Involvement of presynaptic alpha-adrenoceptors in the cardiovascular and sedative effects of FLA-136

Abstract

1. The effects of FLA-136 [4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazol] on blood pressure and heart rate in anaesthetized, normotensive rats, stimulation-induced tachycardia in pithed rats and sedation in mice were studied. 2. Following intravenous administration to anaesthetized normotensive rats FLA-136 caused a dose-dependent decrease in mean arterial pressure accompanied by a reduction in cardiac frequency. Both actions showed a slow onset and maximal effects were reached about 1 h after application. Yohimbine and piperoxan almost completely inhibited these haemodynamic effects of FLA-136, whereas prazosin was ineffective. The efficacy of FLA-136 in reducing blood pressure and heart rate was partly impaired after pretreatment with reserpine (5 mg/kg), and totally abolished in animals which had received this reserpine treatment twice and α-methyl-p-tyrosine methylester. 3. FLA-136 neither displayed an acute effect on the stimulation-induced tachycardia nor affected the clonidine-induced reduction of the elevated heart rate in pithed rats. In contrast, the cardiac, responses to stimulation were dose-dependently diminished after pretreatment with FLA-136. At high doses FLA-136 moderately decreased the hypertensive effect of clonidine. 4. FLA-136 dose-dependently prolonged the hexobarbitone (75 mg/kg) induced loss of the righting reflex in mice. This action of FLA-136 was antagonized by previous pretreatment with yohimbine and piperoxan, whereas mianserin was less effective. Prazosin tended to increase the sedative effect of FLA-136. 5. The results suggest the involvement of presynaptic α-adrenoceptors in the cardiovascular and sedative properties of FLA-136. These effects, however, may not be caused by FLA-136 itself, but are possibly mediated by one more active metabolites.