Use-Dependent Loss of Acetylcholine- and Bradykinin-Mediated Vasodilation After Nitric Oxide Synthase Inhibition

Abstract

In the present study, we examined the possibility that the endothelium-dependent vasodilators acetylcholine and bradykinin release preformed pools of nitric oxide–containing factors. Successive injections of selected doses of acetylcholine (1.18±0.3 μg/kg IV) or bradykinin (5 μg/kg IV) caused reproducible hypotensive and vasodilator responses within sympathetically intact and sympathetically denervated hindlimbs of conscious rats. After administration of the nitric oxide synthesis inhibitor Nω-nitro-l-arginine methyl ester (L-NAME, 25 μmol/kg IV), the first injection of acetylcholine or bradykinin produced pronounced depressor and vasodilator responses that, in the case of bradykinin, were greater than those observed before L-NAME administration. However, each successive injection of acetylcholine and bradykinin produced progressively smaller responses, such that the later injections elicited a markedly diminished hypotension and vasodilation. This “use-dependent” loss of endothelium-dependent vasodilatio...