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(Circulation. 1997;96:1616-1623.)
© 1997 American Heart Association, Inc.
Articles |
Selective Modulation of Inducible Nitric Oxide Synthase Isozyme in Myocardial Infarction
From the Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany (S.M.W., S.W., W.P.W., B.R.), and the Department of Experimental Cardiology, Huntington Medical Research Institutes, Pasadena, Calif (H.S., D.H., R.R.D., K.A.).
Correspondence to Stephen M. Wildhirt, MD, Department of Cardiac Surgery, Ludwig-Maximilians University, Marchioninistr 15, 81377 Munich, Germany. E-mail wildhirt{at}hch.med.uni-muenchen.de
Background Inducible nitric oxide synthase (iNOS) is activated in cardiac disorders. We investigated the contribution of increased iNOS activity to the development of left ventricular dysfunction after myocardial infarction by selective inhibition of the isozyme.
Methods and Results Male New Zealand rabbits were
subjected to myocardial infarction. Animals were treated with either
saline, S-methylisothiourea sulfate (SMT) (a selective iNOS
inhibitor), or
N
-nitro-L-arginine (L-NNA) (a
nonselective NOS inhibitor). Inducible and constitutive NOS
(cNOS) activity, plasma NOx, cGMP,
hemodynamics, and myocardial blood flow were measured
before and 5, 24, and 72 hours after coronary occlusion.
Infarction 72 hours after occlusion resulted in increased myocardial
iNOS activity, increased cardiac NOx production,
and elevated cGMP levels. cNOS remained unchanged. Infarction increased
left ventricular end-diastolic pressure (LVEDP)
and decreased maximum +dP/dt and -dP/dt. L-NNA inhibited iNOS and cNOS
activities and plasma NOx levels. L-NNA further increased
LVEDP and reduced myocardial blood flow. Administration of SMT 72 hours
after infarction significantly inhibited iNOS and cardiac
NOx production but had no effects on cNOS. SMT
improved left ventricular maximum +dP/dt and -dP/dt and
decreased LVEDP. Myocardial blood flow in the remote
myocardium increased.
Conclusions These findings suggest that induction of iNOS activity 72 hours after infarction exerts negative inotropic effects and contributes to the development of myocardial dysfunction; selective modulation of increased iNOS activity by SMT improves cardiac performance, enhances myocardial blood flow, and may be beneficial in the treatment of acute myocardial infarction.
Key Words: myocardial infarction • regional blood flow • hemodynamics • ischemia
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