120 - 150 mm Hg , a linear relation exists between HR decrease & arterial pressure increase Long term increase in BP due to Baroreceptor loss is called Neurogenic hypertension

97. Baroreceptors Receptor firing increases with increased arterial pressure More number of impulses carried away from afferents to brain

98. R espond to changes in P O2, P CO2 & H + ions Located in carotid body and aortic body Chemoreceptors exert their effects on respiration Consists of two cell types Type I/ glomus cells g lomus cells have afferent nerve endings Type II/ sustentacular cells glial cells, supporting glomus cells Nerve innervations: carotid body - Hering nerve, aortic body - aortic nerve Function Activated by hypoxia , hypercapnea & higher H + ions Send inhibitory impulses to vasodilator area Hyperpnea, ↑ catecholamine secretion, tachycardia Vagal tone decreases and heart rate ↑ Chemoreceptors

99. Mechanism of action of baroreceptors & chemoreceptors together constitute sinoaortic mechanism Vasomotor centre regulates vasoconstriction/vasodilation Baroreceptors & Chemoreceptors sends sensory inputs to vasomotor centre for short term regulation of BP Sensory nerve fibers from baroreceptors reach NTS, located adjacent to vasomotor centre in medulla oblongata Supplying nerves are called buffer nerves Mechanism is also called pressure buffer mechanism Regulates heart rate, blood pressure & respiration BP Regulation – Sinoaortic Mechanism

100. Increased blood p ressure stimulates Baroreceptors Mainly by rising BP than steady BP Response depends on rate of increase in BP Result: decreased PR & CO, brings BP back to normal Pressure Buffer M ech.− Baroreceptors stimulatory impulses

101. Decreased blood pressure Decreased blood flow to chemoreceptors Decreased O 2 , increased CO 2 & H + ion Activate C hemoreceptors Stimulate Vasoconstrictor centre Blood pressure & blood flow increases Chemoreceptors

102. Atrial & Pulmonary Artery Reflexes Low pressure stretch receptors in atria, ventricles & pulmonary arteries Cardiopulmonary receptors – volume receptors Minimize AP variations caused by volume changes Detect AP changes in low pressure areas caused by blood volume changes (pulmonary artery, atria etc.) Example: If 300 mL blood infused to an adult dog AP rises ≈ 15 mm Hg, when all Receptors intact AP rises ≈ 40 mm Hg, when all receptors intact except Baroreceptors AP rises about ≈ 100 mm Hg, when all receptors intact except Baroreceptors & low pressure receptors

103. Increased atrial pressure Increases Heart Rate Stretching of SA node Increased pulse frequency Vasomotor Centre Atrial stretch receptors Vagus Sympathetic Prevent damning of blood in veins, atria & Pulmonary circulation Bainbridge Reflex

104. Kidneys — Volume Reflex Atrial Kidneys — Volume Reflex mechanism of BP control ↓Blood volume , ↓AP Stretch of atria R eflex dilation of afferent arterioles of glomerulus & signals from atria to hypothalamus ↑Efferent arteriolar resistance ↑Glomerular capillary pressure (↑GFR ) ↑Fluid filtration volume ↓ Decreased reabsorption ( ↓ ADH secretion) ↑ B lood volume, ↑AP

105. ↓Blood flow to the vasomotor centre in the lower brain stem ↑Nutritional deficiency/ C erebral ischemia ↑Firing of vasoconstrictor, Cardio-accelerator neurons ↑Systemic arterial pressure rises as high as heart can pump ↑CO2, lactic acid concentration i n brain VM centre ↑Sympathetic vasomotor nervous centre activity CNS Ischemic Response V ery powerful & generalized vasoconstrictor response Emergency & rapid pressure control system, last ditch stand Only kicks in at low pressure range (< 60 mm of Hg)

106. Abdominal Compression R eflex S timulation of vasoconstrictor system Baroreceptor reflex Chemoreceptor reflex Other factors Vasomotor Centre ↑Abdominal muscle tone Compression of abd . musc . & Venous reservoirs Translocation of blood towards the Heart Increases CO Increases AP Spinal nerves

