Comparison of Pre- and Postsynaptic Alpha-adrenoceptor Blocking Effects of E-643 in the Isolated Vas Deferens of the Rat

Effectiveness of E-643, a newly developed alpha-blocker, and four alpha-antagonists in blocking pre- and postsynaptic alpha-adrenoceptors were compared in the isolated rat vas deferens. The inhibitory effect of clonidine on the field-stimulated twitch response was antagonized in the presence of the alpha-antagonist. The order of affinity (pA2) for presynaptic alpha-receptors, as assessed from parallel shift of the dose-response curve to clonidine, was: phentolamine greater than yohimbine greater than tolazoline greater than E-643 greater than or equal to prazosin. At concentrations from 10(-8) to 10(-6) M, neither E-643 nor prazosin had any effect on the twitch which had been depressed by the treatment with clonidine, whereas phentolamine, yohimbine and tolazoline partially reversed it. Contractile effects of cumulative concentrations of noradrenaline were also antagonized by alpha-antagonists. The order of affinity (pA2) for postsynaptic alpha-receptors was: E-643 greater than or equal to prazosin greater than phentolamine greater than yohimbine greater than tolazoline. Selectivity for pre- versus postsynaptic alpha-receptors was assessed by comparing KB values for pre- and postsynaptic alpha-receptors. The order of selectivity for the presynaptic alpha-receptors was : yohimbine greater than tolazoline greater than phentolamine much greater than prazosin greater than or equal to E-643. It is concluded that E-643 is a potent and highly selective postsynaptic alpha-blocker.