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

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Abstract
1 The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative α2-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 α1-adrenoceptor antagonist, prazosin, was also studied. 2 Prazosin (0.03-1 mg kg−1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 μg kg−1, i.v.). L-657,743 (0.01-1 mg kg−1, 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 μg kg−1, i.v.), methoxy-idazoxan (1–100 μ kg−1, i.v.), BRL44408 (0.1–3 mg kg−1, i.v.) and atipamezole (0.03-1 mg kg−1, i.v.) and fluparoxan (10–300 μ 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−1, 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 α2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular α1-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 α2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.