Nitric-oxide-mediated regulation of cardiac contractility and stretch responses.
In the heart, nitric oxide (NO) is constitutively produced by the vascular and endocardial endothelium, the cardiomyocytes and the autonomic nerves. Whereas stimulation of NO release from the vascular endothelium has consistently been shown to quicken the onset of left ventricular (LV) relaxation and cause a small reduction in peak contraction, the role of myocardial NO production in regulating cardiac function appears to be more complex and controversial. Some studies have shown that non-isoform-specific inhibition of NO synthesis with L-arginine analogues has no effect on basal contraction in LV myocytes. However, others have demonstrated that stimulation of myocardial NO production can offset the increase in contraction in response to a rise in intracellular Ca(2+). Cardiac NO production is also activated by stretch and under these conditions NO has been shown to facilitate the Frank-Starling response and to contribute to the increase in intracellular Ca(2+) transients that mediates the slow increase in contraction in response to stretch (i.e., the Anrep effect). These findings suggest that NO can mediate diverse and even contrasting actions within the myocardium, a notion that is difficult to reconcile with the early description of NO as a highly reactive and diffusible molecule possessing minimal specificity in its interactions. The purpose of this short review is to revisit some of the 'controversial' aspects of NO-mediated regulation of myocardial function, taking into account our current understanding of how mammalian cells may target and regulate the synthesis of NO in such a way that NO can serve diverse physiological functions.
John Radcliffe Hospital, University Department of Cardiovascular Medicine, Headley Way Headington, OX3 9DU, Oxford, UK. barbara.casadei@cardiov.ox.ac.uk
Barbara
B
Casadei
Claire E
CE
Sears
D000818:Animals; D001120:Arginine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D020033:Protein Isoforms; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D020033:Protein Isoforms; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase