Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta.
Our laboratory previously demonstrated that nitric oxide and natriuretic peptides can synergistically enhance cAMP elevations and vasorelaxations in rat aortic rings induced by calcitonin gene-related peptide, likely involving cyclic guanosine monophosphate (cGMP)-mediated inhibition of type-3 phosphodiesterase (PDE3). It was predicted that this cellular mechanism may also serve as a point of synergism between adrenomedullin (ADM) and brain natriuretic peptide (BNP) in aortic smooth muscle cells. The current study shows that ADM (100 nM)-induced vasorelaxations in isolated aortic rings of Sprague-Dawley rats are dependent on endothelium (34.1 +/- 4.2% relaxation with endothelium versus 3.0 +/- 0.6% relaxation without endothelium; P < 0.001). To determine interactions between ADM and BNP in smooth muscle cells without interference from endothelium-derived factors, further studies used aortic rings denuded of endothelium. Pretreatment with BNP (1 nM), which elevated cGMP levels 1.6 fold, uncovered direct vasorelaxant effects of ADM in endothelium-denuded rings, showing 5.6 +/- 1.8%, 20.9 +/- 6.1%, and 55 +/- 9.4% relaxations with ADM at 1, 10, and 100 nM, respectively (n = 6). ADM (100 nM) significantly (P < 0.05) increased cyclic adenosine monophosphate (cAMP) levels in denuded aortic rings pretreated with BNP (1 nM), but not in denuded rings without BNP. Quazinone (20 microM), a PDE3 inhibitor, caused similar enhancement of direct cAMP elevations to ADM (100 nM). The data indicate vasodilatory synergism between ADM and BNP in aorta, likely mediated by enhanced accumulation of cAMP in smooth muscle cells resulting from BNP/cGMP-induced inhibition of PDE3. This synergistic mechanism may be especially important in subjects with dysfunctional endothelium, in which BNP may uncover direct vasorelaxant effects of ADM in arteries that normally require healthy (nitric oxide-releasing) endothelium for ADM-induced vasorelaxations to occur.
Fung
Erik
E
Department of Physiology, Faculty of Medicine, The Epithelial Cell Biology Research Center, and The Center for Gerontology & Geriatrics, The Chinese University of Hong Kong, Shatin, Hong Kong.
Fiscus
Ronald R
RR
D053607:Adrenomedullin; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000502:physiology*
D010455:Peptides; D020097:Natriuretic Peptide, Brain; D053607:Adrenomedullin; D009569:Nitric Oxide; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide