Regulation of blood pressure by the type 1A angiotensin II receptor gene.

Abstract

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in The renin-angiotensin system (RAS) is one of the primary physiological regulators of sodium and fluid balance (1). The RAS regulates body-fluid homeostasis through several distinct mechanisms-including effects on hemodynamics and vascular tone, direct stimulation of sodium reabsorption by the kidney, and stimulation of aldosterone production by the adrenal glands (2). The propensity of the RAS to cause elevated blood pressure was first recognized in acquired disorders such as renovascular hypertension (3), and alterations in the activity of this system have been strongly implicated in the pathogenesis of essential hypertension. For example, variations in genes encoding renin (4, 5), angiotensinogen (6, 7), angiotensinconverting enzyme (8,9), and angiotensin receptors (10)(11)(12) have been associated with hypertension in human populations and in animal models of sodium-sensitive hypertension.The major biologically active product of the RAS is the multifunctional peptide angiotensin 11 (1). The physiological effects of angiotensin II are elicited through binding to specific cell-surface receptors (13). Angiotensin II receptors belong to the large family of rhodopsin-like G protein-associated receptors and have been divided into two pharmacologically distinct types designated type 1 (AT1) and type 2 (AT2) (13-17). AT1The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.receptors are thought to mediate the known functions of angiotensin 11 (13-15); they are defined pharmacologically by their high-affinity binding to the nonpeptide antagonist losartan (Dup 573). AT2 receptors exhibit high-affinity binding to the antagonists PD 123177 and CGP 42112, but the physiological function of and signaling mechanisms used by AT2 receptors are not known (13,16,17).Among the AT1 receptors, two subtypes ATlA and ATlB have been identified in human, rat, and mouse (18-21). These receptors are products of separate genes, share substantial sequence homology, and have wide tissue distributions. The ATlA receptor seems to predominate in most tissues except the adrenal gland and the anterior pituitary (18-26), and expression of ATlA and ATlB receptors may be differentially regulated in the heart and the adrenals (22,25,26). This differential tissue distribution and regulation of AT1 receptor subtypes may serve to modulate the biological effects of angiotensin II. However, due to the lack of discriminatory pharmacological antagonists, the individual functions of the two AT1 receptor subtypes (A and B) have not been defined.Associations between alterations in AT1 receptor-encoding genes and hypertension have been identified in previous studies. For example, Deng and associates (10, 11) fou...

Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system

“…Figure 2A shows that blood pressures were significantly reduced in F 1 (C57BL/6 × 129) Agtr1a -/-mice (89 ± 8 mmHg) compared with wild-type controls (112 ± 3 mmHg; P = 0.03). The magnitude of the blood pressure reduction in Agtr1a -/-animals was very similar to that observed in our previous experiments using tail cuff manometry (2). We also analyzed a series of 24-hour blood pressure recordings and found that the general nature of blood pressure fluctuations was similar in Agtr1a +/+ and Agtr1a -/-mice ( Figure 2B), which indicated that the absence of AT 1A receptors does not affect qualitative patterns of diurnal variation in blood pressure.…”

“…The critical role of this pathway in regulation of blood pressure is highlighted by the impressive efficacy of angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with hypertension and in mice lacking the AT 1A receptor, the major murine AT 1 receptor isoform. These animals have very low blood pressure and profound salt sensitivity (2,3). Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the RAS (4).…”

“…In the vascular system, stimulation of AT 1 receptors causes potent vasoconstriction (2). In the adrenal cortex, their activation stimulates the release of aldosterone (12), thereby promoting sodium reabsorption in the mineralocorticoid-responsive segments of the distal nephron (13).…”

The angiotensin II type 1 receptor and receptor-associated proteins

“…Mice lacking the expression of these genes show that the AT1A receptor is far more important in the control of blood pressure. Systolic blood pressure is markedly reduced in mice that have no AT1A receptors while no significant difference of blood pressure is observed between wild type control animals and mice lacking the AT1B receptor gene [32][33][34]. Rat AT1A, AT1B and human AT1 5'-flanking region sequences have been determined.…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…13,[42][43][44][45] Gene-targeting studies further pointed out that these effects are mainly mediated by AT 1a receptors. 46,47 Knock out (À/À) of the AT 1a receptor gene decreased baseline blood pressure 46,48 and abolished the pressor response to Ang II infusion, 46,49 whereas deletion of AT 1b genes did not alter baseline blood pressure, nor the pressor response to Ang II. 46,50 Ang II induced dose-dependent increases in blood pressure in AT 1a (À/À) mice pretreated with an ACE inhibitor, which were inhibited by AT 1 receptor blockade.…”