Abstract 1620: Endothelin-1 Increases Myocardial Distensibility through Nitric Oxide and Prostaglandins Release
Endothelin-1 (ET-1) increases myocardial distensibility in conditions of cardiac overload, an effect that is mediated by ETA receptors and modulated by the endocardial endothelium (EE). The present study investigated the role of nitric oxide (NO) and prostaglandins on ET-1 induced diastolic distensibility. The effects of ET-1 (0.1, 1, 10 nM) were tested in papillary muscles from New Zealand white rabbits (Krebs-Ringer; 1.8mM CaCl2, 35°C) in the presence of: (i) intact endocardial endothelium (EE) (n=9); (ii) damaged EE (n=10); (iii) NG-Nitro-L-Arginine (LNA; nitric oxide synthase inhibitor, n=9), and (iv) Indomethacin (INDO; cyclooxigenase inhibitor, n=6). In papillary muscles with intact EE, ET-1 induced dose-dependent positive inotropic and lusitropic effects, which were maintained when ET-1 was given after damaging EE, in the presence of LNA or in the presence of INDO. The highest concentration of ET-1 increased: 88.6±18.3% active tension (AT), 103.7±21.5% maximum velocity of tension rise (dT/dtmax) and 85.6±16.9% maximum velocity of tension decline (dT/dtmin) in muscles with intact EE; 74.1±12.5% AT, 97.7±13.5% dT/dtmax and 60.0±14.4% dT/dtmin after damaging EE; 84.3±19.3% AT, 126.7±16.6% dT/dtmax and 69.8±24.8% dT/dtmin in the presence of LNA and 87.6±33.0% AT, 109.6±40.0 dT/dtmax and 87.7±40.0% dT/dtmin in the presence of INDO. When muscles were overloaded from an isotonic to an isometric twitch, ET-1 reduced resting tension (increased diastolic distensibility) by 3.2±1.3%, 6.0±1.6% and 8.8±2.7% (at 0.1, 1 and 10 nM, respectively) in muscles with intact EE, effect that was abolished after damaging EE or in the presence of LNA or INDO. This study demonstrated that the increase in myocardial distensibility induced by ET-1 is dependent of nitric oxide and prostaglandins release. As this increase in diastolic distensibility might contribute to ventricular dilation, these findings might improve our understanding about the role of ET-1 and endothelial dysfunction in the pathophysiology of heart failure.