107. Skeletal muscle contraction during Exercise Vasomotor Centre ↑Abdominal muscle tone & compression of venous reservoirs Compression of blood vessels throughout the body Translocation of blood towards Heart & Lungs Increases CO Increases AP Spinal nerves Exercise induced increases in CO & AP

108. Cause rapid and significant increase in BP Entire repertoire of vasoconstrictor and cardio-accelerator function of sympathetic nervous system is stimulated To counterbalance when not needed, the parasympathetic fibers in vagus nerve, sends inhibitory signals to heart All resistance vessels are vasoconstricted, ↑TPR, ↑BP Venoconstricton moves blood to heart ↑CO & ↑BP Sympathetics directly stimulate heart to increase both its rate and strength of cardiac muscle contractility (2-3X normal volume of blood can be pumped) Vasodilatory control of circulation is not of significance in normal state, but in exercising subject , vasodilation may allow for anticipatory increase in blood flow Neural regulation of BP - Summary

109. Vasovagal syncope Intense emotional disturbances causes activation of vasodilatory fibers and inhibits heart via cardio-inhibitory vagal signals Rapid decrease in Blood pressure & flow to brain causes unconsciousness Disturbing thoughts in cerebral cortex may be involved Pathway includes hypothalamus, vagal nerve fibers and spinal cord vasodilator fibers Also known as “ emotional fainting ” Examples of N ervous R egulation of BP

110. Exercise Greater demand for nutrients & oxygen in muscle tissue Sympathetic stimulation ↑BP & blood flow Demands are met by local vasodilation & ↑blood flow BP↑ by 30-40 % & blood flow by 2 X normal supported by activating vasoconstrictor & cardio-acceleratory areas of the vasomotor centre Extreme fright Extra blood flow to supply nutrients to manage the dangerous situation BP raises by 2 X normal within few seconds, an alarm reaction Examples of N ervous R egulation of BP

111. Long term Regulation of Arterial Pressure by Kidneys

112. An evolutionary conserved mechanism in all vertebrates Primarily carried out by modulating ECF volume in response to arterial pressure (AP) changes Renin-Angiotensin-Aldosterone mechanism Physiological variables of importance includes: Circulatory variables ECF volume Blood volume Cardiac output Total Peripheral resistance Renal variables Perfusion pressure in glomerulus Urinary intake/output of salt & water (Kidneys) Long term Regulation of Arterial Pressure

113. Renal Function Curve When Arterial P ressure increase, Kidney acts to cause Pressure D iuresis: increased urinary output Pressure Natriuresis: increased salt output AP ( mm Hg) Urine output (folds) < 55 ≈ 90 normal ≈150 4 X normal ≈190 8 X normal Renal regulation of AP is an ‘ Infinite Feedback Gain ’ mechanism

114. How Pressure Diuresis Control AP? Renal–Body Fluid System for arterial Pressure Control In an experimental dog , first all nervous reflex mechanisms of AP are blocked 400 mL blood was intravenously infused, after 1 hour CO − ↑ 2 folds AP − ↑ 2 folds Pressure diuresis: UO − ↑12 folds CO & AP returned normal in 1 hour a case of volume loading hypertension, corrected by kidneys

115. Two factors determine arterial p ressure level renal output of water & salt ( renal output curve ) level of net water and salt intake ( salt water intake curve/line ) If, renal output of salt & water = intake of salt and water, the pressure will always adjust back to equilibrium point (MAP = 100 mm Hg.) AP control by Renal–Body Fluid S ystem

116. How do the equilibrium point change? 1. Changing the pressure level of the renal output curve for salt & water E.g : Kidney disorder , ↑AP, equilibrates at 150 mm Hg Two ways 2. Changing the level of the water & salt intake E.g : higher intake level (4 fold) equilibrates ) AP at 160 mm Hg

