Nitric Oxide and Central Antihypertensive Drugs

Abstract

Abstract-NO is known to be involved in the peripheral and central regulation of the cardiovascular function. It plays a neuromodulatory role via a direct action on presynaptic nerve terminals, stimulating the release of ␥-aminobutyric acid, glutamate, and norepinephrine. Our aim was to study the possible role of NO in the cardiovascular effects of the central antihypertensive drugs clonidine, rilmenidine, and ␣-methyl-norepinephrine (␣-MNA). Sites and mechanisms of the hypotensive action of these drugs were different; clonidine and rilmenidine acted on imidazoline receptors in the nucleus reticularis lateralis, whereas ␣-MNA acted upon ␣ 2 -adrenoceptors in the nucleus tractus solitarius. The influence of N G -nitro-L-arginine, an NO synthase inhibitor, on the central hypotensive effects of these drugs was investigated in pentobarbital-anesthetized rabbits. The intracisternal (IC) administration of ␣-MNA (30 g/kg) induced hypotension (79Ϯ2 versus 103Ϯ4 mm Hg) and bradycardia (222Ϯ8 versus 278Ϯ4 bpm) (PϽ0.05) (nϭ5). Clonidine (0.07 g/kg IC) also induced hypotension (69Ϯ5 versus 99Ϯ4 mm Hg) and bradycardia (266Ϯ7 versus 306Ϯ10 bpm) (PϽ0.05) (nϭ5). In addition to clonidine, rilmenidine (1 g/kg IC) induced hypotension (64Ϯ4 versus 97Ϯ4 mm Hg) and bradycardia (264Ϯ11 versus 310Ϯ4 bpm) (PϽ0.05) (nϭ5). Pretreatment with N G -nitro-L-arginine (900 g/kg IC) completely prevented the hypotensive effect of ␣-MNA but influenced the cardiovascular effects of neither clonidine nor rilmenidine. These results confirm that imidazoline drugs, such as clonidine, rilmenidine, and the catecholamine Key Words: nitric oxide Ⅲ blood pressure Ⅲ clonidine Ⅲ norepinephrine Ⅲ central nervous system T he free radical NO is known to be involved in the central and peripheral regulation of the cardiovascular function (for a review, see Krukoff 1 ). In the central nervous system, NO has a neuromodulatory role, influencing the peripheral autonomic function. 2,3 In neurons, the synthesis of NO from L-arginine is catalyzed by the NO synthase enzyme (nNOS), which is calcium/calmodulin dependent. This enzyme is stimulated by glutamate-induced activation of N-methyl-Daspartate receptors, which increases the intracellular influx of calcium; in turn, the diffusible NO activates soluble guanylyl cyclase, producing cGMP in neighboring neurons and astrocytes to trigger its effect. 1,4 Immunohistochemical studies have shown the existence of cellular groups containing nNOS that are constitutive of many important autonomic structures of the hypothalamus, brain stem, and spinal cord. [5][6][7][8][9] We are particularly interested in the brain stem structures of the baroreflex arch, including the nucleus tractus solitarius (NTS) and the rostroventrolateral medulla/nucleus reticularis lateralis (RVLM/NRL). The NTS is the site of the hypotensive action of ␣-methyl-norepinephrine (␣-MNA), the active metabolite of ␣-methyl-dopa, which is a catecholamine, full agonist at ␣ 2 -adrenoceptors. 10,11 The RVLM/NRL is the major site of the hypotensive effect of imidazoli...

Central blockade of nitric oxide synthesis reduces moxonidine‐induced hypotension

“…Dobrucki et al (2001) showed that the a 2 -adrenoceptor/imidazoline receptor agonist clonidine, injected into the rat LV, decreased MAP and HR and simultaneously increased NO release in the NTS, and that blockade of NOS activity by injection of the NOS inhibitor N G -nitro-L-arginine-methyl ester (L-NAME) into the LV abolished these effects of clonidine. In contrast, intracisternal pretreatment with L-NAME in rabbits reduced the hypotension produced by an injection of a-methyl-noradrenaline (a 2 -adrenoceptor agonist), but not that induced by either clonidine or rilmenidine injected at the same site (Sy et al, 2001). Also in rabbits, blockade of NOS in the RVLM abolished the hypotension produced by central activation of a 2 -adrenoceptors, but not that induced by central activation of imidazoline receptors (Sy et al, 2002).…”

“…Nitric oxide (NO) is an important mediator that modulates cardiovascular function by a peripheral or central mechanism of action (Gardiner et al, 1990;Zanzinger et al, 1995;Colombari et al, 1998;Kadekaro & Summy-Long, 2000;Patel et al, 2001;Sy et al, 2001). The presence of the enzyme nitric oxide synthase (NOS) that catalyzes the synthesis of NO from L-arginine has been demonstrated in different areas of the central nervous system involved in cardiovascular control; these include the nucleus tractus solitarii (NTS), rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla (CVLM) and paraventricular nucleus of the hypothalamus (PVN) (Vincent & Kimura, 1992;Patel et al, 2001).…”

“…Inhibition of NO synthesis by NOS inhibitors injected intracerebroventricularly or into specific central sites involved in cardiovascular regulation, such as the NTS, RVLM and PVN, increases sympathetic activity and MAP (Zanzinger et al, 1995;Kadekaro & Summy-Long, 2000;Patel et al, 2001). It has been suggested that the central NO system is involved in the development of hypertension (Patel et al, 2001); inhibition of central NOS reduces the hypotension induced by centrally acting drugs (Colombari et al, 1998;Dobrucki et al, 2001;Sy et al, 2001).…”

“…The possible involvement of NO-dependent mechanisms in the responses induced by clonidine and rilmenidine (a 2 -adrenoceptor/imidazoline receptor agonists), administered centrally or peripherally, has been proposed by several authors (Soares de Moura et al, 2000;Dobrucki et al, 2001;Figueroa et al, 2001;Sy et al, 2001;2002). Dobrucki et al (2001) showed that the a 2 -adrenoceptor/imidazoline receptor agonist clonidine, injected into the rat LV, decreased MAP and HR and simultaneously increased NO release in the NTS, and that blockade of NOS activity by injection of the NOS inhibitor N G -nitro-L-arginine-methyl ester (L-NAME) into the LV abolished these effects of clonidine.…”

“…Differences in the effects of central L-NAME on the hypotensive responses induced by a 2 -adrenoceptor/imidazoline receptor agonists have recently been reported (Dobrucki et al, 2001;Sy et al, 2001;2002). Only the hypotensive responses induced by clonidine, a drug that binds equally to a 2 -adrenoceptors and imidazoline receptors, have been tested after L-NAME injections into the LV (Dobrucki et al, 2001).…”