Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats

Abstract

Angiotensin AT₁ receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT₁ receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the pressor responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT₁ receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT₁ receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT₁ receptor antagonists dose-dependently attenuated the pressor responses to central angiotensin AT₁ receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o., respectively). We conclude that systemically administered angiotensin AT₁ receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT₁ receptor blockade following peripheral application may vary between different representatives of this class of drugs.

Introduction

Angiotensin II, the effector peptide of the renin–angiotensin system, exerts its effects by interacting with specific receptors. Two subtypes of angiotensin receptors, AT₁ and AT₂, have been cloned and pharmacologically characterised (Timmermans et al., 1993; Unger et al., 1996). Peripheral angiotensin AT₁ receptors mediate most of the known effects of angiotensin II on hemodynamics, cardiac and renal functions. Angiotensin peptides acting at peripheral angiotensin AT₁ receptors have been implicated in the pathogenesis of various cardiovascular diseases. Antihypertensive effects of the non-peptide angiotensin AT₁ receptor antagonists have been demonstrated in genetically and experimentally induced animal models of hypertension and in hypertensive patients (Wong et al., 1990b; Van den Meiracker et al., 1995; Griendling et al., 1996; Gillis and Markham, 1997). This class of drugs may also be beneficial in the treatment of congestive heart failure, cardiac hypertrophy, myocardial infarction and ventricular remodelling as well as restenosis after angioplasty (Griendling et al., 1996).

Besides the peripheral renin–angiotensin system, the existence of a brain renin–angiotensin system has been firmly established. All components of the renin–angiotensin system have been identified in the brain, and it has become evident that the brain can generate its own angiotensin peptides independently of the peripheral renin–angiotensin system (Unger et al., 1988; Steckelings et al., 1992). The brain renin–angiotensin system has been implicated in cardiovascular control, regulation of volume and electrolyte homeostasis, dipsogenic responses and endocrine functions (Unger et al., 1988; Saavedra, 1992). There is also evidence that the brain renin–angiotensin system may substantially contribute to the development and maintenance of hypertension. In spontaneously hypertensive rats, an animal model of genetic hypertension, biochemical, neurophysiological and molecular biological studies have yielded results pointing to an overactive renin–angiotensin system in the brain (Phillips and Kimura, 1988). Spontaneously hypertensive rats also show increased angiotensin II-binding activity in brain areas implicated in the cardiovascular control (Plunkett and Saavedra, 1985; Gutkind et al., 1988).

While the antihypertensive effects of angiotensin AT₁ receptor antagonists are mainly ascribed to the inhibition of angiotensin AT₁ receptors in the periphery, evidence has been provided that inhibition of central angiotensin AT₁ receptors may also contribute to the antihypertensive effects of these compounds (Gyurko et al., 1993). However, experiments aimed to investigate the penetration of the blood–brain barrier by losartan ((2n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl] imidazol), the first non-peptide angiotensin AT₁ receptor antagonist used for the treatment of hypertension, have yielded conflicting results so far (Song et al., 1991; Bui et al., 1992; Li et al., 1993).

Irbesartan ((2-n-butyl-3-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) represents another potent and selective non-peptide angiotensin AT₁ receptor antagonist which inhibits the binding of ${}^{125}\text{I}$-angiotensin II in rat liver membranes with an IC₅₀ of 1.3 nM. In the same preparation, the affinity of irbesartan for angiotensin AT₁ binding sites exceeds that of losartan (IC₅₀=14 nM). In conscious rats, irbesartan and losartan equipotently antagonized the pressor responses to intravenously (i.v.) injected angiotensin II in a dose-related manner. In conscious cynomolgus monkeys, irbesartan was at least 10-fold more potent than losartan (Cazaubon et al., 1993; Timmermans et al., 1993). Little is known as to what extent irbesartan, which appears to be more lipophilic than losartan (Cazaubon et al., 1993), is able to interact with central angiotensin AT₁ receptors after systemic treatment. In the present study, we compared the effects of irbesartan and losartan administered i.v. or orally with respect to their ability to affect the following angiotensin II effects mediated by central angiotensin AT₁ receptors: increase in mean arterial pressure, release of vasopressin from the posterior pituitary into the circulation, and drinking response.