These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.
Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
Background Apelin-13 (APLN) through apelin receptor (APJ) exerts peripheral vasodilatory and potent positive inotropic effects. We examined the effects of exogenous intravenous infusion of APLN on left ventricular (LV) systolic function in dogs with heart failure (HF, LV ejection fraction, EF~30%). Methods and Results Studies were performed in 7 dogs with microembolization-induced HF. Each dog received an intravenous infusion of low dose and high dose APLN followed by washout period. LV end-diastolic volume (EDV), end-systolic volume (ESV) and LV EF were measured at specified time points. APLN protein level was determined in plasma at all time points. mRNA and protein levels of APLN and APJ in LV tissue were also measured in 7 normal (NL) and 7 heart failure (HF) dogs. APLN reduced EDV only at the high dose, significantly reduced ESV and increased EF with both doses. In plasma of HF dogs, APLN levels were reduced significantly compared to NL dogs. APLN treatment in HF dogs significantly increased the plasma APLN levels at both low and high doses. Expression of APLN, but not of APJ, was reduced in LV tissue of HF dogs compared to NL. Conclusion Exogenous administration of APLN improved LV systolic function in dogs with advanced HF.
1Previous studies suggested that endothelin-l (ET-1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ETA and ETB receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2 Anaesthetized male Wistar rats were subjected to 20 min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 ftm) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition.3 Bosentan, administered at a dose which virtually abolished the pressor response to big ET-1 (3 mg kg-', i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion-induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 ± 4, n = 10; bosentan: 60 ± 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium-dependent relaxations to acetylcholine (maximal response: sham: 59 + 4%, n = 9; ischaemia-reperfusion: 26± 6%, n = 8; P<0.01), characteristic of reperfusion-induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 ± 5%, n = 9; P<0.01 vs sham; P = NS vs ischaemia/ reperfusion). 4 These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion.
Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (AII) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA-ETB receptor antagonist bosentan or of the ETA antagonist BQ-123 in the absence or the presence of the AII receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan-pretreated rats, bosentan induced a marked, dose-dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control -3 +/- 3, losartan -32 +/- 6; cilazapril -28 +/- 3). Similarly, BQ-123 decreased blood pressure in losartan-pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1 receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.
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