A comparative study of the reversal by different α₂‐adrenoceptor antagonists of the central sympatho‐inhibitory effect of clonidine

Abstract

1 The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative o2-adrenoceptor antagonists was investigated in pentobarbitone anaesthetized rats. The activity of four substances containing an imidazoline structure: idazoxan, methoxy-idazoxan, BRL44408 and atipamezole was compared with the effect of fluparoxan, yohimbine and L-657,743; in addition the effect of the ac-adrenoceptor antagonist, prazosin, was also studied. 2 Prazosin (0.03-1 mgkg-1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 ,ug kg'-, i.v.). L-657,743 (0.01-1 mg kg-', i.v.) induced a recovery of blood pressure, heart rate and renal sympathetic nerve activity. Yohimbine (0.03-3 mg kg-1, i.v.) completely reversed the sympatho-inhibitory effect of clonidine but did not alter its hypotensive effect. 3 The four imidazoline drugs: idazoxan (10-300 ,ug kg-1, i.v.), methoxy-idazoxan (1-100 mug kg 1, i.v.), BRL44408 (0.1-3 mg kg-1, i.v.) and atipamezole (0.03-1 mg kg-', i.v.) and fluparoxan (10-300 jg kg-1, i.v.) reversed the clonidine-induced hypotension but produced only a partial recovery of the renal sympathetic nerve activity and of the heart rate. After pretreatment with prazosin (0.1 mg kg-', i.v.), the recovery of the sympathetic nerve activity elicited by these compounds was significantly higher. In hexamethonium (10 mg kg-1, i.v.) pretreated rats, these five drugs induced dose-related hypertension which was reduced by pretreatment with prazosin (0.1 mg kg-1, i.v.). 4 Our results indicate that the putative CX2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular a1-adrenoceptors; this property of the compounds may be partly responsible for the reversal of the hypotensive action of clonidine. Considering the structure and the affinities of the drugs tested, our data indirectly suggest that a2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.

The stimulatory effect of clonidine on locus coeruleus neurons of rats with inactivated α2-adrenoceptors: involvement of imidazoline receptors located in the nucleus paragigantocellularis

“…The lack of a hypotensive effect due to clonidine after complete blockade of a 2 -adrenoceptors by EEDQ, which we observed, could hence be explained by Sannajust and Head's (1994) hypothesis. Another possibility is, as other authors propose, that the hypotensive effect of clonidine and clonidine-like drugs is mainly mediated by a 2 -adrenoceptors (Hieble and Kolpak 1993;Urban et al 1994;Vayssettes-Courchay et al 1996) in which case this effect would also have been blocked by EEDQ treatment. The activity of LC neurons is modulated by changes in blood pressure (Bousquet et al 1984;Valentino 1989).…”

The role of several α1‐ and α2‐adrenoceptor subtypes mediating vasoconstriction in the canine external carotid circulation

“…Even with BRL44408, the immediate increase in blood pressure was short lasting. This eect may have been due to a direct activation of vascular a 1 -adrenoceptors, as shown with other a 2 -adrenoceptor antagonists in anaesthetized rats (Vayssettes-Courchay et al, 1996). Alternatively, such a vasopressor eect could also be explained by a blockade of prejunctional a 2 -adrenoceptors leading to an enhancement of neuronal release of noradrenaline (Homan & Lefkowitz, 1996).…”

α2-Adrenoreceptor mediated sympathoinhibition of heart rate during acute hypoxia is diminished in conscious prostacyclin synthase deficient mice

“…on a different experiment day (WT n=7 and PGID n=5). Selection of drug doses was assumed to achieve maximal or near maximal receptor antagonism [27,28] and cyclooxygenase inhibition [29][30][31], respectively.…”