Investigation of postjunctional α 1 ‐ and α 2 ‐adrenoceptor subtypes in vas deferens from wild‐type and α 2A/D ‐adrenoceptor knockout mice

The subtypes of α 1 ‐ and α 2 ‐adrenoceptor mediating contractions of vas deferens have been examined in wild‐type and α 2A/D ‐adrenoceptor knockout mice. Maximum contractions to noradrenaline but not phenylephrine were significantly greater in vas from wild‐type. The α 1A ‐adrenoceptor antagonist RS100329 (5‐methyl‐3‐[3‐[4‐[2‐(2,2,2,‐trifluoroethoxy)phenyl]‐1‐piperazinyl]propyl]‐2,4‐(1H)‐pyrimidinedione) (10 n M ) significantly shifted the potency of noradrenaline. The α 2D ‐adrenoceptor antagonist BRL 44408 (2‐[(4,5‐dihydro‐1H‐imidazol‐2‐yl)methyl]‐2,3‐dihydro‐1‐methyl‐1H‐isoindole) significantly reduced the maximum contraction to noradrenaline in wild‐type but not in knockout. Following prazosin (0.1 μ M ), a component of the contraction to noradrenaline in wild‐type but not in knockout was sensitive to the α 2 ‐adrenoceptor antagonist yohimbine. Nifedipine (10 μ M ) or suramin (100 μ M ) reduced the contraction to 10 Hz stimulation for 4 s to an early peak and small maintained response. The peak was abolished by the α 1 ‐adrenoceptor antagonist prazosin. RS100329 or prazosin inhibited 10 Hz stimulation evoked contractions with a U‐shaped concentration‐response curve: inhibiting responses up to 0.1 μ M , with a reversal of inhibition above this concentration. In the presence of suramin or nifedipine, the reversal of inhibition by high concentrations of prazosin was reduced. The α 1D ‐adrenoceptor selective antagonist BMY7378 (8‐[2‐(4‐(2‐ methoxyphenyl)piperazin‐1‐yl)ethyl]‐8‐azaspiro[4,5]decane‐7,9‐dione) produced inhibition of 10 Hz evoked contractions only in high concentrations. In conclusion, contractions to nerve stimulation in mouse vas deferens involve largely α 1A ‐adrenoceptors and purinoceptors. α 1 ‐Adrenoceptor antagonists in high concentrations increase the purinergic response presumably by blocking prejunctional α 2 ‐adrenoceptor‐mediated inhibition. In the presence of nifedipine, responses are predominantly α 1 ‐adrenoceptor mediated. Contractions to exogenous noradrenaline involved both α 1A ‐ and α 2A/D ‐adrenoceptors in wild‐type mice.British Journal of Pharmacology (2003) 138 , 1069–1076. doi: 10.1038/sj.bjp.138-0705137