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BACKGROUND: Evidence indicates that myocardial NO production can modulate contractility, but the source of NO remains uncertain. Here, we investigated the role of a type 1 NO synthase isoform (NOS1), which has been recently localized to the cardiac sarcoplasmic reticulum, in the regulation of basal and beta-adrenergic myocardial contraction. METHODS AND RESULTS: Contraction was assessed in left ventricular myocytes isolated from mice with NOS1 gene disruption (NOS1(-/-) mice) and their littermate controls (NOS1(+/+) mice) at 3 stimulation frequencies (1, 3, and 6 Hz) in basal conditions and during beta-adrenergic stimulation with isoproterenol (2 nmol/L). In addition, we examined the effects of acute specific inhibition of NOS1 with vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO, 500 micromol/L). NOS1((-/-)) myocytes exhibited greater contraction at all frequencies (percent cell shortening at 6 Hz, 10.7+/-0.92% in NOS1(-/-) myocytes versus 7.21+/-0.8% in NOS1(+/+) myocytes; P<0.05) with a flat frequency-contraction relationship. Time to 50% relaxation was increased in NOS1(-/-) myocytes at all frequencies (at 6 Hz, 26.53+/-1.4 ms in NOS1(-/-) myocytes versus 21.27+/-1.3 ms in NOS1(+/+) myocytes; P<0.05). L-VNIO prolonged time to 50% relaxation at all frequencies (at 6 Hz, 21.28+/-1.7 ms in NOS1(+/+) myocytes versus 26.45+/-1.4 ms in NOS1(+/+)+L-VNIO myocytes; P<0.05) but did not significantly increase basal contraction. However, both NOS1(-/-) myocytes and NOS1(+/+) myocytes treated with L-VNIO showed a greatly enhanced contraction in response to beta-adrenergic stimulation (percent increase in contraction at 6 Hz, 25.2+/-10.8 in NOS1(+/+) myocytes, 68.2+/-11.2 in NOS1(-/-) myocytes, and 65.1+/-13.2 in NOS1(+/+)+L-VNIO myocytes; P<0.05). CONCLUSIONS: NOS1 disruption enhances basal contraction and the inotropic response to beta-adrenergic stimulation in murine ventricular myocytes. These findings indicate that cardiac NOS1-derived NO plays a significant role in the autocrine regulation of myocardial contractility.

Type

Journal article

Journal

Circulation

Publication Date

25/06/2002

Volume

105

Pages

3011 - 3016

Keywords

Adrenergic beta-Agonists, Animals, Cells, Cultured, Heart Ventricles, Isoproterenol, Mice, Mice, Knockout, Myocardial Contraction, Myocardium, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Stimulation, Chemical, Ventricular Function