MODULATION OF VASOACTIVE-INTESTINAL-PEPTIDE PULMONARY RELAXATION BY NO IN TRACHEALLY SUPERFUSED GUINEA-PIG LUNGS

The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with t he use of inhibitors of nitric oxide synthase (NOS) and by direct meas urement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 muM N(G)-nitro-L-arginine were resistan t to the relaxant effects of VIP in these lungs; the 50% inhibitory do se (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), whi ch was approximately 100-fold greater than the ID50 of control lungs w hich was 0.39 nmol/kg, (0.16-0.79, P < 0.0001). This inhibitory effect could be overcome with excess L- but not D-arginine. In contrast, VIP -induced relaxation of isolated guinea pig trachea was not modified by inhibitors of NOS. To confirm that VIP infusion resulted in NO genera tion in whole lungs, we measured NO equivalents in lung effluent by tw o distinct technologies. We found that VIP injection caused a signific ant increase in NO equivalents from 0.11 +/- 0.04 muM to 0.78 +/- 0.15 muM (P < 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibi tor methylene blue were less responsive to VIP [ID50 4.0 nmol/kg (1.5- 10), P < 0.005 compared with control lungs], consistent with a physiol ogically significant guanosine 3',5'-cyclic monophosphate-dependent me chanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.