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I. Non-hemodynamically-

medlated effects:

A. Increased expression of proto-oncogenes

B. Increased production of growth factors

C. Increased synthesis of extracellular matrix proteins

II. Hemodynamically-

mediated effects:

A. Increased afterload (cardiac)

B. Increased wall tension (vascular)

^ Rapid Pressor Response Slow Pressor Response j ^Hypertrophy and Remodellingj

FIGURE 30-4 Summary of the three major effects of angiotensin II and the mechanisms that medrnte them. NE, norepinephrine.

Release of Aldosterone from the Adrenal Cortex AngII stimulates the zona glomerulosa of the adrenal cortex to increase the synthesis and secretion of aldosterone and also exerts permissive effects that augment responses to ACTH and K+. Increased output of aldosterone is elicited by concentrations of AngII that have little or no acute effect on blood pressure. Aldosterone acts on the distal and collecting tubules to cause retention of Na+ and excretion of K+ and H+. AngII-induced stimulation of aldosterone synthesis is enhanced by hyponatremia or hyperkalemia.

Altered Renal Hemodynamics Reduced renal blood flow markedly attenuates renal excretory function, and AngII reduces renal blood flow by directly constricting the renal vascular smooth muscle, enhancing renal sympathetic tone (a CNS effect), and facilitating renal adrenergic transmission. AngII-induced vasoconstriction of preglomerular microvessels is enhanced by endogenous adenosine. ATj receptors are highly expressed in the vasa recta of the renal medulla, and AngII may reduce Na+ excretion in part by diminishing medullary blood flow. AngII variably influences glomerular filtration rate (GFR) via several mechanisms: (1) constriction of the afferent arterioles, which reduces intraglomerular pressure and tends to reduce GFR, (2) contraction of mesangial cells, which decreases the capillary surface area within the glomerulus available for filtration and also tends to reduce GFR, and (3) constriction of efferent arterioles, which increases intraglomerular pressure and tends to increase GFR. The outcome of these opposing effects depends on the physiological state. Normally, GFR is slightly reduced by AngII; however, during renal artery hypotension, the effects of AngII on the efferent arteriole predominate and AngII increases GFR. Thus, blockade of the renin-angiotensin system may cause acute renal failure in patients with bilateral renal artery stenosis or in patients with unilateral stenosis who have only a single kidney.

MECHANISMS BY WHICH AngII ALTERS CARDIOVASCULAR STRUCTURE

Several cardiovascular diseases are accompanied by changes in the morphology of the heart and/or blood vessels that increase morbidity and mortality, including: (1) increased wall-to-lumen ratio in blood vessels (associated with hypertension), (2) concentric cardiac hypertrophy (also associated with hypertension), (3) eccentric cardiac hypertrophy and fibrosis (associated with congestive heart failure and myocardial infarction), and (4) thickening of the intimal surface of the blood vessel wall (associated with atherosclerosis and angioplasty). The renin-angiotensin system, particularly AngII, may contribute importantly to these deleterious structural changes.

AngII stimulates migration, proliferation, hypertrophy, and/or synthetic capacity of vascular smooth muscle cells, cardiac myocytes, and fibroblasts.

In addition to these direct cellular effects of AngII on cardiovascular structure, changes in cardiac preload (volume expansion owing to Na+ retention) and afterload (increased arterial blood pressure) probably contribute to cardiac hypertrophy and remodeling. Hypertension also contributes to hypertrophy and remodeling of blood vessels.

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN LONG-TERM MAINTENANCE OF ARTERIAL BLOOD PRESSURE DESPITE EXTREMES IN DIETARY Na+ INTAKE Blood pressure is a major determinant of Na+ excretion, as illustrated graphically by plotting urinary Na+ excretion versus mean arterial blood pressure (Figure 30-5), a plot known as the renal pressure-natriuresis curve. Chronically, Na+ excretion must equal Na+ intake; therefore, the set point for long-term levels of blood pressure will be the intersection of a horizontal line representing Na+ intake with the renal pressure-natriuresis curve. If the renal pressure-natriuresis curve were fixed, then over the long-term, arterial blood pressure would be greatly affected by dietary Na+ intake. However, the renin-angiotensin system plays a major role in maintaining a constant set point for long-term levels of arterial blood pressure despite extreme changes in dietary Na+ intake (Figure 30-5). When dietary Na+ intake is low, renin release is stimulated, and AngII acts on the kidneys to shift the renal pressure-natriuresis curve to the right; when dietary Na+ is high, renin release is inhibited, and the withdrawal of AngII shifts the renal pressure-natriuresis curve to the left. Consequently, despite large swings in dietary Na+ intake, the intersection of salt intake with the renal pressure-natriuresis curve remains near the same set point. When modulation of the renin-angiotensin system is blocked by drugs, changes in salt intake markedly affect blood pressure.

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