Autoregulation : Role and mechanism

Autoregulation : Role and mechanism

1. AUTOREGULATION: Role and Mechanism Presenter : Dr. Parul Gupta Moderator : Dr. Anshuman Singh

2. DEFINITION Autoregulation is defined as the intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. It is a manifestation of local blood flow regulation . Autoregulatory response occurs in the absence of neural and hormonal influences and therefore is intrinsic to the organ.

3. For example – I f perfusion pressure is decreased to an organ (e.g., by partially occluding the arterial supply to the organ ) - blood flow initially falls, then returns toward normal levels over the next few minutes . This is autoregulatory response.

4. When perfusion pressure ( P A -P V ) initially decreases, blood flow (F) falls because of the following relationship between pressure, flow and resistance : F = ( P A – P V ) / R When blood flow falls, arterial resistance (R) falls as the resistance vessels (small arteries and arterioles) dilate. As resistance decreases, blood flow increases despite the presence of reduced perfusion pressure .

5. Passive vascular bed that doesnot show autoregulation - Pressure falls (100-70mmHg) – rapid fall in blood flow (also due to passive constriction as the intravascular pressure falls) Vascular bed capable of autoregulation – Presssure falls – rapid fall in flow – flow then gradually increases as the vasculature dilates, and achieves a steady state.

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7. Different organs display varying degrees of autoregulatory behaviour – The renal, cerebral, and coronary circulation - excellent autoregulation. S keletal muscle and splanchnic circulations - moderate autoregulation. C utaneous circulation - little or no autoregulatory capacity.

8. Role of autoregulation Autoregulation ensures that critical organs have an adequate blood flow and oxygen delivery . Changes in systemic arterial pressure can lead to autoregulatory responses in certain organs. It is a process within many biological systems, resulting from an internal adaptive mechanism that works to adjust that system's response to stimuli.

9. E.g.1. In hypotension, despite baroreceptor reflexes that constrict much of the systemic vasculature, blood flow to the brain and myocardium does not decline appreciably (unless the arterial pressure falls below the autoregulatory range) because of the strong capacity of these organs to autoregulate . E.g.2. Whenever a distributing artery to an organ becomes narrowed (e.g., atherosclerotic narrowing of lumen, vasospasm, or partial occlusion with a thrombus ) - It results in a reduced pressure at the level of smaller arteries and arterioles. These vessels dilate in response to reduced pressure and blood flow.

10. mechanism Four mechanisms of autoregulation — Metabolic Myogenic Tubuloglomerular feedback Tissue pressure Fifth possible mechanism — local neural control

11. Metabolic hypothesis According to this hypothesis blood flow and tissue metabolism are tightly coupled in such a way that any reduction in arterial inflow causes a buildup of vasodilator metabolites in the tissue. This buildup could be due to a reduced rate of washout of aerobic vasodilator metabolites such as CO2 or increased production of vasodilator substances due to hypoxia or to both. There is substantial evidence that the dependence of tissue oxygen on blood flow is responsible for autoregulation in organs with high oxygen consumption.

12. Both myocardium and brain exhibit a high degree of autoregulation , and in both organs blood flow is highly dependent on tissue oxygen consumption. In myocardium the hypothesis has been suggested that blood flow is regulated to maintain a constant tissue PO 2 . The relation between vascular resistance and venous PO 2 was identical under conditions of functional hyperemia and autoregulation, suggesting that the same mechanism may be operating in both circumstances.

13. In some tissues elevated O 2 consumption greatly enhances autoregulation The key factor in the enhancement of autoregulation may be a lowering of tissue oxygen levels as O 2 consumption increases.

14. Venous O 2 levels in resting skeletal muscle are relatively high (70% saturated), reflecting a high tissue PO 2 . An increase in metabolism in skeletal muscle leads first to increased O2 extraction and lowered venous O2 content with modest increase in flow. This increased extraction is apparently aided by a more widespread perfusion of the capillary bed to include vessels previously without flow.

15. The terminal arterioles are more sensitive than the larger arterioles to reduction in tissue oxygen tension This response would allow perfusion of more capillaries and greater oxygen extraction without substantially altering overall vascular resistance. R elatively small changes in tone of the distal arterioles may have a disproportionate effect on capillary perfusion.

16. When the capillary network is well perfused and O 2 extraction is maximized, a drop in arterial pressure and flow would lower tissue PO 2 and lead to relaxation of the larger arterioles and restoration of blood flow . Low tissue PO 2 , whether due to elevated metabolism or low blood flow , favors autoregulation.

17. Renal autoregulation

18. Feedback mechanisms intrinsic to kidney keep the RBF and GFR relatively constant despite marked changes in arterial blood pressure. Within a range of 70- 160 mmHg Without autoregulation, even a slight change in BP would cause a significant change in GFR. For e.g. at 100mmHg – 180 L/ day GFR, 1 L/ day of urine. If 25% rise in BP to 125mmHg – 225 L/ day of GFR, 46 L/ day of Urine.

19. Arteriole myogenic mechanism It depends upon a characteristic shared by most smooth muscle cells of the body . On stretching a smooth muscle cell, it contracts ; when stimulus is stopped it relaxes, restoring its resting length. This mechanism also works in the afferent arteriole that supplies the glomerulus.

20. When blood pressure increases, smooth muscle cells in the wall of the arteriole are stretched and respond by contracting to resist the pressure, resulting in little change in flow. When blood pressure drops, the same smooth muscle cells relax to lower resistance, allowing a continued even flow of blood.

21. Increased perfusion pressure causes increased stretch. Phospholipase C is activated, resulting in diacylglycerol production, which causes arachidonic acid release. Cytochrome P450 4A2 (CYP 4A2) converts the arachidonic acid to 20 -hydroxy eicosa tetraenoic acid (20 HETE ), which in turn activates protein kinase C . T his activation inhibits potassium channels, especially the calcium-activated potassium channel, resulting in lowering of the membrane potential of the vascular smooth muscle, with increased smooth muscle activation (probably mediated through a rise in intracellular calcium levels), causing vasoconstriction .

22. Autoregulation is antagonised by EET, which is produced in an analogous fashion when glutamate that spills over from metabolically active neurones activates PLC in astrocytes . Cerebral autoregulation may be quite heterogeneous. For example, autoregulation in small brainstem vessels may be dependent on K ATP

23. It contributes upto 50% of total autoregulatory response. It occurs very rapidly, reaching a full response in 3-10 seconds. It is seen in preglomerular resistance vessels – arcuate , interlobular and the afferent but not seen in efferent arterioles (lack of voltage gated Ca channels)

24. Role of myogenic theory in regulation of blood flow can be experimentally proved . When papavarine is injected, papavarine brings about the paralysis of smooth muscles. Hence, after injection of papavarine , when the perfusion pressure is increased, there will be increase of blood flow without any autoregulation. It proves the role of smooth muscle fibers of blood vessels in the auto regulatory mechanism. This theory holds good for almost all organs.

25. Tubuloglomerular feedback This is a feedback mechanism that links sodium and chloride concentration at the macula densa with control of renal arteriolar resistance . It acts in response to acute perturbations in delivery of fluid and solutes to the JGA. It has 2 components Afferent arteriolar feedback Efferent arteriolar feedback

26. It helps in Autoregulation of GFR Controls distal solute delivery, hence tubular reabsorption

27. REGULATION OF TUBULOGLOMERULAR FEEDBACK Mediators- Adenosine ATP Modulators Neuronal NOS Angiotensin II Endothelin

28. Tissue fluid pressure theory There will be constant movement of fluids between blood and tissues at the level of capillaries . Exchange of fluid occurs at the level of capillaries because of the capillary dynamics . When there is increase of perfusion pressure, initially there will be increase of blood flow .

29. This increases the hydrostatic pressure both at the arterial and venous end of capillaries . Because of this, more fluid goes out at the arterial end of the capillary and less fluid returns at the venous end of the capillaries . This leads to increased accumulation of fluid in the tissue spaces.

30. This in turn leads to compression of blood vessels . So blood flow is regulated . This theory is applicable in the case of encapsulated organs, like kidney, liver, etc.

