Regulation of Arterial Blood Pressure 2 George D. Ford, Ph.D. OBJECTIVES: 1. Describe the Central Nervous System Ischemic Response. 2. Describe chemical sensitivities of arterial and cardiopulmonary chemoreceptors, and the responses to these chemicals. 3. Describe the role of hypothalamus in blood pressure regulation. 4. Describe the role of stress relaxation and reverse stress relaxation in the regulation of blood pressure. 5. Describe the role of the Renin-Angiotensin-Aldosterone system in the regulation of arterial blood pressure. 6. Describe the role of Atrial natriuretic factor (ANP) in the regulation of arterial blood pressure. 7. Describe the mechanisms which maintain, arterial blood pressure normal in response to varying intakes of sodium (dei/dt). I. OVERVIEW We will begin by looking at some receptors that can influence the cardiovascular system that are not baroreceptors but instead are chemoreceptors. Then we will discuss how two different hormonal systems, the renin-angiotensin-aldosterone system and the atrial natriuretic peptide (ANP) system can influence the renal function curve and thereby play a major role in the regulation of blood pressure. II. ARTERIAL PERIPHERAL CHEMORECEPTORS MONITOR PLASMA OXYGEN AND CARBON DIOXIDE PRESSURES IN ARTERIAL BLOOD. Peripheral receptors for plasma po 2, and pco 2, are found in close proximity to the carotid sinus baroreceptors and aortic baroreceptors and are named the carotid bodies and aortic bodies respectively. The major function of these receptors is to increase respiration in responses to decreases in oxygen tension (po 2 ) and increases in carbon dioxide tension (pco 2 ). Activation of these receptors also activates the vasomotor center. This activation is, however, weak as compared to the central ischemic response to be described later. If the chemoreceptors are activated at the same time that the baroreceptors are responding to a decrease in blood pressure the actions of the two signals synergize; i.e., the blood pressure response is greater than the sum of the actions of the arterial baroreceptor and arterial chemoreceptor. III. THE CENTRAL NERVOUS SYSTEM (CNS) ISCHEMIC RESPONSE, WHICH OPERATES IN RESPONSE TO CENTRAL CHEMORECEPTORS, IS THE MOST POWERFUL ACTIVATOR OF THE SYMPATHETIC TETRALOGY.
When blood flow to the vasomotor center is decreased to the point of ischemia, the vasomotor center becomes strongly excited (the excitation may be due to a failure to remove CO 2, rather than a failure to supply nutrients, particularly O 2 ). This leads to strong activation of the sympathetic tetralogy which produces a strong increase in CO (cardiac output), TPR (total peripheral resistance), and Pa (arterial pressure). Mean arterial pressure may rise as high as 270 mmhg. The effect of activating the sympathetic tetralogy on the kidney may be so strong that blood flow to this organ ceases. This reflex may be activated when Pa falls to 60 mmhg or less. The Pa must be low enough to cause low blood flow to the vasomotor center. The Cushing reaction is a special case of the Central Ischemic Response. In the Cushing reaction an increase in cerebrospinal fluid pressure is the cause of the increases in intracranial pressure. The increase in intracranial pressure decreases the caliber of capillaries and veins thereby increasing the resistance to blood flow in the brain. The decreased cerebral blood flow activates the vasomotor center and sympathetic tetralogy. The increase in Pa produced by the activation of the vasomotor center will persist as long as the increase in cerebrospinal fluid pressure persists. This cerebrospinal fluid pressure/cns ischemic response is called the Cushing Reaction after the surgeon who first described it. IV. THE INTEGRITY OF THE HYPOTHALAMUS IS ESSENTIAL TO THE PROPER FUNCTIONING OF LOWER BRAINSTEM AREAS AND PRODUCES EFFECTS OF ITS OWN ON BLOOD PRESSURE. Behavioral and emotional effects on blood pressure are generally processed through the hypothalamus. Being scared into a dead faint for example involves CNS-induced depression of the vasomotor center. Experimentally general stimulation of the anterior hypothalamus produces hypertension and bradycardia while general stimulation of the posteriolateral region of the hypothalamus produces hypertension and tachycardia. V. THE PLASTICITY OF THE VASCULATURE ALSO PROVIDES SOME PROTECTION AGAINST BLOOD PRESSURE CHANGES INDUCED BY RAPID INCREASES AND DECREASES IN BLOOD VOLUME. Rapid changes in blood volume can lead to rapid changes in Pms, and thus in CO, and finally in Pa. Such changes in blood volume can occur as the result of hemorrhage or the over transfusion of blood. Stress relaxation. When blood volume is increased, smooth muscle passively stretches increasing unstressed vascular volume and decreasing stressed volume. Stressed volume is sometimes referred to effective circulating volume in some
texts. There is a resultant decrease in Pms, CO, and Pa. The increase in unstressed volume, due to passive stretch of vascular smooth muscle is called stress relaxation. Stress relaxation can provide about a 50 per cent compensation for the blood pressure increase produced by an increase in blood volume. Reverse stress relaxation. When blood volume is decreased, smooth muscle passively decreases in length and vascular unstressed volume decreases. This compensatory decrease in unstressed volume, termed reverse stress relaxation, produces a compensatory increase in vascular stressed volume, and a compensatory increase in Pms, Q, and Pa. The degree of decrease in blood volume which can be partially compensated by this mechanism is much lower than the compensation which can be achieved for increases in blood volume. VI. HORMONAL REGULATION OF ARTERIAL BLOOD PRESSURE: THE RENIN, ANGIOTENSIN, ALDOSTERONE SYSTEM AND ATRIAL NATRIURETIC PEPTIDE. Baroreceptors are the primary regulators of blood pressure over the short term. Over the longer term the renin-angiotensin-aldosterone (RAA) system is thought to be the primary regulator of arterial blood pressure. As with the baroreceptors, this system operates on components of the renal-body fluid system. The components primarily affected are: 1) the kidney which regulates the volume of extracellular fluid (E) and hence CO, and 2) TPR. Renin is an enzyme released by the kidney. Renin enzymatically cleaves angiotensin-i from angiotensinogen. Angiotensin-I is converted to angiotensin-ii (the active peptide) by the action of the angiotensin converting enzyme (ACE). Angiotensin-II stimulates the release of aldosterone, a steroid hormone from the adrenal cortex. This is the second active principle in the system. A. RENIN RELEASE Three signals, all of which can arise as a consequence of a fall in arterial blood pressure, are primarily responsible for the release of renin. They are: 1) a decrease in renal perfusion pressure (renal arterial pressure) sensed by renal baroreceptors in renal afferent arterioles (see Fig. 1), 2) a decrease in the volume, or sodium composition of fluid reaching the macula densa (see Fig. 1), and 3) an increase in β- receptor -mediated sympathetic neural activity to Juxtaglomerular cells (see Fig. 1). (Recall that decreases in Pa increase sympathetic neural activity.)
Figure 1. Schematic of the relation between Macula Densa cells, Juxtaglomerular cells, glomerulus, and afferent and efferent arterioles of the kidney. (See Figs. 34-4, p. 627 and 36-5, p. 676 in Berne et al, Physiology, 5 th Edition). See also Fig. 4-33 in Costanzo, Physiology, 3 rd Edition, p. 160. In response to one or more of three signals renin is released from Juxtaglomerular cells lining the afferent arterioles of the kidney. The signal is believed to arise as the product of a decrease in the sodium load
to the kidney (sodium load = plasma sodium concentration x glomerular filtration rate). A decrease in sodium load can be due either to a decrease in glomerular filtration rate or a decrease in plasma sodium concentration, or both. All of these signals can arise as a consequence of a fall in extracellular fluid volume because extracellular fluid volume is a major determinant of cardiac output and hence arterial pressure. B. ATRIAL NATRIURETIC PEPTIDE (ANP) AND THE RELEASE OF RENIN Atrial Natriuretic Factor, also called atrial natriuretic peptide or (ANP), is a peptide which can suppress the release of renin. ANP is found in the atria of the heart and released by increases in atrial pressure. The signal is generated by an increase in stretch on the atrial fibers. Stretch on atrial fibers, for example by over expansion of extracellular fluid volume, blood volume, or volume buildups secondary to decreases in cardiac contractility release ANP The physiological functions of ANP are not fully understood. The current view is that ANP is a potent inhibitor of smooth muscle contraction. A particularly important site of this action is the afferent arteriole of the kidney. Relaxing the afferent arteriole produces an increase in pressure on renal baroreceptors and increases glomerular filtration rate. Both of these effects inhibit the release of renin. Evidence exists that ANP can also block the release of renin by a direct action. ANP has also been shown to increase the renal excretion of sodium by direct inhibition of renal tubular sodium transport mechanisms. C. ANGIOTENSIN-I (A-I) AND ANGIOTENSIN II (A-II) FORMATION Renin, a proteolytic enzyme converts angiotensinogen, a plasma protein released from the liver, to angiotensin-i (A-1), Fig.1. A-I is converted to A-II by angiotensin converting enzyme (ACE) found in vascular endothelium of the lung and other tissues. The rate limiting step in the formation of A-II is the release of renin. Thus, the levels of A-II in the blood correlate directly with levels of renin. D. ACTIONS OF ANGIOTENSIN-II Angiotensin-II produces two important effects. The first, and perhaps most important effect is to decrease the rate of loss of extracellular fluid (deo/dt) through the kidney. This can be diagramed as a shift in the renal function curve to the right. That is for any given Pa the rate of loss of extracellular fluid (deo/dt) is decreased. The second effect is to constrict arterioles, including the arterioles of the kidney. A-II is not a potent constrictor of veins. The effect of the generalized constriction of arterioles is to increase TPR (total peripheral resistance). A-II is one of the most
potent naturally occurring vasoconstrictors known. E. ALDOSTERONE SECRETION AND ITS EFFECTS Aldosterone is synthesized and released from glomerular cells of the adrenal cortex primarily in response to A-II and increases in plasma potassium. Effects of aldosterone. The important action of aldosterone is to decrease renal excretion of sodium and thus extracellular fluid (deo/dt). This is equivalent to a shift in the renal function curve to the right. See Figure 2 below. Figure 2. shows two renal function curves: one at zero angiotensin-ii concentration and one at an angiotensin level 2.5 times normal. (Note: aldosterone produces similar shifts in renal function curves.) The rate of extracellular fluid excretion (deo/dt) or sodium intake (dei/dt), in units of times normal, is shown on the ordinate. Arterial pressure is shown on the abscissa. The straight horizontal line is drawn for a sodium intake, dei/ dt, 1 times normal. The arterial pressures required to excrete sodium (deo/dt) at the rate of sodium intake are the pressures at which the horizontal lines intersect the two renal function curves. VII. INFLUENCE OF ATRIAL NATRIURETIC PEPTIDE ON RENAL FUNCTION By its very name, one would predict that a natriuretic factor would have an opposite effect to the renal-angiotensin-aldosterone axis, particularly a factor such as ANP which also acts as a vasodilator as well. Indeed its overall effect is to promote the loss of extracellular fluid ( deo/dt). This would effective shift the
renal function curve to the left as shown in Figure 3 below. Notice I have included ADH on this figure. ADH is involved with a system primarily regulating plasma osmolarity or water content. Naturally that can t be divorced from Na + regulation since Na + is the major osmotically active substance in our body. The primary action of ADH, as its name implies, is antidiuresis To retain water, one must retain Na +. Hence ADH has basically the same effect as the RAA system. Figure 3. The effects of both the RAA, ADH, and ANP systems on renal function curves. VIII. COMPENSATION FOR CHANGES IN DIETARY INTAKE OF SODIUM IS ACHIEVED BY THE COMBINED EFFECTS OF ANGIOTENSIN-II AND ALDOSTERONE ON RENAL EXCRETION OF SODIUM. When the renal-body fluid system for regulating blood pressure was discussed little attention was paid to the consequences of changes in dei/dt, i.e. the input of sodium. Without the intervention of some control system increases in dei/dt can only be compensated by increases in Pa until deo/dt = dei/dt. At this point we start a discussion of how a constant blood pressure can be maintained in the face of changing inputs of sodium (dei/dt). Recall that changes in E (extracellular fluid) are regulated primarily by regulating the excretion of sodium. Secondary reflexes maintain osmolarity constant by excreting or conserving water as necessary. Recall also that in the steady state the rate of loss of extracellular fluid (sodium) must equal the rate of gain of extracellular fluid. The solution to this problem involves the release of renin and formation of A-II and release of aldosterone in a reciprocal inverse relationship to sodium intake.