117. Hypervolemia & AP In an experimental dog K idney volume ↓ to 30% normal Salt intake ↑to 6 X normal Acute effects (2 days) Arterial pressure (AP) − ↑ 30% ECF volume (ECFV) − ↑33% Blood volume (BV) − ↑20% Cardiac output (CO) − ↑40% Total resistance (TPR) − ↓ 13% Long-term effects (2 W ks) ECFV, BV, CO restored Secondary rise in TPR – ↑ 33% Arterial pressure – ↑40%

118. Volume loading & Arterial Pressure Changes ↑ECF in intercellular spaces & ↑Blood volume (BV) ↑Venous return (VR) ↑ A rterial Pressure (AP) ↑Right ventricular filling pressure ↑Cardiac Output (CO) Autoregulation ↑Total Peripheral resistance (TPR) Excess salt & water intake/Fluid transfusion ↑Mean Circulatory filling pressure

119. Renal Regulation of Arterial Pressure K idneys removes excess water & salt ( ↑Urinary Output)  Systemic arterial pressure is brought back to normal Regulation by kidneys ↑ ECF in intercellular spaces & ↑ B lood volume ↑Venous return ↑Right ventricular filling pressure ↑Cardiac output, CO Autoregulation ↑Total Peripheral resistance (TPR) ↑ A rterial P ressure

120. Kidney mass/function is essential for AP regulation 70% Kidney mass removed in Dogs: Arterial Pressure increases with increased Na + & H 2 0 intake

121. )   Arterial pressure can be altered either by changing CO or TPR or both In conditions where CO > normal , AP maintained by reducing TPR E.g., Hyperthyroidism In conditions where CO < normal , AP maintained by increasing TPR E.g., Hypothyroidism When both CO & TPR are normal (100%), AP is also normal

122. Renal regulation of Arterial Pressure A few mm. Hg rise in AP can increase water (Pressure Diuresis ) & salt (Pressure Natriuresis), excretion Excretion of water & salt by kidney is sensitive to AP changes Long-term AP control is related to body fluid homeostasis Works primarily by regulating ECF volume via. Thirst center: High osmolality of ECF stimulates the thirst centre in the brain causing to drink extra amounts of water to return the extracellular salt concentration to normal, increase in ECF volume, increase in BP ADH hormone (Pressure diuresis ): increased salt in extracellular fluid rises tissue osmolality , which then releases ADH from posterior-Pituitary. ADH causes water retention, thereby increasing water level in ECF & restores ECF osmolarity, volume and BP

123. Renin - Angiotensin mechanism Renin secretion is stimulated by ↓arterial blood pressure, ↓ECF volume, ↑ SNS activity, ↓ load of sodium and chloride in macula densa. Angiotensin II, III, IV 1 st set of actions: direct renal effects (very potent): constriction of renal arterioles, ↓blood flow, ↓ glomerular filtration, ↑salt & water retention, ↑ECF volume & ↑AP 2 nd set of actions: action via. Aldosterone: stimulates aldosterone secretion, reabsorption of sodium from renal tubules,↑water reabsorption, ↑ECF volume, ↑blood volume & ↑AP Renin-Angiotensin mechanism amount of salt that accumulates in the body is the main determinant of the extracellular fluid volume. RA mechanism is key in mode of BP control

124. Increasing renal retention of salt & water by angiotensin infusion E.g., Blockage of Renin-angiotensin pathway, MAP equilibrates to 75 mm. of Hg. & infusion of angiotensin (2.5 x normal) ↑MAP equilibration to a higher level at 115 mm. Hg Effects of Angiotensin on BP

125. Renin- Angiotensin mechanism

126. After haemorrhage: Acute decrease of the arterial pressure to 50 mm Hg Arterial P ressure rose back to 83 mm Hg when the renin-angiotensin system back to function Renin- Angiotensin mechanism

127. Rapid/Quick Exclusively nervous reflexes CNS ischemic response Baroreceptor reflex Chemoreceptor reflex Intermediate Renin-Angiotensin System Stress relaxation of vasculature Shift of fluids in and out of circulation to adjust blood volume Long-term Renal body fluid system Summary of arterial pressure regulation

