Rapid tachyphylaxis to hemodynamic effects of PACAP-27 after inhibition ofnitric oxide synthesis

The vasodilator effects of pituitary adenylate cyclase-activating polypepti de (PACAP)-27 are subject to tachyphylaxis in rats treated with the nitric oxide (NO) synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME). W e examined whether this tachyphylaxis could be prevented by administration of the putative endothelium-derived nitrosyl factor S-nitroso-L-cysteine (L -SNC) and whether L-SNC may exert its effects via increases in cGMP levels in vascular smooth muscle. Five doses of PACAP-27 (2 nmol/kg iv) produced p ronounced vasodilator responses in saline-treated rats. These responses wer e not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME-treated (50 mu mol/kg iv) rats produced vasodilator responses similar to those in saline-treated rats, whereas subsequent injections pro duced progressively smaller responses. The injection of L-SNC (1,200 nmol/k g iv) before each injection of PACAP-27 prevented tachyphylaxis to the CT, protein-coupled receptor agonist in L-NAME-treated rats, whereas equihypote nsive doses of the NO donor sodium nitroprusside (100 mu g/kg iv) did not. The injection of the membrane-permeant cGMP analog 8-(4-chlorophenylthio)gu anosine 3',5'-cyclic monophosphate (8-CPT-cGMP; 30 mu mol/kg iv) to L-NAME- treated rats restored resting hemodynamic values to pre-L-NAME levels but d id not prevent the development of tachyphylaxis to PACAP-27. These results suggest that nitrosyl factors prevent the development of tachyphylaxis to t he hemodynamic actions of PACAP-27. These nitrosyl factors may act independ ently of their ability to generate cGMP in vascular smooth muscle.