Efeitos agudos e crônicos do carvedilol após o infarto do miocárdio em ratos

Abstract

The present study sought to evaluate the acute and chronic effects of carvedilol in post-infarct left ventricular (LV) remodeling in rats. Male Wistar rats (8-9 weeks) were infarcted by left main coronary occlusion. Twenty-four hours later, animals were assigned to receive carvedilol (IM-CARV; 20 mg/kg/day, gavage) or vehicle (IMPLAC; metilcelulose 0.5%). On the third and on the 28Th day, cardiac function was assessed by LV catheterism. In addition, in situ LV pressure-volume relationship was obtained using a double-lumen catheter. A sub-sample was selected and submitted to progressive maximal exercise tolerance test on a treadmill. Angiotensin converting enzyme (ACE) activity assay was done in plasma and LV fragments, and western blots were performed to detect AT1 and AT2 protein expressions. Collagen volume fraction and myocyte cross sectional area were evaluated in transversal slices of LV. Data are depicted as mean ± standard error of mean. Infarct area (3 days) and extension (28 days) were similar between infarcted groups. Maximal exercise tolerance was reduced after infarction, and improved after carvedilol treatment (IMPLAC= 11.9±1, IM-CARV= 17.3±1 min). Four weeks after coronary occlusion, LV end-diastolic pressure (SO= 7±1, IM-PLAC= 20±2, IM-CARV= 12±3 mmHg, P < 0,05) and LV dilation (SO= 10.5±1.2, IM-PLAC= 4.4±0.6, IM-CARV= 6.3±1 mmHg/ml.kg1 ) were increased as compared to SHAM group, and carvedilol partially reverted these parameters. Interstitial collagen volume fraction and myocyte cross sectional area were increased after infarction. However, carvedilol reduced fibrosis proliferation (SO= 1.8±0.3, IM-PLAC= 7.1±0.5, IM-CARV= 5.4±0.5 %) in the viable tissue without alteration in the myocyte cross sectional area (SO= 393.1±16, IM-PLAC= 574.2±14.5, IM-CARV= 562.9±11.6 %). ACE activity was increased in the LV without alteration in its plasmatic activity after infarction, and it was blocked by carvedilol (SO= 43.5±2.6, IM-CONT= 51.1±1.85, IM-CARV= 37.1±2.5 nmol/mg/min). Moreover, AT1 and AT2 protein expressions were increased in the LV after infarction. Carvedilol blocked the increased AT1 expression, but did not alter AT2 expression. In conclusion, carvedilol was related to better cardiac function, reduced LV dilation and improved exercise tolerance in post-infarction heart failure rats, with decreased ACE activity and AT1 expression in the LV. These changes were associated with higher post-infarction survival.