Enzymatic modulation of vasoactive intestinal peptide and nonadrenergic noncholinergic inhibitory responses in guinea...

The airways of the guinea pig are innervated by four types of autonomic nerves: cholinergic excitatory, adrenergic inhibitory, nonadrenergic noncholinergic (NANC) excitatory, and NANC inhibitory. Tachykinins (neurokinins A and B and substance P) are believed to mediate NANC excitatory responses, and vasoactive intestinal peptide (VIP) has been proposed as the chemical mediator of the NANC inhibitory system. Enzymatic degradation represents an important means by which the biologic actions of neurotransmitters are terminated. In the present study, relaxation responses of guinea pig tracheae to NANC nerve stimulation and to exogenous VIP administration were compared in the absence and presence of various peptidase inhibitors. NANC inhibitory responses elicited by electrical field stimulation were unaffected by aprotinin or soybean trypsin inhibitor but were depressed by thiorphan or leupeptin. Concentration-response curves to exogenous VIP were shifted to the left by soybean trypsin inhibitor but were not affected by aprotinin, leupeptin, or thiorphan. After tachykinin depletion with capsaicin, thiorphan also induced a leftward shift in the VIP concentration-response curve. Under the same conditions, thiorphan failed to influence NANC inhibitory responses. These results indicate that the NANC inhibitory neurotransmitter is not metabolized by enzymes susceptible to inhibition by aprotinin, leupeptin, soybean trypsin inhibitor, or thiorphan and, accordingly, distinguish NANC nervous responses from those induced by VIP. The results also suggest that the NANC excitatory system can interact functionally with the NANC inhibitory system, as evidenced by the blunting of NANC relaxation responses following inhibition of tachykinin metabolism and elimination of this effect by capsaicin.