Figure 4. Arterial pressures, renal function curves, and angiotensin-ii (aldosterone) levels at different rates of sodium intake. The problem before us is to discern how the body manages to maintain arterial blood pressure normal in the face of changing sodium input. To understand the answer two principles need to be recalled: 1) increases in sodium load to the kidney decrease renin secretion and therefore blood levels of angiotensin-ii, and 2) decreases in angiotensin-ii shifts the renal function curve to the left (Fig. 2). Figure 4 shows the 4 levels of angiotensin-ii (in units times normal) which are produced by 4 levels of sodium intake (in units times normal). Sodium intake is shown by the horizontal lines within the graph. Note that as sodium intake increases angiotensin-ii levels decrease. Fig. 4 also shows the 4 renal function curves which are produced by the 4 levels of angiotensin-ii. Note that as angiotensin-ii levels decrease the renal function curves are shifted to the left. The arterial pressures produced by the intersection of the sodium input lines and the renal function curves identify the arterial pressures required to balance sodium input with sodium output. Note that over a 40 fold range of sodium intake (0.25-10 times normal) the arterial pressure (Pa) required to match sodium excretion to sodium intake does not change because the levels of angiotensin-ii are changed to match the changing sodium intake. Subjects unable to make these shifts are classified as salt-sensitive. IX. ALTERNATE LEARNING RESOURCES 1. Berne, R. M., Levy, M. N., Koeppen, B. M., and Stanton, B. A. "Physiology", 5 th Edition, 2004. The renin, angiotensin, aldosterone
system, and atrial natriuretic peptide (ANP) are covered on pages 672-683. Also blood pressure changes in response to signals from: peripheral chemoreceptors, hypothalamus, cerebrum, skin and viscera, pulmonary reflexes, and central chemoreceptors are covered on page 391-392. 2. Guyton, "Textbook of Medical Physiology", W.B. Saunders, 8 th Edition, 1991. Chapter 19, pp 205-220. 3. Scher, A. in "Textbook of Physiology", Patton et al. editors, W. B. Saunders Co., Philadelphia, 1989, Volume 2, Chapter 51, pp. 972-990. 4. Costanzo, L. S., Physiology, 3 rd Edition, 2006, pp. 159-163. X. PRACTICE PROBLEMS Identify each true answer. More than one answer may be true. Abbreviations: Pms, mean systemic pressure; TPR, total peripheral resistance; Q, cardiac output; A-II angiotensin-ii; E, extracellular fluid; deo/dt, rate of loss of extracellular fluid. 1. A rise in arterial blood pressure would produce which changes in the plasma concentrations of these hormones? A. increase vasopressin, increase norepinephrine, increase A-II B. increase vasopressin, decrease norepinephrine, increase A-II C. increase vasopressin, decrease norepinephrine, decrease A-II D. decrease vasopressin, decrease norepinephrine, decrease A-II 2. A fall in arterial blood pressure would produce which set of changes? A. increase renin, increase aldosterone, shift the renal function curve to the right B. decrease renin, increase aldosterone, shift the renal function curve to the right C. decrease renin, decrease aldosterone, shift the renal function curve to the right D. decrease renin, decrease aldosterone, shift the renal function curve to the left 3. An increase in salt and water intake (dei/dt) would produce which changes in a cardiovascular system under neuronal and hormonal control? A. decrease A-II decrease aldosterone, shift renal function curve to right B. decrease A-II, decrease aldosterone, shift renal function curve to left
ANSWERS C. increase A-II decrease aldosterone, shift renal function curve to right D. increase A-II, increase aldosterone, shift renal function curve to left 1. D 2. A 3. B