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Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein., (Copyright 2001 Academic Press.)

Interaction between locally released endothelin-1 (ET-1) and the endothelial ET(B)receptor could modulate pulmonary vascular tone. We evaluated pulmonary ET-1 clearance and ET-1-ET(B)receptor interaction in the modulation of pulmonary vascular tone. Controls and rats with Monocrotaline (MCT)-induced pulmonary hypertension (PH) were studied. Lungs were isolated and perfused under constant pressure. The effect of the selective ET(B)antagonist BQ-788 (10(-12)-10(-8)mole) on perfusion flow rate and(125)I-ET-1 extraction was determined. Baseline(125)I-ET-1 extraction was reduced from 62+/-5% in controls to 49+/-10% in PH (P=0.012). BQ-788 inhibited extraction with a higher half-inhibitory dose in the MCT group (-Log ID(50)= 8.9+/-0.4 vs. 9.5+/-0.1, P=0.03). BQ-788 induced a mild reduction in perfusion flow rate of 0.7+/-0.3 ml/min in controls. In the MCT group, this occurred at a lower dose and was more pronounced with a maximal reduction of 3.3+/-0.7 ml/min (P<0.01 vs. control). ET-1 was undetectable in the effluent at baseline but was present in similar concentrations in both groups after ET(B)blockade. Addition of 2 pg/ml ET-1 to lung perfusate did not modify pulmonary ET-1 clearance or the effect of BQ788 on perfusion flow rate in control lungs. In normal rat lungs, the ET(B)receptor plays a minor regulatory role on vascular tone. In MCT hypertension however, despite a reduction in ET(B)mediated extraction, luminal production of ET-1 attenuates the increase in pulmonary vascular tone., (Copyright 2000 Academic Press.)

The purpose of this study was to determine if endothelin-1 (ET-1) mediates endothelium-dependent enhancement of rat aortic contractility following exposure to hypoxia. Rats breathed room air or 10% oxygen for 12 or 48 h. Thoracic aortas and plasma were analysed for ET-1 content by radioimmunassay. Aortic rings were mounted in organ bath myographs for measurement of isometric tension during activation by phenylephrine (10(-9)-10(-4) M), in the presence and absence of BQ-123. In some rings, the endothelium was removed. Plasma ET-1 levels were 0.79+/-0.09 pg/ml, 2.00+/-0.36 and 1.88+/-0.21 pg/ml, in normoxic rats and rats exposed to hypoxia for 12 or 48 h respectively (P<0.001, 12 or 48 h vs. control). Aortic ET-1 concentrations were 202.3+/-20.8 fg/mg in normoxic rats, compared to 274.9+/-40.6 fg/mg and 292.4+/-24.4 fg/mg in rats exposed to hypoxia for 12 and 48 h, respectively (P<0.01, 12 or 48 h vs. control) and 155.0+/-43.1 fg/mg in de-endothelialized aortas from rats exposed to hypoxia for 48 h (P>0.05 vs. normoxic controls). Maximum tension during phenylephrine-induced contraction was 0.46+/-0.04 mg/g and 0.33+/-0.03 mg/g in endothelialized rings from rats exposed to hypoxia for 48 h in the presence and absence of BQ-123, respectively (P<0.05 for difference), and 0.28+/-0.07 mg/g in rings in which the endothelium had been removed. Local endothelin release is an important mechanism by which the responsiveness of the systemic vasculature to agonists may be preserved during hypoxia., (Copyright 1998 Academic Press.)