Effects of intracavernous administration of selective antagonists of alpha(1)-adrenoceptor subtypes on erection in anesthetized rats and dogs

The proerectile properties of three novel alpha(1)-adrenoceptor (alpha(1)-A DR) antagonists with different profiles of selectivity for the alpha(1)-ADR subtypes have been evaluated in anesthetized rats and dogs on intracaverno us (IC) injection, in comparison with prazosin and phentolamine. In rats, t he tested compounds decreased blood pressure (BP) and increased IC pressure (ICP), as well as the ratio ICP/BP. Rec 15/2841 (alpha(1a)-plus alpha(1L)- ADR-selective antagonist) and Rec 15/2615 (alpha(1b)-ADR selective) were th e most potent compounds. The ICP/BP ratios calculated after injection of Re c 15/3039 (alpha(1d)-ADR selective) were not markedly different from those observed after vehicle injection. Prazosin and phentolamine proved poorly a ctive, their main effect being hypotension. Approximate ED25 values (dose o f compound in micrograms inducing 25% increase of ICP/BP ratio) were Rec 15 /2615 (22 mu g/kg) > = Rec 15/2841 (29 mu g/ kg) > prazosin (136 mu g/kg) > phentolamine (1298 mu g/kg) > Rec 15/3039 (9600 mu g/kg). Submaximal stimu lation of the cavernous nerve elicited an ICP rise whose amplitude was not altered by Rec compounds. In contrast, prazosin and phentolamine decreased this ICP rise. All compounds but 15/3039 induced significant increase of th e ICP/BP ratio in dogs. Rec 15/2615 proved to be the most interesting compo und, inducing significant increases of ICP/BP at doses practically devoid o f effects on BP. The rank order of potency in dog in increasing the ICP/BP ratio was similar to that observed in rats. Only at the highest doses teste d, all compounds, except Rec 15/3039, decreased the ICP rise elicited by su bmaximal stimulation of the cavernous nerve. Our data demonstrate that the alpha(1b)- and alpha(1L)-ADR subtypes are functionally relevant for the ere ctile function in these models, and that alpha(1b)- and/or alpha(1L)-ADR su btypes selective antagonists could represent a real advantage in erectile d ysfunction therapy.