Studies on the possible contribution of a peripheral presynaptic action of clonidine and dopamine to their vascular effects under in vivo conditions

Abstract

The functional consequences of drug-induced stimulation under in vivo conditions of alpha-adrenoceptors and dopamine receptors at vascular adrenergic nerve endings (presynaptic receptors) was studied in the autoperfused hindquarters or hindlegs of cats anaesthetized with urethane. The changes in perfusion pressure in response to electrical stimulation of the lumbar sympathetic chain were taken as a measure of noradrenaline release from the vascular adrenergic nerves. Presynaptic inhibitory alpha-adrenoceptors and dopamine receptors were activated by clonidine and dopamine, respectively. According to in vitro experiments these two drugs are more potent stimulants of peripheral presynaptic than postsynaptic receptors. The lowest frequency of stimulation of the lumbar sympathetic chain which yielded a reproducible pressor response was 4 HZ for the autoperfused hindquarters and 1 HZ for the hindlegs; Clonidine was tested over a wide dose range (1-100 mug/kg i;v). A reduction of the stimulation-induced pressor response in the autoperfused hindquarters or hindlegs was observed only after the rather high dose of 100 mug/kg of clonidine. The inhibition was marked at low frequencies of stimulation (1-4 HZ) and weak or absent at high frequencies (16 and 32 HZ). The dose of clonidine (100 mug/kg) which proved to be effective at presynaptic receptors produced a transient increase in blood pressure and in perfusion pressure of the hindquarters and hindlegs and virtually abolished spontaneous sympathetic nervous activity. In spinal cats, the clonidine-induced increases in blood pressure and perfusion pressure were very pronounced and of rather long duration. Thus, under in vivo conditions clonidine showed no selectivity for presynaptic alpha-adrenoceptors in a blood-perfused vascular bed, and its presynaptic action was negligible as compared to its powerful central sympatho-inhibitory effect. Dopamine was constantly infused into the auto-perfused hindquarters or hindlegs at increasing rates until a vasoconstriction due to stimulation of vascular (postsynaptic) alpha-adrenoceptors occurred. The monoamine did not inhibit the stimulation-induced increases in perfusion pressure of the autoperfused hindquarters or hindlegs and, thus, an effect on presynaptic receptors was not found. The results underscore the importance of in vivo experiments for assessing the therapeutic significance of drug-induced stimulation of presynaptic receptors.