A study of some agents which modulate neurotransmission in the mouse vas deferens.

The effects of nitric oxide (NO) and histamine as modulators of neuromuscular transmission in the mouse vas deferens have been studied. Controls exerted by these agents have not previously been identified in this tissue. A pharmacological approach was taken to investigate the various activities of NO. The presence and identity of histamine receptors in this tissue was also determined by this method. The use of specific antagonists also showed that histamine is secreted during nerve stimulation. Contractions evoked by low frequency (5Hz) electrical nerve stimulation (5-50V) were recorded to give information about pre and postjunctional effects. Contractions evoked by the agonists noradrenaline or alphabeta-methylene ATP (alphabeta-met. ATP) gave information about postjunctional responses. Intracellular and focal recording techniques recorded evoked electrical activity (EJPs and EJCs); these reflect the neuronal release of ATP. Quantal analysis of EJC amplitudes permitted pre and postjunctional effects to be determined. Sodium nitroprusside (4x10-6m) depressed nerve evoked contractions suggesting a NO sensitivity. These contractions were also depressed by L-arginine (L-Arg), the natural precursor of NO. The nitric oxide synthase (NOS) inhibitor L-arginine methyl ester (L-AME) (2.3x10-4m), caused all mechanical responses to increase in amplitude suggesting a physiological depressive role for NO synthesis. An elevation of EJC amplitudes by L-AME (2.3x10-4m) was rapidly reversed by L-Arg (3.4x10-4m) suggesting that endogenous NO normally depresses ATP secretion. In the longer term L-Arg (3.4x10-4m) revealed a new RB2 sensitive low-threshold current of positive sign. L-Arg (3.4x10-4m) may have degranulated mast cells. This histamine may have been taken up and released as a neuro-transmitter. Thioperamide (6x10-6m) and ranitidine (1x10-4M) showed that endogenous histamine acts at H3 and H2 receptors to depress contractions but not those evoked by exogenous a?-met. ATP. Exogenous histamine (1x10-6M) also depressed EJC amplitudes by a physiological mechanism. The results showed that nitric oxide is a modulator of transmission in this tissue which depresses pre and postjunctional activities. Endogenous histamine also modulates transmission processes with effects similar to those of NO.