Inhibition of NOS2 ameliorates cardiac remodeling, improves heart function after myocardial infarction in rats

Abstract.

Objective:

Previous studies have shown increased expression of nitric oxide synthase 2 (NOS2) in rat heart several weeks after myocardial infarction (MI). The aim of this study was to examine the effect of chronic administration of S-methylisothurea (SMT), a selective NOS2 inhibitor, commenced one week after MI on hemodynamic parameters and left ventricular (LV) remodeling in rats.

Methods:

Rats with MI induced by left coronary ligation were given SMT (0.5 mg/kg/d) or saline by gavage starting one week after MI. After chronic administration for five weeks, hemodynamic and cardiac morphologic studies were performed, and lung water content, plasma NO_x concentration, NOS2 protein level, myocyte size and collagen volume fraction of noninfarct LV area were quantified.

Results:

The NO_x concentration in plasma and the NOS2 protein level in noninfarct myocardium in MI rats were higher than controls. When compared with the MI rats receiving saline, chronic administration of SMT reduced myocyte size (15.1 ± 1.6 µm vs 16.9 ± 2.3 µm, P < 0.05), collagen volume fraction of noninfarct LV area (4.4% ± 1.1% vs 5.7% ± 1.2%, P < 0.01) and lung water content (77.4% ± 1.4% vs 79.3% ± 0.9%, P < 0.01), without affecting infarct size. Administration of SMT had no significant effect on heart rate and mean arterial pressure, but decreased LV end-diastolic pressure (8.7 ± 2.1 mmHg vs 13.4 ± 3.1 mmHg, P < 0.01), central venous pressure (0.9 ± 0.3 mmHg vs 1.5 ± 0.5 mmHg, P < 0.01) and inner LV diameter (6.9 ± 0.3 mm vs 7.2 ± 0.3 mm, P < 0.05) in the MI rats. Plasma level of NO_x in the MI rats receiving SMT was reduced to control level.

Conclusions:

Chronic administration of SMT had beneficial effects on LV remodeling and cardiac dysfunction in MI rats, suggesting the possibility that inhibition of NOS2 could be a therapeutic tool for cardiac dysfunction after MI.