Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs
Lilly, C.M.; Stamler, J.S.; Gaston, B.; Meckel, C.; Loscalzo, J.; Drazen, J.M.
American Journal of Physiology 265(4 Pt 1): L410-L415
1993
ISSN/ISBN: 0002-9513 PMID: 8238376 Document Number: 422389
The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with the use of inhibitors of nitric oxide synthase (NOS) and by direct measurement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 mu-M N-G-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID-50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), which was apprx 100-fold greater than the El),, of control lungs which was 0.39 nmol/kg, (0.16-0.79, P lt 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 generation in whole lungs, we measured NO equivalents in lung effluent by two distinct technologies. We found that VIP injection caused a significant increase in NO equivalents from 0. 11 +- 0.04 mu-M to 0.78 +- 0.15 mu-M (P lt 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibitor methylene blue were less responsive to VIP (ID-50 4.0 nmol/kg (1.5-10), P lt 0.005 compared with control lungs), consistent with a physiologically significant guanosine 3',5'-cyclic monophosphate-dependent mechanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.