The interaction of WB4101, and other α‐adrenoceptor antagonists, on 5‐hydroxytryptamine receptors

previous studies in which high concentrations of aa&enoceptor antagonists have been applied to rat isolated vas deferens have shown that spontaneous spiked contractions were induced (Drew 1977; Doggerel1 gr paton 1978). The mechanism by which these contractions were produced was not evaluated. The potent a-adrenoceptor blocking drug WB4101 (Mottram & Kapur 1975; Greenberg et a1 1976) has also been observed to induce spiked contractions in rat vas deferens and the present study was undertaken to investigate this phenomenon in an attempt to establish the mechanism by which a-adrenoceptor antagonists induce the spontaneous contractions in rat isolated vas deferens. Male rats, 200-300g, were killed by a blow to the head. The vasa were excised, stripped of extraneous material and suspended in organ baths containing Mgfree Krebs solution (composition (g litre-l): NaCI, 6.923; CaCI,, 0.285, NaHCO,, 2-1 ; KCI, 0.354: KHIP04, 0.162 and glucose 2.0), maintained at 37 “C and aerated with a mixture of 5% C02 in oxygen. It has previously been reported (Hughes et a1 1975; Jenkins et a1 1977) that contractile responses are enhanced in Mg-free Krebs solution, and previous work on this tissue has been carried out in Krebs solution of this composition (Kapur & Mottram 1978). Isometric contractions were recorded with Devices 2 oz strain gauge transducers and two channel recorder. All drugs were freshly prepared in Krebs solution. a-Adrenoreceptor antagonists at concentrations in excess of those required for a-blockade were administered to vasa and left in contact with the tissues for periods of up to 1 h, after either a single or cumulative dose regime. The a-blocking drugs investigated were: WB4101 (2(N-[2,6-dimethoxyphenoxyethyl])aminomethyl-l ,4-benzodioxane) (6 X 10-6 to 2 X 10-6~) , phentolamine (8 x to 10-8~) , yohimbine (8 x 10-a to 8 x 10-6~), thymoxamine (8 x Phentolamine failed to produce a contractile response, whilst WB4101, yohimbine and thymoxamine all produced dose-dependent spontaneous contractions of the vas deferens (Fig. 1). The onset of action following the administration of these drugs was immediate though the maximal height of the spiked contraction took some 15 min to develop. Contractions continued for over 1 h after administration. Contractions elicited by WB4101 (4 x 10-s~vr) were challenged by a series of antagonists. Atropine and phenoxybenzamine had no effect on the spiked contractions, at any dose. Mepyramine (2 x ~O-’M), pimozide (lo-“), and chlorpromazine (2 x lo-%), produced a blockade, but at far higher concentrations than those normally required. The only effective to 6 x 10-6~).