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 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 microM NG-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), which was approximately 100-fold greater than the ID50 of control lungs which 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 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 microM to 0.78 +/- 0.15 microM (P < 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 [ID50 4.0 nmol/kg (1.5-10), P < 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.
Lilly
C M
CM
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
Stamler
J S
JS
Gaston
B
B
Meckel
C
C
Loscalzo
J
J
Drazen
J M
JM
D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D010477:Perfusion / Q000379:methods; D011312:Pressure; D014132:Trachea / Q000187:drug effects; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide