WINDSOR UNIVERSITY SCHOOL OF MEDICINE

1. WINDSOR UNIVERSITYSCHOOL OF MEDICINE Regulation of Blood Pressure Dr.Vishal Surender.MD.

2. Learning objectives • Define the bulk flow relationship in terms of arterial pressure, cardiac output and total peripheral resistance • Define the features of a negative feedback control system and describe how it relates to the baroreceptor reflex • Describe how the baroreceptor reflex works in the short term control of blood pressure (BP) • Explain why the baroreceptor reflex is limited in the long term control of BP • Explain how a strong emotional response and how stress affects the BP • Describe briefly how the chemoreceptors play a role in maintaining BP • Briefly describe the cerebral ischemic response and the Cushing response • Explain how BP is controlled in the long term and the role played by the renin-angiotensin system • Briefly describe the role played by the volume receptors in BP control

3. Bulk Flow/Pouseuilles Law: Flow = Pressure gradient/Resistance (P/R) Equivalent to: CO = MAP/TPR Therefore: MAP = CO x TPR An  in CO or  TPR or both will  MAP A  in either or both will  MAP • Maintenance of arterial pressure is of vital importance. • If the BP is too low, tissue perfusion is inadequate and tissues become ischemic. If it is too high, the heart has to work extremely hard to eject blood into the circulation,in addition, a high BP causes blood vessels to rupture which would also result in tissue ischemia. • BP, together with temperature, respiration rate and pulse, is one of the vital signs and a significantly abnormal BP constitutes a medical emergency.

4. There is a short term and long-term regulation of blood pressure • The short-term regulation of BP (on a time scale of seconds to minutes) occurs via neural pathways • The long-term regulation of BP (on a time scale of hours or days) occurs via pathways that target the blood vessels, as well as the kidneys, in their control of extracellular fluid volume

5. Short-term regulation of Arterial Pressure • Systemic mean arterial blood pressure is the principal variable that the cardiovascular system controls • As in many others body systems, the short-term regulation of BP (on a time scale of seconds to minutes) occurs via neural pathways, and targets the heart, vessels, and adrenal medulla • Neural reflexes mediate the short-term regulation of mean arterial pressure, and they operate as a series of negative feedback loops

6. The negative feed-back loops that control BP(Baroreceptor reflex) have the following: - Detector: A sensor or receptor which quantitates the controlled variable and transduces it into an electrical signal that is a measure of the controlled variable - Afferent neural pathway: conveys message to the CNS - Coordinating center in the CNS: compares the signal detected in the periphery to a set point, generates a signal, processes the information, and generates an appropriate response - Efferent neural pathways: These convey the response from the coordinating center to the periphery - Effectors are elements that act on the controlled variable and correct its deviation from the set point

7. Baroreceptor Reflex • High-Pressure Baroreceptors at the Carotid Sinus and Aortic Arch are Stretch Receptors that Sense Changes in MAP • Consistituents: baroreceptors (i.e., the detectors), afferent neuronal pathways, control center in the medulla, efferent neuronal pathways, and the heart and blood vessels (i.e., the effectors) • The negative feedback loop is designed so that  MAP causes vasodilation and bradicardia, whereas  MAP causes vasoconstriction and tachycardia • The sensor consists of a set of mechanoreceptors located at strategic high-pressure sites, carotid sinus and the aortic arch. Stretching the vessel walls at eithervasodilation and bradicardia

8. Fig. 1. Baroreceptor control of MAP. In this example is assumed that  in MAP (violet box) is the primary insult

9. Fig. 2. Location of arterial baroreceptors

10. Fig. 3. Afferent pathways of the high-pressure baroreceptors. In (B), the chemoreceptors (i.e., aortic bodies) are located on the underside of the aortic arch, as well as at the bifurcation of the brachiocephalic artery.

11. 2. Baroreceptors and the Afferent Pathways • Baroreceptors are naked nerve endings of myelinated sensory afferents. Those in aortic arch are subserved by the aortic depressor nerve (vagus branch), and those in the carotid sinus by the carotid sinus nerve ( a branch of glossopharingeal nerve) • Baroreceptors are tonically active, and there is always some action potentials being transmitted along these afferent nerves. When BP they  firing rate and vice versa • Although baroreceptors are sensitive to absolute level of BP, they are most sensitive to rapid change in AP and the rate of change • Afferent nerves from the baroreceptors synapse with neurons of the nucleus tractus solitarius (NTS) to the medullary cardiovascular center

12. 3. The cardiovascular Coordinating Centers • There are a group of nuclei in the medullary brain stem which consist of the vasomotor (vasoconstrictor) center, a cardioacceleratory center and a cardioinhibitory (cardiac decelerator) center • The vasomotor and cardioacceleratory centers project via bulbospinal pathways, to the sympathetic preganglionic neurons in the lateral horn of the T1 to L3 segments of the spinal cord. • The cardioinhibitory center is the dorsal motor nucleus of the vagus. This center inhibits heart rate via the vagus nerve • All the above centers are tonically active and their level of activity is regulated by the projection from the NTS

13. Fig. 5. Medullary control centers for CVS. Ach, acetylcholine; CN, cranial nerves; NTS, nucleus tractus solitarius

14. 4. Efferent Pathways and Efferent Organs • Effects of Sympathetic activity:  HR and  Contractility (SV) - Preganglionic SN synapse with postganglionic SN in sympathetic ganglia. - Preganglionic SN release Ach. • -Postganglionic SN release NE which acts on 1receptors of the heart to  HR and contractility; • -and on 1receptors on arteries, arterioles and veins to cause vacoconstriction - Preganglionic SN also innervates the adrenal medulla releasing epinephrine and norepinephrine into the circulation

15. Effects of parasympathetic activity:  HR - Parasympathetic nerves travel to the heart from the dorsal motor nucleus of the vagus via vagalefferents (preganglionic fibers) • Parasympathetic ganglia are found within the effector organs • Postganglionic parasympathetic fibers innervate mainly SA node and AV node and release acetylcholine (Ach) which acts on M2 receptors • - Parasympathetic activity causes bradycardia

16. -Putting things together-postural hypotention. Effects of α1 receptor antagonist drugs Certain drugs used in the treatment of hypertension also cause marked postural hypotension as a side effect. These are the α1 receptor antagonists. They prevent the reflex NE-mediated vasoconstriction that normally restores the arterial pressure. As a consequence, individuals on α1 receptor antagonists must rise to their feet slowly in case they faint.

17. Control of Cardiovascular Centers by Higher Centers • Cerebral cortex and hypothalamus control the activity of the medullary CVS center • Stress, originating in the limbic system probably  activity of the vasomotor and cardioaccelerator centers, via hypothalamus + release of epinephrine from adrenal medulla (the reaction “fight or flee”) • Stress reduction can be achieved by practicing the relaxation yoga techniques which are associated with  vagal activity

18. Fig. 9. Summary of the components of the baroreceptor reflex. If the initial change were a decrease of BP, all the arrows in the boxes would be reversed

19. Chronic hypertension and re-setting of the set point • Baroreceptor reflex is of little/no importance in the long term regulation of BP because the baroreceptors reset in 1-2 days to whatever pressure level they are exposed • This adaptive nature(baroreceptors have adapted to the increased stretch by becoming less sensitive)of the baroreceptors explains why this reflex is not useful for controlling BP in chronic states (hypertension) • The reflex still operates in the short term control of BP – even in chronic hypertensives. For instance, when a hypertensive patient stands up suddenly his baroreceptor reflex still comes into play but the set point at which it now operates is raised

20. Chemoreceptor Reflex is other mechanism involved in short term control of blood pressure: Effects of  PO2 on BP when it falls too low

21. Peripheral chemoreceptors in carotid and aortic bodies are sensitive to changes in PO2 , PCO2 and pH of arterial blood • The bodies (glomus caroticus and glomus aorticus) are small organs lying next to carotid sinus or adjacent to aortic arch, abundantly supplied with BF • When BP  below a critical level (~ 80 mm Hg) they become stimulated because diminished BF PO2 as well as  PCO2 and H+ ions. • The afferent discharge from the bodies excite the vasomotor centerssympathetic discharge and  BP back to normal • The reflex is not so powerful as the baroreceptor reflex but it does help to return BP back to normal whenever it falls too low

22. Fig. 11. Chemoreceptor control of CVS.  PO2 ,  PCO2 or  pH is the primary insult (violet box). A, bradycardia occurs when ventilation is fixed or prevented (e.g. breath-holding). B, effects of breading overcome the intrinsic CV response, producing bradycardia

23. Other reflexes Involved in the Control of BP • Cardiopulmonary (Low Pressure or Volume) Receptors - Receptors are found in the veins, pulmonary artery and atria, referred to as “volume receptors” or “low pressure receptors” - They respond to changes in BV and are strategically located in the venous site of the circulation where most of the BV is held . - The receptors in atria respond to  “fullness” of the CVSANP secretionvasodilation of afferent renal arteriolesGFR salt and water excretion ECF - also  ADH secretion water excretion - also  heart rate (unlike activation of baroreceptors HR) The  HR in response to  activity of the “ low pressure receptors” is called the Bainbridge reflex. HR CO renal perfusion Na+ and water excretion

24. Fig. 12. Low-pressure receptors. In B, A-type receptors (orange), located mainly in right atrium; B-type receptors are located mainly in superior and inferior vena cava; ECG, electrocardiogram

25. Direct effects on the vasomotor area: Cerebral Ischemic Response and Cushing Reaction (reflex)

26. Cerebral Ischemic Response - When BP falls below the autoregulatory range, cerebral ischemia occurs, the neurons of the vasomotor center are directly stimulated by  H+ and  PCO2 - The  H+ and  PCO2 causes a massive  in Sympathetic discharge BP - This is “ CNS ischemic response” and can result in  in BP to ~ 250 mm Hg for as long as 10 minutes - The reflex is very powerful but it does come into play only when MAP falls to well below 60 mm Hg (severe hemorrhage) - The reflex is to prevent irreversible brain damage when BP falls below critical levels

27. Cushing Reaction (reflex) - It is a special type of cerebral ischemic response occurring when CSF pressure  so much that it is greater than BP (trauma of the brain) and blood supply of the brain is compromised - The result is great  in BP and reflex  heart rate via the arterial baroreceptors. This is why bradycardia rather than tachycardia is characteristically seen in patients with  intracranial pressure - The reflex is a result of direct effect of local hypoxia and hypercapnia to vasomotor centers - When BP > CSF pressure, cerebral flow is restored thus relieving the cerebral ischemia - Cushing reaction helps to protect the vital centers of the brain from loss of nutrients if the CSF pressure rises high enough to compress the cerebral arteries

28. 2. BLOOD VOLUME and Long-term control of Blood Pressure • The effector organs that play a dominant role in the long-term control of BP are the kidneys which control extracellular fluid volume (ECF) • When the ECF is high, the BP rises and this in turn directly affects the kidneys to excrete the excess extracellular fluid and return BP back to normal • Because BP influences blood volume (BV) but BV also influences BP, the BP can stabilize, in the long run, only at a value at which blood volume is also stable • Accordingly, steady-state BV changes are the single most important long-term determinant of BP

29. Fig. 13. Causal reciprocal relationship between BP and BV.  in BP due to  CO induces BV by promoting fluid excretion by the kidneys, which tends to restore BP to original value

30. A low circulating BV triggers four parallel effector pathways that act on the kidney, either by changing the hemodynamics or by changing Na+ transport by the renal tubule cells: • Renin-angiotensin-aldosterone system • Sympathethic Nervous System • Posterior Pituitary releasing Arginine Vasopressin (ADH) from hypothalamus • Atrial Natriuretic Peptide (ANP

31. The Renin-Angiotensin System - This system is another long-term regulator of BP -  BP reduces renal perfusion pressure - The baroreceptor (and chemoreceptor) neurotransducerJuxtaglomerular (JG) cells in the afferent arterioles of the kidney sense the fall in BP and respond by converting the precursor prorenin to the enzyme renin- In circulation renin catalyses the conversion of angiotensinogen to angiotensin I which has little/none activity • - In the lungs angiotensin I is conversted by angiotensin converting enzyme (ACE) to the biologically active vasoconstrictor angiotensin II

32. Angiotensin II has many actions: - Vasoconstriction TPR MAP -  Na+ reabsorption in the kidney H2 O retention -  Thirst and H2 O intake -  ADH secretion H2 O retention by the kidney -  Aldosterone synthesis Na+reabsorption and H2 O • The overall effect of angiotensin II is to  ECF which blood volume, and  TPR - The increase in blood volume venous return and  CO (via Frank-Starling mechanism) - The  CO, together with the  TPR to  MAP

33. Fig. 17. The renin-angiotensin-aldosterone axis

34. Fig. 18. Structure of the juxtaglomerular apparatus