Brain natriuretic peptide enhances the endothelium-independent cAMP and vasorelaxant responses of calcitonin gene-related peptide in rat aorta

Calcitonin gene-related peptide (CGRP) causes vasorelaxation in rat aorta i nvolving endothelium/nitric oxide (NO)-dependent elevations of both cAMP an d cGMP levels. When endothelium is removed, preincubation with exogenous NO uncovers and potentiates direct (endothelium-independent) cAMP elevations and vasorelaxations caused by CGRP. This enhancing effect of NO potentially involves elevation of cGMP and inhibition of Type III (cGMP-inhibitable) p hosphodiesterase, causing accumulation of cAMP. However, NO may have other actions. The aim of the present study was to determine if brain natriuretic peptide (BNP), which elevates cGMP levels independent of NO, could enhance cAMP accumulations and vasorelaxations induced by CGRP in rat aortic rings denuded of endothelium. When added separately, neither CGRP (100 nM) nor B NP (10 nM) altered cAMP levels. When added in combination, CGRP (100 nM) an d BNP (10 nM) significantly elevated cAMP levels (from control of 0.95 +/- 0.08 to 1.53 +/- 0.09 pmol/mg protein) at 2 min. BNP (10 nM) elevated cGMP levels 10-fold at 2 min and this response was not altered by co-administrat ion of CGRP (100 nM). Pretreatment with BNP at concentrations as low as 1 nM in endothelium-denud ed aortic rings greatly enhanced the direct vasorelaxant effects of CORP (1 00 nM) (from control of 0% to 57.6 +/- 6.8% relaxation of phenylephrine-pre contractions). Our findings indicate that BNP enhances direct (endothelium- independent) cAMP elevations and vasorelaxations caused by CGRP in rat aort a, thus supporting the concept that cGMP inhibits cAMP metabolism and enhan ces CORP-induced responses in aortic smooth muscle cells.