Previous studies have shown that the development of tolerance to nitroglycerin is related to reduction of endogenous calcitonin gene-related peptide (CGRP) release. In the present study, Nitroglycerin caused a concentration-dependent relaxation concomitantly with a significant increase in the release of CGRP in the isolated rat thoracic aorta, an effect that was reduced by preincubation with capsaicin. Pretreatment with nitroglycerin significantly decreased its vasodilation and depressor effect and the release of CGRP, which was restored in the presence of vinpocetine, an inhibitor of phosphodiesterase. The present results suggest that reversal of tolerance to nitroglycerin with vinpocetine is related to the increased release of CGRP in the rat.