Selective modulation of inducible nitric oxide synthase isozyme in myocardial infarction.
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.


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(omega)-nitro-L-arginine (L-NNA) (a nonselective NOS inhibitor). Inducible and constitutive NOS (cNOS) activity, plasma NO(x), 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 NO(x) 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 NO(x) levels. L-NNA further increased LVEDP and reduced myocardial blood flow. Administration of SMT 72 hours after infarction significantly inhibited iNOS and cardiac NO(x) 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.
Wildhirt
S M
SM
Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany. wildhirt@hch.med.uni-muenchen.de
Suzuki
H
H
Horstman
D
D
Weismüller
S
S
Dudek
R R
RR
Akiyama
K
K
Reichart
B
B
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D011817:Rabbits; D016277:Ventricular Function, Left
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D007550:Isothiuronium; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; D006152:Cyclic GMP