31. Neural regulation Sympathetic nerve fibers innervate afferent and efferent arterioles During excessive Sympathetic stimulation (Brain Ischemia, Severe Hemorrhage) lasting from few minutes to few hours can stimulate the vessels. Vasoconstriction occurs – thus causing conservation of blood volume( hemorrhage) and causes a fall in GFR. Parasympathetic Nervous System – Acetylcholine causes release of NO from the Endothelial cells, hence Vasodilation.

32. Hormonal regulation of GFR VASOCONSTRICTORS Norepinephrine Epinephrine (released in stressful situations, alongside the Sympathetic stimulation) Endothelin (ARF , Toxaemia of pregnacy , Vascular Injury, Chronic uraemia ) Angiotensin II (Produced by Renin, released by JGA cells) Leukotrienes – LTC4, LTD4 VASODILATORS NO Prostaglandin E2 Prostaglandin I2 Bradykinin Leukotriene LTB4

33. Autoregulation tests 2 categories- That rely on naturally occurring variability in ABP and CBF (convenient but long time) That induce changes in ABP and assess change the response in CBF (quick)

34. Manoeuvers - 1. Thigh cuff: large pneumatic BP cuffs are inflated around both thighs above SBP for >2min and subsequently deflated – drop in ABP lasting for abt. 10sec before it is normal . 2. Lower body negative pressure: The lower part of the subject’s body is placed in a box in which the pressure is reduced, typically by means of attachment to a vacuum cleaner for approx. 50min and ABP changes are seen 3. Head-up/down-tilting: The subject lies on a bed and is then tilted up/ down from 30-60 .

35. 4. Cold pressor : One of the subject’s hands is placed in a bowl of cold water, normally for one minute, and then removed and measure BP and HR – vasoconstriction - inc. Pulse pressure. 5 . Isometric hand grip: The subject clenches his fist forcefully for a a sustained time until fatigued – inc. afterload – squeezes arterioles and inc. total peripheral resistance. 6. Valsalva manoeuvre: The subject blows into a syringe to maintain an intrathoracic pressure and then releases the pressure .

36. 7. Sit-stand: The subject stands from a sitting position . 8. Squat-stand: The subject stands from a squatting position . 9. Transient hyperaemia : The subject’s carotid artery is compressed briefly.

37. The tests for parasympathetic control Heart rate variability (HRV) in response to: 1. Deep breathing 2. Standing 3. Valsalva maneuver .

38. HRV methods are age-dependent but independent of the intrinsic heart rate. They are the standard screening methods for autonomic dysfunction. Valsalva maneuver is influenced by both parasympathetic and sympathetic activity.

39. The tests for sympathetic control 1. Standing or passive tilting 2. Sustained handgrip 3. Response to the Valsalva maneuver:

40. The baroreflex is the main mechanism responsible for maintaining a stable blood pressure (BP). The Valsalva maneuver provides specific information on components of the baroreflex arc through a sequential series of BP perturbations and resultant heart rate alterations .

41. The maneuver is performed with the subject supine and rested, typically for 20min. The subject is asked to blow into a bugle with a small air leak (to ensure an open glottis) for 15s at 40mmHg . Heart rate and blood pressure are monitored 30s before and 2min after testing. Expiratory pressures less than 30mmHg and for less than 10s are insufficient. Pressures higher than 40mmHg and for 15s are more difficult to sustain, resulting in greater variability.

42. During phase 1, there is an increase in intrathoracic pressure that mechanically causes a brief increase in blood pressure and decrease in heart rate. In early phase 2, there is a reduction of venous return and a subsequent decrease in stroke volume, causing a decrease in blood pressure. In late phase 2, the decreased blood pressure activates the baroreflex that causes a sympathetically mediated increase in heart rate and blood pressure back toward baseline levels .

43. When the patient terminates the Valsalva maneuver, blood refills the pulmonary vasculature. This causes the change seen in phase 3 – a temporary further decline in blood pressure. During phase 4, there is an increase in venous return , which leads to a compensatory decrease in heart rate and increase in blood pressure that may overshoot baseline blood pressure.

44. The Valsalva ratio is calculated from the ECG waveform B y dividing the longest R-R interval after the maneuver (in phase IV) to the shortest R-R interval during the maneuver . A Valsalva ratio < 1.2 is abnormal.