Clonidine‐induced nitric oxide‐dependent vasorelaxation mediated by endothelial α₂‐adrenoceptor activation

Abstract

1 To assess the involvement of endothelial a 2 -adrenoceptors in the clonidine-induced vasodilatation, the mesenteric artery of Sprague Dawley rats was cannulated and perfused with Tyrode solution (2 ml min 71 ). We measured perfusion pressure, nitric oxide (NO) in the perfusate using chemiluminescence, and tissue cyclic GMP by RIA. 2 In phenylephrine-precontracted mesenteries, clonidine elicited concentration-dependent vasodilatations associated to a rise in luminal NO. One hundred nM rauwolscine or 100 mM L o -nitro-Larginine antagonized the clonidine-induced vasodilatation. Guanabenz, guanfacine, and oxymetazoline mimicked the clonidine-induced vasorelaxation. 3 In non-contracted mesenteries, 100 nM clonidine elicited a maximal rise of NO (123+13 pmol); associated to a peak in tissue cyclic GMP. Endothelium removal, L o -nitro-L-arginine, or rauwolscine ablated the rise in NO. One hundred nM aminoclonidine, guanfacine, guanabenz, UK14,304 and oxymetazoline mimicked the clonidine-induced surge of NO. Ten mM ODQ obliterated the clonidineinduced vasorelaxation and the associated tissue cyclic GMP accumulation; 10 ± 100 nM sildena®l increased tissue cyclic GMP accumulation without altering the clonidine-induced NO release. 4 a 2 -Adrenergic blockers antagonized the clonidine-induced rise in NO. Consistent with a preferential a 2D -adrenoceptor activation, the K B s for yohimbine, rauwolscine, phentolamine, WB-4101, and prazosin were: 6.8, 24, 19, 165, and 1489 nM, respectively. 5 Rat pretreatment with 100 mg kg 71 6-hydroxydopamine reduced 95% tissue noradrenaline and 60% neuropeptide Y. In these preparations, 100 nM clonidine elicited a rise of 91.9+15.5 pmol NO. Perfusion with 1 mM guanethidine or 1 mM guanethidine plus 1 mM atropine did not modify the NO surge evoked by 100 nM clonidine. 6 Clonidine and congeners activate endothelial a 2D -adrenoceptors coupled to the L-arginine pathway, suggesting that the antihypertensive action of clonidine involves an endothelial vasorelaxation mediated by NO release, in addition to presynaptic mechanisms. British Journal of Pharmacology (2001) 134, 957 ± 968

Sympathetic Vasoconstrictor Antagonism and Vasodilatation Relieve Mechanical Allodynia in Rats With Chronic Postischemia Pain

“…28,60 The α 2 -agonist clonidine may also be particularly effective due to a combination of spinal analgesic and local vasodilatory effects. 20,25 We have previously shown that the I-R injury associated with CPIP produces persistent tissue ischemia, indicated by reduced muscle perfusion, 38 as well as vasoconstrictor hyper-responsiveness, indicated by an enhanced reduction in hind paw blood flow after close arterial injection of NE. 78 The results here are consistent with a vasoactive role for NE from sympathetic efferents, in which activity at α 1 -receptors is pronociceptive due to vasoconstriction in already ischemic tissue.…”

Dexmedetomidine and Clonidine Inhibit Ventricular Tachyarrhythmias in a Rabbit Model of Acquired Long QT Syndrome

“…The receptor suppresses its own adrenaline release from the terminal reticulum to the effecter including brain system, vasculature, and the heart, achieving sedation, analgesia, decreased BP, and bradycardia. Receptors in the peripheral vasculature control vessel tone in a contradictory fashion: vasoconstriction, 8-10 vasorelaxation, 11 and modifying each other. 12 Shimizu et al reported that medetomidine, a selective α-2 AR agonist, modifies the cardiac autonomic state not only by suppressing cardiac noradrenaline release but also by activating vagal acetylcholine release.…”

Central blockade of nitric oxide synthesis reduces moxonidine‐induced hypotension

“…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.…”