Effects of ACE inhibition on myocardial interleukin-6 in rats with LV dysfunction

Abstract

Activation of pro-inflammatory cytokines such as interleukin-6 (IL-6) has been implicated in the pathogenesis of cardiovascular disease, and its modulation has been proposed as a potential therapeutic target. Furthermore, ACE inhibition has been shown to have inhibitory effects on cytokine production in vitro. However, the role of cytokines as a target for ACE inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibition may modulate myocardial IL-6 in rats with left ventricular (LV) dysfunction, we studied the effects of chronic treatment with ramipril on myocardial interleukin-6 in rats with catecholamine induced cardiomyopathy (CMP). Following the administration of isoproterenol (ISO; 225 mg/kg BW sc.) rats were treated with tap water (CMP; n = 8) or with ramipril (10 mg/kg BW/d po., n = 8) for 2 weeks; healthy rats served as controls (n = 8; CTRL). Histomorphological characterization of CMP hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Echocardiographically, ISO induced an increase of LV enddiastolic diameter (5.9 ± .2 v 5.1 ± .2 mm; p < .05), which was attenuated by treatment with ramipril (5.2 ± .2 mm; p < .05 v CMP). Furthermore, LV enddiastolic pressure was markedly increased in CMP rats (12 ± 2 v 3 ± 2 mmHg of CTRL; p < .05) and normalized following ramipril (5 ± 3 mm Hg, ns. v CTRL). Measurements of LV myocardial IL-6 (ELISA) revealed a significant increase in rats with CMP as compared to CTRL (6898 ± 355 vs. 3436 ± 432 pg/mg protein, p < .05). ACE inhibition by ramipril strongly suppressed myocardial IL-6 in rats with catecholamine induced CMP (3073 ± 366 pg/mg protein, p < .05 vs. CMP). Therefore, modulatory effects of ACE inhibitors on myocardial cytokines may also contribute to their overall therapeutic efficacy in the treatment of cardiovascular disease.