Inhibition by nucleotides acting at presynaptic P2-receptors of sympathetic neuro-effector transmission in the mouse isolated vas deferens.

Effects of nucleotides and nucleosides on smooth muscle tension and the release of previously stored [3H]-noradrenaline were studied in the mouse isolated vas deferens. The tissue was stimulated twice by 20 electrical field pulses delivered at 2 Hz (S1, S2). alpha,beta-Methylene-ATP, ATP gamma S, ATP and UTP elicited contraction, with potency decreasing in that order; there was no contractile response to adenosine (up to 100 mumol/l) and uridine (up to 1 mmol/l). The electrically evoked overflow of tritium was reduced by the drugs in the following order of potency: ATP gamma S greater than ATP = adenosine greater than UTP; alpha,beta-methylene-ATP (up to 10 mumol/l) and uridine (up to 1 mmol/l) did not significantly change the evoked overflow. 8-(p-Sulphophenyl)theophylline did not alter the contractile responses to the nucleotides; it prevented the overflow-inhibiting effect of adenosine and reduced that of UTP; the overflow-inhibiting effects of ATP and ATP gamma S were not significantly attenuated. After prolonged exposure to alpha,beta-methylene-ATP, all contractile nucleotide effects were abolished; in contrast, the depression by adenosine and the nucleotides of the evoked overflow of tritium persisted. None of the effects was changed by indometacin, yohimbine or reactive blue 2. It is concluded that ATP, ATP gamma S, alpha,beta-methylene-ATP and UTP produce contraction of the vas deferens by activation of P2x-receptors. Moreover, the nucleotides inhibit per se the release of [3H]-noradrenaline (and presumably the co-transmitter mixture of noradrenaline and ATP); the effect of ATP is not, or only to a small extent, due to breakdown to adenosine. The presynaptic site of action of the purine nucleotides is a P2-receptor which differs from the P2x-receptor and may be a reactive blue 2-resistant "P2y-like" receptor.