128. Arterial P ressure R egulation Summary Within seconds Baroreceptor mechanism CNS ischemic response Chemoreceptor mechanism 2. Within several minutes Renin-Angiotensin vasoconstrictor mechanism Stress relaxation of vasculature Shift of fluids through capillary walls in tissues 3. Within hours, days & cont. Renal body fluid control Aldosterone control CNS ischemic response

129. Renin- Angiotensin mechanism Decreased BP BP restored to normalcy

130. ↑Salt & water Reabsorption Decreased Arterial Pressure ↑Renin secretion by Kidney (JG apparatus) Systemic A rterial P ressure is restored to normalcy Angiotensin II, III, IV Activates Angiotensinogen (renin substrate) Angiotensin I Vasoconstriction Angiotensin converting enzyme (lungs) Adrenal cortex Aldosterone Kidneys ↑ECF and blood volume Cardiovascular system Renin- Angiotensin mechanism

131. Renin-angiotensin system an automatic feedback mechanism Keeps BP in normal range even when salt intake changes

132. Veins

133. Coronary Circulation Two coronary arteries Right artery supplies whole of the RV & posterior wall of LV Left artery supplies anterior & lateral wall of LV Right & Left arteries divide into epicardiac arteries that branch into final arteries or intramural vessels

134. Coronary Circulation Blood volume in CC is ≈200 mL/minute. 4-5% of cardiac output 65 - 70 mL/minute/100 g of cardiac muscle Blood flow Autoregulation Phasic, ↓in systole & ↑in diastole Flow↓: M yocardial pressure > Aortic pressure Changes when AP is out of 60 - 150 mm Hg range Physiological shunt: Deoxygenated blood in Thebesian veins → cardiac chambers deoxygenated blood from bronchial circulation → pulmonary vein

135. Factors affecting flow Oxygen: Higher myocardial O 2 extraction, hypoxia Metabolic factors: A denosine, K + , H + , CO 2, NO, kinin, prostacycline Coronary perfusion pressure in LV = ADP – LVEDP Nervous factors ( ANS): Sympathetic NS Parasympathetic NS Coronary Circulation

136. Coronary Circulation - Venous Drainage Coronary sinus from aorta , anterior coronary v eins from RV Thebesian Veins from myocardium Arterio-sinusoidal & -luminal vessels from arterioles

137. Foetal Circulation Foetal lungs are nonfunctional Placenta = Foetal lung Site of gas & nutrient exchange is placenta Heart development completes at 4th week of gestation Foetal HR is ≈65 BPM, ↑ to ≈140 BPM before birth Foetal heart pumps large quantity of blood into placenta Umbilical veins collect blood from placenta & passes through liver & then enters RA via . IVC Umbilical vein blood enters IVC via. Ductus Venosus B lood flows from RA into LA via. F oramen O vale

138. Anatomy of Foetal Circulation

139. Fetal Circulation Vs. Adult Circulation UV UA 55% Foetal CO passes through Placenta Umbilical venous blood has 80% O 2 Sat. vs. 98% in adult arteries Ductus Venosus diverts UV blood to IVC, O 2 sat . 67% Portal & systemic venous blood is 26 % O 2 sat. Blood from IVC → LA via patent Foramen Ovale Blood from SVC → RV → Pulmonary artery P ulmonary artery → Aorta via. D uctus Arteriosus Unsaturated blood in RV perfuse trunk & lower body of the fetus Better-oxygenated blood from LV perfuses head From aorta , blood → umbilical arteries → placenta Blood in aorta & umbilical arteries is ≈ 60% O 2 Sat.

