[Myocardial effects of nitric oxide, NO. Clinical and experimental evidence].
The vasodilatory properties of nitric oxide (NO) are well documented, but its direct effects on myocardial contractility are somewhat controversial. The present report follows a series of articles in which we reported the translocation of NO synthase isoforms both after myocardial infarction in aged rats and in human heart failure (HF). This redistribution is due to nNOS1 translocation from the sarcoplasmic reticulum to the caveolae in the outer membranes. Translocation is determined by strong interactions between the enzyme and caveoline-3 (a marker of caveolae). It suggests a regulatory role of nNOS1 in both normal inotropism and HF. The physiological consequences of this translocation were studied in a well-documented experimental model of myocardial infarction with HF in adult rats. Myocardial function was analyzed before and after adrenergic activation, both ex vivo on isolated hearts and in vivo with a Millar probe.--In rats, as in humans, the level of nNOS1 is enhanced, and this is associated with translocation to the caveolae. Such a process is seen in both humans and rats with HF.--In HF, ventricular elastance (E(s), in mmHg/microL: a load-independent measure of contractility) is reduced, and the time constant of relaxation, tau, is prolonged. In basal conditions, in non HF controls, specific nNOS1 inhibition by L-VNIO induces a 33% increase in E(s) and a 17% increase in the time constant of relaxation. The response to an adrenergic stimulation is attenuated in HF. The main result of this work is that pharmacological inhibition of nNOS1, either ex vivo with L-VNIO, or in vivo with SMTC, normalizes the adrenergic response of failing hearts. nNOS1 translocation is thus a major contributor to the autocrine regulation of contractility in HF, and is probably responsible for hampering the adrenergic response in HF.
Heymes
Christophe
C
U689-INSERM, Hôpital Lariboisière. 41 Bd de la Chapelle, 75475 Paris 10.
Swynghedauw
Bernard
B
Samuel
Jane-Lise
JL
D000818:Animals; D022461:Caveolins / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000201:enzymology*; D006801:Humans; D009203:Myocardial Infarction / Q000201:enzymology*; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats
D022461:Caveolins; D019001:Nitric Oxide Synthase