1 The subtypes of a 1 -and a 2 -adrenoceptor mediating contractions of vas deferens have been examined in wild-type and a 2A/D -adrenoceptor knockout mice. 2 Maximum contractions to noradrenaline but not phenylephrine were significantly greater in vas from wild-type. The a 1A -adrenoceptor antagonist RS100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H)-pyrimidinedione) (10 nm) significantly shifted the potency of noradrenaline. The a 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.3 Following prazosin (0.1 mm), a component of the contraction to noradrenaline in wild-type but not in knockout was sensitive to the a 2 -adrenoceptor antagonist yohimbine. 4 Nifedipine (10 mm) or suramin (100 mm) reduced the contraction to 10 Hz stimulation for 4 s to an early peak and small maintained response. The peak was abolished by the a 1 -adrenoceptor antagonist prazosin. 5 RS100329 or prazosin inhibited 10 Hz stimulation evoked contractions with a U-shaped concentration-response curve: inhibiting responses up to 0.1 mm, 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.

Because little is known of the intracellular mechanisms involved in the vasoconstrictor effect of melatonin (Mel), we examined the in vitro effects of Mel by using perfused cylindrical segments of the rat tail artery loaded with the intracellular Ca(2+) concentration ([Ca(2+)](i))-sensitive fluorescent dye, fura 2. Mel (10(-14) to 10(-4) M) had no effect on baseline perfusion pressure or [Ca(2+)](i) but increased, at submicromolar concentrations, the vasoconstrictor effect of norepinephrine (NE) (P = 0.0029). Mel did not modify NE-induced [Ca(2+)](i) mobilization, and thus the [Ca(2+)](i) sensitivity of NE-induced contraction increased in the presence of Mel. Mel consistently increased KCl-induced vasoconstriction and [Ca(2+)](i) sensitivity of contraction, but differences were not statistically significant. In conclusion, Mel increases the [Ca(2+)](i) sensitivity of vasoconstriction evoked by NE suggesting that Mel may amplify endogenous vasoconstrictor responses to sympathetic outflow.

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1 We have investigated pre-and post-junctional responsiveness in vas deferens from wild-type and a 2A/D -adrenoceptor knockout mice. The response to a single stimulus was not signi®cantly di erent between wild-type and knock-out mice. The isometric contraction to 10 Hz stimulation for 4 s was signi®cantly larger in vas deferens from knockout as compared with wild-type. 2 The maximum potentiation of 10 Hz stimulation-evoked contractions by yohimbine was to 206.2+38.0% of control in wild-type but to 135.8+13.6% of control in knockout. The a 2A/Dadrenoceptor selective antagonist BRL 44408 signi®cantly increased the 10 Hz stimulation-evoked contraction in wild-type but not knockout, and the reverse was true for the a 2C -adrenoceptor selective antagonist spiroxatrine. The a 2B -adrenoceptor antagonist imiloxan had no e ect on the evoked contraction except at high concentrations, and only in wild-type. Following cocaine (3 mM) and BRL 44408 (1 mM), 10 Hz responses were similar in shape and maximum between wild-type and knock-out. 3 The a 2 -adrenoceptor agonist xylazine virtually abolished the early component of the contraction to 10 Hz stimulation in the presence of nifedipine (10 mM) in vas deferens from knockout mice in a way consistent with a change of receptor subtype but without clear evidence for a reduced receptor number. However, the late component of the contraction to 10 Hz stimulation was signi®cantly potentiated by xylazine in tissues from knock-out mice. 4 It is concluded that, although non-a 2A/D -adrenoceptors replace a 2D -adrenoceptors in this knockout, the a 2 -adrenoceptor agonist and antagonist data are contradictory. The antagonist data suggest a major loss of prejunctional a 2 -adrenoceptors, but this is not necessarily supported by the agonist data.

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