140. Pulmonary circulation in Foetus Foetal & new-born tissues are resistant to hypoxia O 2 saturation of maternal blood in the placenta is very low vs. Foetal blood O 2 affinity, of Hgb F > Hgb A, b inding of Hgb F with 2,3-DPG is less vs. Hgb A DA & FO makes left & right hearts parallel pumps Placental circulation ceases at birth & TPR increases suddenly A asphyxiation at birth opens up foetal lungs Higher – ve Intrapleural pressure (– 30 to –50 mm Hg) causes foetal lung expansion

141. Pathophysiological aspects Blood flow to LV is mainly during diastole , especially blood flow in subendocardial portions of heart LV systolic pressure > Aortic pressure (∆P = −1) – Minimal flow Subendocardial area of heart are more prone to ischemia as no blood flow during systole Exercise: Coronary blood flow ↑ if myocardium metabolism ↑ ↓ Aortic diastolic pressure – ↓coronary blood flow Tachycardia: When HR ↑, Diastole period ↓ − ↓ LV coronary blood flow Stenosis of Aortic valves: Requires high LV pressure than Aorta to eject blood, more stronger systole – less LV perfusion Congestive heart failure: ↑ Venous pressure – ↓ EPP – ↓ coronary flow

142. Cardiac Output & Venous Return Curves

143. Cardiac O utput (CO): the quantity of blood pumped into aorta each minute by heart or the quantity of blood that flows through the circulation at any point of time Venous Return (VR): the quantity of blood flowing from veins into right atrium each minute Ideally, CO = VR , in young men, CO = 5.6 L/min, women = ~4.9 L/min Factors the affect CO: Basal metabolic rate Physical activity, e.g., exercise Chronological age Body size Cardiac index: CO per square meter of body surface area E.g., Bd. Wt. = 70 Kgs, SA = 1.7 m 2 , 3L/min/ m 2 Cardiac Output & Venous Return

144. Cardiac Output & Venous Return Cardi ac Output is controlled by Venous Return VR matches the sum of the local blood flow regulation in all local tissues of the body CO regulation is the sum of all local blood flow regulations In unstressed condition, heart is not a major control node of CO, but rather VR, Frank Starling law of heart When TPR ↑, CO ↓ Cardiac Output = Peripheral factors that affect CO: CO decreases ↓ blood volume Acute venodilation Obstruction of large veins ↓ tissue mass, e.g , skeletal muscle atrophy  

145. Factors increasing CO (Hyper-effective hearts) – Left shift Nervous system regulation: SNS stimulation & PSN inhibition, increases HR (2-3X) & Cardiac contractility (2X) Hypertrophy of heart Chronically high workload ↑myocardial mass & contractility Excitation of Cardiac nerves Factors decreasing CO (Hypo-effective hearts) – Right shift Decreased functioning of heart Coronary blockage, Nervous inhibition, Arrhythmias, Valvular heart diseases, Hypertension, myocarditis, hypoxia, congenital heart disease Shift of plateau to right CO↑ ↓CO

146. Intact Nervous signal: Dinitrophenol - metabolic booster & Vasodilator Enhanced cardiac output almost 4X, and no significant changes in AP Compromised Nervous signal: Dinitrophenol injection led to little increase in CO, & a significant drop in AP Physical exercise is another example where CO increase due to enhanced metabolism & VR, nervous signals keeps AP unchanged

147. CO ↑, when TPR ↓ ↑ Diameter ↑VR CO ↓, when ↓ Heart Pumping ↓Venous return MI Myocarditis Valvular diseases Metabolic disorders

148. Extracardiac pressure P ressure outside the heart, intra-pleural pressure (IPP) Ranges – 6 to –2 mm Hg (Avg. – 4 mm Hg) High intra-pleural pressure − venous return & CO – ↓ E.g., open heart surgeries & in positive pressure ventilation Low intra-pleural pressure − venous return & CO – ↑ E.g., negative pressure breathing Rise in IPP shifts CO curve to right by same amount of pressure increase in right atrium Factors changing IPP Respiration (±2 to ±50 mm Hg) Negative pressure ventilation Positive pressure ventilation Opening thoracic cage Cardiac Tamponade Rt )

149. Venous Return Three factors regulate Venous return (VR) Right atrial pressure: backward force on the veins to impede blood flow from veins into RA Mean systemic filling Pressure: represents d egree of filling of the systemic circulation that forces the systemic blood towards RA Resistance to blood flow: impedance to flow of blood between the peripheral blood vessels and RA When RA pressure increases, VR decreases due to back-pressure in RA, & CO eventually decreases Venous return curves demonstrate relationship between venous return & right atrial pressure When all nervous reflexes blocked, VR will be zero when RA pressure ≥ + 7, a pressure called ‘ mean systemic filling Pressure’

