Abstract
We demonstrated previously that adrenomedullin (AM), when given during early reperfusion, limited infarct size in rat heart. The present study was undertaken to provide direct evidence of the NO-dependency of AM's cardioprotective action by assessing NO biosynthesis and involvement of the soluble guanylyl cyclase (sGC) pathway. Perfused hearts from male CD-1 mice were subjected to 30-min left coronary occlusion and 60-min reperfusion. Infarct size was determined by tetrazolium staining. AM 10 nM was administered from 20 min after coronary occlusion until 10 min after reperfusion. Coronary effluent was analysed for NO2- and NO3-, and myocardial samples were analysed for NO2-, NO3-, nitroso-adducts and cGMP concentration. To examine the role of NO/sGC signalling in the infarct-limiting action of AM, further hearts received the sGC inhibitor ODQ 2 microM. AM treatment stimulated NO synthesis, indicated by increased NO2- efflux in coronary effluent throughout reperfusion (summarised as area under curve, AM 29.2 +/- 3.9 vs. control 14.4 +/- 2.8 micromol min2 mL(-1), P < 0.05). AM limited infarct size (35.4 +/- 2.7 vs. 12.2 +/- 2.3%, P < 0.01), associated with a 2.45-fold increase (P < 0.05) in myocardial cGMP concentration at 10 min after reperfusion. ODQ abolished the infarct size-limiting effect of AM (28.9 +/- 4.3%). These data provide the first evidence that AM increases NO bioavailability in intact murine myocardium and confirm that the NO/sGC/cGMP pathway is central to the cytoprotective action of AM against ischaemia-reperfusion injury.
Highlights
Adrenomedullin (AM) is widely expressed in mammalian tissues, predominantly within the cardiovascular system where it exerts a diverse range of actions, including vascular development in utero, regulation of volume/pressure homeostasis, and cell growth and division [41, 42, 46, 47].Basic Res Cardiol (2010) 105:257–266In many cardiovascular disease states, especially those characterised by increased mechanical loading or hypoxia, circulating levels of AM may be markedly increased [15, 23]
We report data from 39 hearts that underwent biochemical analysis for nitric oxide (NO) derivatives and 27 that were used for infarct size analysis and cGMP estimation
Adrenomedullin enhances the pool of NO derivatives in ischaemia–reperfusion
Summary
Adrenomedullin (AM) is widely expressed in mammalian tissues, predominantly within the cardiovascular system where it exerts a diverse range of actions, including vascular development in utero, regulation of volume/pressure homeostasis, and cell growth and division [41, 42, 46, 47].Basic Res Cardiol (2010) 105:257–266In many cardiovascular disease states, especially those characterised by increased mechanical loading or hypoxia, circulating levels of AM may be markedly increased [15, 23]. In acute ischaemia–reperfusion, the rate and extent of irreversible cell injury is determined by a multitude of factors, including circulating hormones and locally produced autacoids [2–4, 6, 10, 13, 19, 25, 37, 45] These chemical factors have been the subject of intense scrutiny in recent years, and it is clear that several cardiac-derived autacoids that are rapidly generated, released or upregulated by ischaemia–reperfusion have the potential to exert cytoprotective effects during ischaemia–reperfusion which could be therapeutically exploitable [3, 10]. Haploinsufficiency of endogenous AM in mice with heterozygous deletion of the prepro-AM gene resulted in a marked increase in infarct size and mortality during experimental myocardial infarction, corroborating the cytoprotective action of the native peptide [17] The mechanisms of this protective effect of AM in myocardial ischaemia–reperfusion are not clearly elucidated. Previous studies have implicated activation of the cAMP pathway rather than the cGMP pathway by AM in cardiac myocytes [21, 22, 43], and there has been no direct evidence demonstrating enhanced NO production in myocardium by AM
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