Nitric oxide discriminates the sites and mechanisms of action of centrally acting anti-hypertensive drugs in rabbits

Central blockade of nitric oxide synthesis reduces moxonidine‐induced hypotension

“…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). Hence, in rats, the central blockade of NOS seems to reduce the hypotension produced by activation of imidazoline receptors, whereas in rabbits NO is involved only in the hypotension dependent on activation of central a 2 -adrenoceptors.…”

“…Although previous studies have suggested that the hypotensive effects of moxonidine are due to the sympathoinhibition as a result of its action in the brain stem (Gomez et al, 1991;Haxhiu et al, 1994;Ernsberger & Haxhiu 1997;Nurminen et al, 1998;Tolentino-Silva et al, 2000), the findings of the present study are the first to show that an a 2 -adrenoceptor/imidazoline agonist acting centrally can produce vasodilatation in different vascular beds. Although the NTS has been implicated as the site of action of a 2 -adrenoceptor/imidazoline agonists in the brain stem (Head & Burke, 1998;Sy et al, 2002), evidence has been presented showing that moxonidine reduces sympathetic activity and MAP by an effect in the RVLM (Gomez et al, 1991;Haxhiu et al, 1994;Ernsberger & Haxhiu, 1997;Tolentino-Silva et al, 2000). Hence, it is still unclear whether a 2 -adrenoceptor/imidazoline agonists activate imidazoline receptors and/or a 2 -adrenoceptors in the brain stem to inhibit sympathetic activity and reduce arterial pressure, or, as suggested for moxonidine, they activate imidazoline receptors in the RVLM to produce hypotensive responses (Gomez et al, 1991;Haxhiu et al, 1994;Guyenet, 1997;Tolentino-Silva et al, 2000).…”

“…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).…”

The central hypotensive effect induced by α2-adrenergic receptor stimulation is dependent on endothelial nitric oxide synthase

“…Kishi et al [4,5] demonstrated that overexpression of endothelial NOS (eNOS) in the brain stem decreased blood pressure (BP) and heart rate (HR) and improved impaired baroreflex HR control in stroke-prone spontaneously hypertensive rats. We previously reported that administration of a central hypotensive drug that acts exclusively on medullary a 2 -adrenergic receptors (a 2 -ARs) triggers a neuronal GABAergic pathway, and that the effect is nitric oxide-dependent [6,7]. We also demonstrated recently that nonspecific inhibition of NOS induced by central injection of N-omega-nitro-L-arginine (L-NNA) suppressed the potentiating effect of dexmedetomidine (DXM), a 'selective' a 2 -adrenergic agonist, on reflex bradycardia induced by phenylephrine [6,7].…”