Modulation of noradrenergic transmission in the guinea-pig mesenteric artery: an electrophysiological study.

We carried out electrophysiological experiments on guinea-pig mesenteric arteries in an attempt to clarify the modification of noradrenaline (NA) release from noradrenergic nerve terminals by the action of prejunctional adrenoceptors. NA (10(-7)-10(-5) M) suppressed the amplitude of the first excitatory junction potential (e.j.p.(f], the facilitation process, and the e.j.p. after facilitation was completed (e.j.p.(s]with no change in the post-junctional membrane properties of smooth muscles. These actions of NA on e.j.p.s were antagonized by high concentrations of extracellular Ca, [Ca]o, but not in a simple competitive manner. NA (10(-7) M) suppressed the appearance but not the amplitude of the miniature e.j.p.s. These effects of NA on transmission indicate that NA acts on prejunctional nerve terminals and suppresses the release of NA from nerve terminals rather than producing a desensitization of post-junctional adrenoceptors. Prazosin and phentolamine (10(-6) M) did suppress the NA-induced contraction (greater than 10(-6) M) but did not suppress the contraction evoked by perivascular nerve stimulation, below a frequency of 1.0 Hz. At a dose of 10(-7) M, yohimbine, clonidine, prazosin and phentolamine had no effect on the muscle membrane potential and resistance. Yet on the e.j.p.(f), yohimbine and clonidine caused suppression, phentolamine enhancement and prazosin had no effect. On the e.j.p.(s), yohimbine and phentolamine caused enhancement, clonidine suppression and prazosin had no effect. These results indicate that at least three different adrenoceptors are distributed on the neuromuscular junction in this tissue, i.e. alpha 1-extrajunctional, alpha 2-prejunctional, and an unknown subtype of intrajunctional adrenoceptors. Furthermore, the feedback mechanism on NA release is mediated by suppression of the influx of Ca. Nonselective and non-specific actions of alpha-adrenoceptor agonists and antagonists were also elucidated.