Alpha-adrenoceptor subtypes in the cardiovascular system of the pithed rat
The selectivity of a series of benzoquinolizines has been evaluated for pre and postjunctional α2-adrenoceptors in the pithed rat. Wy 25309, Wy 26392 and Wy 26703 exhibited a similar selectivity for, and potency at α2-adrenoceptors, to those of the α2-adrenoceptor antagonists yohimbine and idazoxan. The α2-adrenoceptor antagonists employed in this study did not reveal a difference between pre and postjunctional α2-adrenoceptors. The α2-adrenoceptor antagonist potencies of Wy 26392, Wy 26703 and yohimbine varied depending on the α2-adrenoceptor agonists employed. In addition to their α2-adrenoceptor agonist properties, B-HT 933, UK-14,304, clonidine, guanabenz and α-methylnoradrenaline were demonstrated to possess α1- or β-adrenoceptor agonist properties, or to be subjected to neuronal uptake. These other pharmacological properties of the α2-adrenoceptor agonists contributed to the varying α2-adrenoceptor antagonist potencies obtained. Under certain experimental conditions, blockade of prejunctional α2-adrenoceptors with Wy 26392 or yohimbine, potentiated the peak tachycardia to cardiac sympathetic nerve stimulation, and prolonged the duration of responses following cessation of stimulation, independently of the peak tachycardia obtained. Under the same experimental conditions, blockade of α1-adrenoceptors with prazosin resulted in a prolongation of the duration of responses following cardiac nerve stimulation without potentiating the peak tachycardia obtained. It is proposed that under these experimental conditions, α1-adrenoceptors participate in an endogenous negative feedback mechanism. Further examination of α1-adrenoceptors modulating responses in the heart revealed that under certain experimental conditions, the α1-adrenoceptor agonist methoxamine inhibited the tachycardia evoked by cardiac sympathetic nerve stimulation, or by isoprenaline, via a prazosin sensitive mechanism. The inhibitory effects of methoxamine on an isoprenaline tachycardia could still be demonstrated in 6-hydroxydopamine treated rats. In addition, the inhibitory effects of methoxamine on an isoprenaline tachycardia were partially blocked with indomethacin. It is proposed that there are two separate inhibitory α1-adrenoceptors in the pithed rat heart.