Regulation of the mammalian heart function by nitric oxide.
The mammalian heart expresses all three isoforms of nitric oxide synthases (NOS) in diverse cell types of the myocardium. Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart. They also attenuate the beta1-/beta2-adrenergic increase in inotropy and chronotropy, and reinforce the pre- and post-synaptic vagal control of cardiac contraction. By doing so, the NOS protect the heart against excessive stimulation by catecholamines, just as an "endogenous beta-blocker". In the ischemic and failing myocardium, induced iNOS further reinforces this effect, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and infarcted heart, but its role (compensatory or deleterious) is less clear. In addition to their direct regulation of contractility, the NOS modulate oxygen consumption, substrate utilization, sensitivity to apoptosis, hypertrophy and regenerative potential, all of which illustrate the pleiotropic effects of this radical on the cardiac cell biology.
Unit of Pharmacology and Therapeutics, FATH 5349, Université catholique de Louvain, Tour Pasteur +2, 53 Avenue E. Mounier, 1200 Brussels, Belgium.
Paul B
PB
Massion
Michel
M
Pelat
Catharina
C
Belge
J-L
JL
Balligand
D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D003971:Diastole; D006321:Heart / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D013599:Systole
D002395:Catecholamines; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase