Pharmacological evidence that adenosine triphosphate and noradrenaline are co-transmitters in the guinea-pig vas deferens.

The contractile response of the guinea-pig vas deferens to tetanic nerve stimulation was biphasic. The first phase was mimicked by exogenously applied ATP. The second more tonic phase was mimicked by exogenously applied noradrenaline (NA). Intracellular micro-electrodes were used to record the electrical response of the vas deferens to nerve stimulation and to exogenously applied ATP and NA. Local application of ATP (10(-5) to 10(-3)M), by pressure ejection from a micropipette, produced a depolarization similar in magnitude and time course to the excitatory junction potential (e.j.p.). NA produced no such response. Superfusion of the vas deferens with ATP and NA (10(-6) to 10(-4)M) produced a depolarization. The depolarization produced by NA was more gradual than that produced by the same concentration of ATP. The ATP-receptor antagonist ANAPP3 (arylazido aminopropionyl-ATP) preferentially antagonized the first component of the neurogenic contractile response and also antagonized the e.j.p. The alpha-receptor antagonist prazosin preferentially antagonized the second phase of the neurogenic contractile response and enhanced the e.j.p. Similar results were obtained using the irreversible alpha-receptor antagonists phenoxybenzamine and dibenamine. Cocaine (10(-6) and 10(-5)M) enhanced the second phase of the contractile response to nerve stimulation, but reduced the first phase. Lidocaine (10(-5) and 10(-4)M) had no such effect. Cocaine (10(-6) and 10(-5)M) reduced the magnitude of e.j.p.s. at all stimulation frequencies from 1 to 8 Hz. In the presence of the selective alpha 2-receptor antagonist yohimbine (10(-7)M), both phases of the contractile response to nerve stimulation were enhanced to the same degree. This concentration of yohimbine also increased the magnitude of e.j.p.s. In the presence of 10(-7) M-yohimbine, cocaine (10(-6) and 10(-5)M) still enhanced the second phase of the contractile response, but no longer reduced the initial phase of the contraction or e.j.p.s to the same degree. In vas deferens from animals pre-treated with reserpine (2 mg/kg.day), the second phase of the contractile response to nerve stimulation was reduced but neither the first phase of the contraction nor the e.j.p.s was blocked. These results suggest that the first phase of the neurogenic contractile response of the vas deferens and the e.j.p. are mediated by ATP acting on P2-purinoreceptors, whereas NA mediates phase two, via alpha 1-adrenoceptors. The results also suggest that release of ATP and NA is influenced by a negative feed-back mechanism involving presynaptic alpha 2-adrenoceptors.