Effect of inhibitors of inducible form of nitric oxide synthase in infarcted heart muscle.
Nitric oxide (NO), an unstable radical, is synthesized from L-arginine by the constitutive (cNOS) and inducible (iNOS) forms of NOS. cNOS is present mainly in endothelial cells and plays a role in the regulation of blood flow. iNOS, the dominant enzyme in heart muscle during myocardial infarction, allograft rejection, and cardiomyopathy, is activated in macrophages. We recently described a significant increase of iNOS activity in macrophages of infarcted rabbit myocardium 24 hours after coronary occlusion, with peak activity occurring 3 days following coronary artery ligation. Inhibitors of NOS are L-arginine derivatives that inhibit both cNOS and iNOS; S-methylisothiourea (SMT) and aminoguanidine (AMG) are specific inhibitors of iNOS. Cyclosporin A and dexamethasone inhibit by interfering with protein synthesis. iNOS inhibition by SMT, NG-nitro-L-arginine (L-NNA), AMG, cyclosporin A and dexamethasone was examined in homogenates of normal, risk and infarcted myocardium. Three days after coronary artery ligation, the heart was excised and divided into normal, risk and infarcted regions. The inhibitory effect was calculated as IC50. Results shows that SMT was the most potent inhibitor with the lowest IC50; its effect, as well as the effects of L-NNA and AMG, depended on the location in the myocardium. Inhibition for SMT and AMG was greater in the normal area than in the risk and infarcted regions. AMG induced an initial rise of iNOS followed by gradual decline in the area of risk and infarction. No inhibitory effects in cyclosporin A and dexamethasone were noted.
Suzuki
H
H
Department of Experimental Cardiology, Huntington Medical Research Institutes, Pasadena, CA 91101, USA.
Wolf
W P
WP
Akiyama
K
K
Horstman
D
D
Grant
P
P
Cannavino
C
C
Bing
R J
RJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D011817:Rabbits
D004791:Enzyme Inhibitors; D006146:Guanidines; D019335:Nitroarginine; D007550:Isothiuronium; D003907:Dexamethasone; D016572:Cyclosporine; D001120:Arginine; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; C004479:pimagedine