150. Venous return curves: c urves demonstrating relationship between venous return & right atrial pressure When right atrial pressure falls < 0, increase in VR almost ceases ≤ –2 mm Hg, VR will reach a plateau – 20 to – 50 mm Hg, plateau is maintained Reason: plateau is due to collapse of veins entering the chest If AP = VP, all flow in the systemic circulation ceases at a pressure of 7 mm Hg, termed Mean Systemic Filling Pressure (+7)

151. Mean systemic filling pressure (P sf ) increase with increase in blood volume ↑ in m ean Circulatory filling pressure is steeply linear with increase of even small quantities of blood Nervous system activity Sympathetic stimulation can cause vasoconstriction, decrease in total capacity of circulatory system, and increase (P sf ) by 2.5 times of normal (from 7 to 17 mm Hg) With PSN activity, (P sf ) change can decrease vs. normal (from 7 to 4 mm Hg ) the greater the difference between the mean systemic filling pressure and the right atrial pressure, the greater is the VR

152. Resistance to venous return, VR = P sf = Mean systemic filling pressure PRA = Right atrial pressure RVR = resistance to venous return 5 = = RVR = 7/5 = 1.40 mm Hg./L   When resistance to flow is 1/2x normal, flow 2X normal When resistance to flow is 2X normal, flow is ½X normal

153. Cardiac f unctional Curves (CO & VR) Conditions in normally functioning Heart & Vasculature CO = VR; RAP = P sf Momentary hearts pumping ability = CO Momentary state of flow from systemic circulation to heart = VR A 20% increase in blood volume ↑ P sf (16 mm Hg), ↑ CO & VR to 3X shifted upwards & right ↑ blood volume→ Venoconstricton, ↓resistance to VR Finally, CO & VR ↑ 2.5 - 3X normal and RAF to + 8 mm Hg Compensatory response to increased CO: ↑capillary pressure, venous dilatation by stress relaxation, ↑ TPR, ↑resistance to venous flow, ↓Psf to normal

154. Sympathetic inhibition by spinal anaesthesia or using hexamethonium : P sf falls to 4 mm Hg Effectiveness of heart pump ↓ to 80% of the normal CO falls to about 60% of the normal Sympathetic stimulation: Heart becomes a stronger pump Increases Psf – 16 mm Hg Increases resistance to VR Opening of an Arteriovenous fistula: Point A: normal Point B: immediate to o/p AV fistula Point C: After sympathetic stimulation Point D: After several weeks after o/p

155. Circulatory Shock: generalized inadequate blood flow through the body that causes damage to body tissues (mainly inadequate supply of oxygen and other nutrients to the body cells) What is a common culprit in terms of hemodynamics? Decreased cardiac output!!! What decreases CO? Factors that ↓Cardiac pumping activity (Cardiogenic Shock) e.g., myocardial infarction, cardio-toxicity, valvular dysfunction, arrhythmias Factors that ↓Venous Return e.g ., ↓ blood volume, ↓decreased vascular tone, obstruction to blood flow Circulatory Shock

156. Circulatory Shock without decreased c ardiac output: Excessive metabolism, so normal CO is not insufficient Tissue perfusion abnormalities causing a major portion of CO going into vessels other than those that perfuse tissues Commonality in most cases of shock: inadequate nutrients delivery to critical tissues organs inadequate removal of cellular waste products from the tissues Circulatory Shock

157. Tissue deterioration is the end in circulatory Shock. Regardless of cause, in advanced stages, shock itself breeds more shock, and spirals down into a vicious cycle Circulatory Shock Detection Arterial pressure is used to assess circulatory sufficiency & cardiac output in shock. Limitation: Sometimes, AP can be misleading. In case of haemorrhages involving severe blood loss, AP falls simultaneous to diminished CO Insufficient blood flow causes the tissues to continuously deteriorate, which leads to progressive decline in CO and tissue perfusion until death