Brain Natriuretic Peptide (BNP)‐Induced Cyclic GMP Elevations Synergistically Enhance the Vasodilatory and Cyclic AMP Responses to Adrenomedullin in Rat Aortic Rings

Abstract

Introduction: BNP, a hypotensive and natriuretic factor derived from cardiac muscle, acts similar to the cardiac hormone atrial natriuretic peptide (ANP), causing endothelium-independent vasorelaxations in rat aortic rings by activating particulate guanylyl cyclase (pGC), elevating cyclic GMP (cGMP) levels and activating protein kinase G (PKG) in vascular smooth muscle cells (VSMCs) [1,2]. Recently, we have shown that BNP [3], like nitric oxide (NO) [4,5], synergistically potentiates the vasorelaxant and cAMP-elevating actions of calcitonin gene-related peptide (CGRP), an important neuropeptide mediating inflammatory vasodilations. Both BNP and NO, via cGMP elevations, inhibit the type-3 phosphodiesterase (PDE3) in VSMC, thus enhancing cAMP accumulation and potentiating the vasorelaxations induced by CGRP [3-5]. We hypothesized that BNP may also synergistically enhance cAMP elevations and vasorelaxations induced by another important peptide, adrenomedullin (ADM), which has vascular properties similar to that of CGRP. Methods R p < 0.001). To uncover interactions between ADM and BNP in VSMCs without the interference from endothelium-derived agents, aortic rings were denuded of endothelium. After precontraction with phenylephrine (100 nM), BNP (1 nM) was added to the endothelium-denuded aortic rings, resulting in vasorelaxations of 20.1 ± 3.7%. This was followed by addition of log incremental concentrations of ADM (1, 10 & 100 nM), resulting in further vasorelaxations of 5.6 ± 1.8%, 20.9 ± 6.1% and 55 ± 9.4%, respectively (n = 6). ADM (100 nM) significantly (p < 0.05) elevated cAMP levels in endothelium-denuded rings pretreated with BNP (1 nM), but had no effect in rings without BNP. By itself, BNP significantly (p < 0.05) elevated cGMP levels by 1.6 folds and had no affect on cAMP levels. Conclusion: BNP synergistically enhances ADM-induced elevations of intracellular cAMP levels in VSMCs, significantly potentiating the endothelium-independent vasorelaxant effects of ADM. This synergistic interaction between BNP and ADM may be especially relevant to certain cardiovascular pathologies, such as septic shock and heart failure, in which both ADM and BNP levels are known to be elevated. 1 Fiscus, Rapoport, Waldman and Murad. Biochim. Biophys. Acta 846:179-184, 1985. 2 Zhou and Fiscus. Neuropeptides 14:161-169, 1989. 3 Fiscus, Lu, Tu, Hao, Yang and Wang. Neuropeptides 32:499-509, 1998. 4 Fiscus, Hao, Wang, Arden and Diana. Neuropeptides 26:133-144, 1994. 5 Lu and Fiscus, Eur. J. Pharmacol. 376:307-314, 1999. (Supported by a Direct Grant for Research)