Chronic administration of olmesartan attenuates the exaggerated pressor response to glutamate in the rostral ventrolateral medulla of SHR

Abstract

It has been shown that the pressor responses to microinjection of l-glutamate in the rostral ventrolateral medulla (RVLM) are augmented in spontaneously hypertensive rats (SHR), and that these augmented responses are not altered by chronic conventional antihypertensive treatment. The aim of the present study was to determine the effect of chronic oral treatment with a new angiotensin II type 1 (AT₁) receptor antagonist, RNH-6270 (the active form of olmesartan medoxomil), on cardiovascular responses to excitatory amino acids in the RVLM of SHR. SHR (12 weeks old) were treated with RNH-6270 (30 mg/kg/day) or vehicle for 4 weeks. At 16 weeks of age, l-glutamate (2 nmol), N-methyl-d-aspartate (NMDA; an ionotropic glutamate receptor agonist (20 pmol)), or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD; a metabotropic glutamate receptor agonist (1 nmol)) was microinjected into the RVLM of rats. The pressor responses to microinjection of l-glutamate or NMDA in the RNH-6270-treated SHR (+28.3 ± 1.0 and +48.3 ± 2.5 mm Hg, respectively) were significantly smaller than those in untreated SHR (+45.7 ± 2.2 and +69.4 ± 7.0 mm Hg, respectively, P < 0.05 each); however, they were still greater than those in the Wistar–Kyoto rats (+21.7 ± 1.0 and +28.6 ± 3.3 mm Hg, respectively, P < 0.05 each). In contrast, the augmented pressor responses to microinjection of (1S,3R)-ACPD in SHR were not affected by the RNH-6270 treatment. These results demonstrated that chronic oral treatment with RNH-6270, an AT₁ receptor antagonist, partly normalizes the pressor responses to l-glutamate or NMDA, but not (1S,3R)-ACPD, in the RVLM of SHR, suggesting that endogenous angiotensin II may be involved in the exaggerated pressor response to l-glutamate, probably through its ionotropic glutamate receptors.

Introduction

Angiotensin II (Ang II) acts not only on vascular smooth muscle and the adrenal cortex but also within the heart, kidneys, and central and autonomic nervous systems [4], [12]. The antihypertensive effects of blocking the renin–angiotensin system have been primarily attributable to the peripheral blockade of this system [4]; however, the contributions of the central nervous system to the antihypertensive effects of renin–angiotensin system blockade have not been adequately studied. Furthermore, the effects of chronic oral treatment with an Ang II type 1 (AT₁) receptor antagonist on the brain renin–angiotensin system and central cardiovascular modulation have not yet been established [19].

The rostral ventrolateral medulla (RVLM) is one of the brain regions which plays an important role in sympathetic and cardiovascular regulation in the central nervous system [14], [20]. Glutamate is the primary neurotransmitter involved in the cardiovascular regulation and the baroreceptor reflex in the RVLM [14]. It activates the ligand-gated cationic channels N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), as well as kainate receptors [8]. However, glutamate also acts through a separate class of receptors, termed metabotropic glutamate receptors (mGluRs), that link to G-protein and intracellular calcium mobilization [15], [17]. On the other hand, it has been shown that cardiovascular responses to glutamate are exaggerated in spontaneously hypertensive rats (SHR) compared to Wistar–Kyoto (WKY) rats, and cannot be normalized by chronic oral antihypertensive treatment with enalapril, an angiotensin converting enzyme inhibitor [22], [23]. However, the effects of chronic oral treatment with AT₁ receptor antagonists on the exaggerated pressor response to glutamate and the glutamate subreceptor agonist have not yet been investigated.

AT₁ receptors are expressed in the RVLM [5], [13], and Ang II has been shown to act at the AT₁ receptors in RVLM to activate the sympathetic nervous system and to increase arterial pressure [1], suggesting that AT₁ receptors in RVLM are involved in cardiovascular regulation in the central nervous system. We hypothesized that chronic oral treatment with an AT₁ receptor antagonist may block the AT₁ receptors in the RVLM, resulting in normalization of the exaggerated pressor response to the microinjection of glutamate or glutamate subreceptor agonist into the RVLM in SHR, because the brain renin–angiotensin system is activated to a higher degree in SHR compared to WKY rats [9], and because AT₁ receptor antagonists are considered to be more effective at blocking the renin–angiotensin system than angiotensin converting enzyme inhibitors [4]. Accordingly, the present study was designed to determine the effects of chronic treatment with RNH-6270 (the active form of olmesartan medoxomil), an AT₁ receptor antagonist, for 4 weeks, on cardiovascular responses to microinjection of l-glutamate, NMDA, or an mGluR agonist into the RVLM in SHR. In addition, in order to confirm that chronic oral treatment with the AT₁ receptor antagonist blocked the AT₁ receptors in the brain, Ang II was also microinjected into the RVLM in the RNH-6270-treated SHR.