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 regulatio n of blood flow. iNOS, the dominant enzyme in heart muscle during myoc ardial infarction, allograft rejection, and cardiomyopathy, is activat ed in macrophages. We recently described a significant increase of iNO S activity in macrophages of infarcted rabbit myocardium 24 hours afte r coronary occlusion, with peak activity occurring 3 days following co ronary artery ligation. Inhibitors of NOS are L-arginine derivatives t hat inhibit both cNOS and iNOS; S-methylisothiourea (SMT) and aminogua nidine (AMG) are specific inhibitors of iNOS. Cyclosporin A and dexame thasone inhibit by interfering with protein synthesis. iNOS inhibition by SMT, N-G-nitro-L-arginine (L-NNA), AMG, cyclosporin A and dexameth asone was examined in homogenates of normal, risk and infarcted myocar dium, Three days after coronary artery ligation, the heart was excised and divided into normal, risk and infarcted regions. The inhibitory e ffect was calculated as IC50. Results shows that SMT was the most pote nt inhibitor with the lowest IC50; its effect, as well as the effects of L-NNA and AMG, depended on the location in the myocardium. Inhibiti on 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 gr adual decline in the area of risk and infarction. No inhibitory effect s in cyclosporin A and dexamethasone were noted.