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(Circulation Research. 2003;92:e52.)
© 2003 American Heart Association, Inc.

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Cardiac Neuronal Nitric Oxide Synthase Isoform Regulates Myocardial Contraction and Calcium Handling

Claire E. Sears, Simon M. Bryant, Euan A. Ashley, Craig A. Lygate, Stevan Rakovic, Helen L. Wallis, Stefan Neubauer, Derek A. Terrar, B. Casadei

From the Department of Cardiovascular Medicine (C.E.S., S.M.B., E.A.A., C.A.L., H.L.W., S.N., B.C.), Oxford University, John Radcliffe Hospital; and the Department of Pharmacology (S.R., D.T.), Oxford University, Oxford, UK.

Correspondence to Dr Claire E. Sears or Dr Barbara Casadei, Department of Cardiovascular Medicine, Oxford University, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail claire.sears{at}cardiov.ox.ac.uk

A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca²⁺ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca²⁺ cycling. To test this hypothesis, we have investigated myocardial Ca²⁺ handling and contractility in nNOS knockout mice (nNOS^-/-) and in control mice (C) after acute nNOS inhibition with 100 µmol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3±0.6% in nNOS^-/- versus 8.1±0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5±2.7 in nNOS^-/- versus 44.9±1.5% in C; P<0.05). nNOS disruption increased I_Ca density (in pA/pF, at 0 mV, -11.4±0.5 in nNOS^-/- versus -9.1±0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of I_Ca by 38% (P<0.05), leading to an increased Ca²⁺ influx and a greater SR load in nNOS^-/- myocytes (in pC/pF, 0.78±0.04 in nNOS^-/- versus 0.64±0.03 in C; P<0.05). Consistent with these data, [Ca²⁺]_i transient (indo-1) peak amplitude was greater in nNOS^-/- myocytes (410/495 ratio 0.34±0.01 in nNOS^-/- versus 0.31±0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca²⁺ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.

Key Words: neuronal nitric oxide synthase • ventricular • contraction • calcium

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