Evaluation of the ability of irbesartan to cross the blood–brain barrier following acute intragastric treatment

Abstract

The present study evaluated in functional tests the ability of the angiotensin AT₁ receptor antagonist irbesartan, 2-n-butyl-3-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, in comparison to losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2′(1H-tetrazol-5-yl) bi-phenyl-4-yl)methyl]imidazole, to cross the blood–brain barrier following acute intragastric administration. Two tests were used: the dipsogenic response to intracerebroventricular injection of angiotensin II, and Na⁺ intake in response to adrenalectomy. In normotensive rats, irbesartan reduced the dipsogenic response to angiotensin II, 10 pmol per rat, at the dose of 90 mg/kg, but not at lower doses. Losartan significantly reduced angiotensin II-induced drinking at 30 mg/kg, but not at a lower dose. In spontaneously hypertensive rats, irbesartan reduced the response to angiotensin II at 50 mg/kg, but not at lower doses, while losartan significantly inhibited angiotensin II-induced drinking even at 10 mg/kg. In adrenalectomized rats, the intake of 2% NaCl was inhibited by the intragastric administration of losartan 30 or 50 mg/kg, while irbesartan did not reduce it in doses up to 50 mg/kg. The results of the present study consistently indicate that after acute intragastric administration, the ability of irbesartan to cross the blood–brain barrier is lower than that of losartan.

Introduction

Angiotensin II is known to be involved in the physiopathological control of blood pressure not only by means of peripheral effects, such as vasoconstriction, stimulation of aldosterone secretion, direct actions on the renal tubule, but also by means of central effects, such as an increase in sympathetic nerve activity, stimulation of vasopressin release, synaptic inhibition of the baroreflex in the nucleus tractus solitarii, stimulation of water and salt intake (Epstein, 1990; Fitzsimons, 1979, Fitzsimons, 1986; Phillips, 1987; Unger et al., 1988). In the central nervous system, angiotensin II may also be involved in the control of the release of adrenocorticotropic and reproductive hormones, in cognitive processes, anxiety and analgesia (Barnes et al., 1990; Phillips, 1987and Wright and Harding, 1994, for review). Therefore, it is of interest to know whether, and under which conditions, peripherally administered drugs that influence the renin–angiotensin system are able to cross the blood–brain barrier to affect central angiotensinergic mechanisms.

The aim of the present study was to evaluate in functional tests whether the angiotensin AT₁ receptor antagonist irbesartan (Cazaubon et al., 1993, Cazaubon et al., 1994; Christophe et al., 1995; Lacour et al., 1994) is able to influence the central renin–angiotensin system after acute intragastric administration in comparison to losartan (Timmermans et al., 1993). The following functional tests in rats were chosen: the dipsogenic response induced by intracerebroventricular (i.c.v.) injection of angiotensin II and the Na⁺ intake response induced by adrenalectomy.

The drinking response to i.c.v. angiotensin II is an appropriate functional test, because it is mediated by angiotensin AT₁ receptors (Fregly and Rowland, 1991; Beresford and Fitzsimons, 1992; Sakai et al., 1994; Polidori et al., 1995), apparently in brain sites inside the blood–brain barrier. The subfornical organ, a circumventricular organ outside the barrier, which is essential for the drinking response elicited by blood-borne angiotensin II, has little if any role in the dipsogenic response to i.c.v. angiotensin II (Lind and Johnson, 1982; Perfumi et al., 1986; Johnson and Edwards, 1990). Regional obstruction or lesion of periventricular tissues of the antero-ventral third ventricular region (including the organum vasculosum of the lamina terminalis, the median preoptic nucleus and the preoptic periventricular nuclei) abolishes the drinking response elicited by i.c.v. angiotensin II (Buggy et al., 1975). However, lesion of the organum vasculosum of the lamina terminalis, a circumventricular organ outside the barrier, has no effect on the drinking response to i.c.v. angiotensin II. Nuclei inside the barrier, such as the median preoptic nucleus or the preoptic periventricular nuclei, are mostly involved in the response (Gardner and Stricker, 1985; Johnson and Edwards, 1990). Angiotensin II induces intense expression of c-Fos protein in the anterior region of the third ventricle, including the organum vasculosum of the lamina terminalis, the subfornical organ and the median preoptic nucleus (Herbert et al., 1992; Lebrun et al., 1995). However, the i.c.v. injection of angiotensin II induces c-Fos expression mainly in the median preoptic nucleus (McKinley et al., 1995), and only in periventricular parts of the two circumventricular organs. These organs show tight junctions over the ependymal surface that preclude rapid access of molecules from the cerebrospinal fluid (McKinley et al., 1990).

Salt intake evoked by adrenalectomy in rats may be another functional test to evaluate the ability of angiotensin AT₁ receptor antagonists to influence the central nervous system. Even though the neuroanatomical substrates for this effect are not well defined yet, the work of Sakai and Epstein (1990)has shown that salt appetite in the adrenalectomized rat is inhibited by i.c.v., but not by intravenous infusion of peptide angiotensin II antagonists. These findings suggest that the receptors that mediate the effect may be inside the blood–brain barrier. Also, the sodium intake induced by angiotensin II is mediated by angiotensin AT₁ receptors (Galaverna et al., 1996; Beresford and Fitzsimons, 1992; Rowland et al., 1992).

The experiments concerning the dipsogenic response to i.c.v. angiotensin II were carried out also in spontaneously hypertensive rats (SHR) because these animals may show altered regulation of the brain renin–angiotensin system (Wright and Harding, 1994), and because the permeability of the blood–brain barrier may be altered by acute or chronic hypertension (Mayhan, 1990; Tang et al., 1992).