Endothelin-1 (ET-1) is considered to be involved in the development and progression of heart failure. Therefore, we analysed the expression of endothelin-converting enzyme-1 (ECE-1), endothelin receptors A (ET A ) and B (ET B ) mRNAs by standard-calibrated, competitive reverse transcriptase-PCR using an internal-deleted in vitro -transcribed cRNA standard. ET-1 peptide levels were measured using isoform-specific rabbit antibodies against synthetic ET-1. mRNA and protein expression was determined in the right atrial myocardium of New York Heart Association class I patients and class IV patients undergoing aorto-coronary bypass surgery. ECE-1 mRNA was upregulated in failing atrial myocardium. Furthermore, ET-1 peptide levels were increased in failing atrial myocardium. Atrial ET A mRNA expression was not changed, while ET B mRNA was downregulated in the failing atrial myocardium. Our results support an upregulation of ET-1 synthesis by induction of ECE-1 in failing atrial myocardium. Pharmacological inhibition of augmented ECE-1 expression might provide a new therapeutic perspective in the treatment of heart failure.

This study investigated vascular reactivity in response to acetylcholine, in the presence of acute inhibition of nitric oxide synthase, in the carotid artery and aorta of obese C57Bl6/J mice fed on a high-fat diet for 30 weeks, and of control mice. A subgroup of obese animals was also treated with the ET A receptor antagonist darusentan (50mg·kg -1 ·day -1 ). In vascular rings from control animals, acetylcholine caused endothelium-dependent contractions in the carotid artery, but not in the aorta. In vascular rings from obese mice, contractility to acetylcholine was also evident in the aorta, and that in the carotid artery was increased compared with control mice. ET A receptor blockade by darusentan treatment of the obese mice prevented enhanced vasoconstriction to acetylcholine, resulting in mild vasodilatation. Thus obesity increases endothelium-dependent vasoconstriction in the absence of endothelial nitric oxide. This effect can be completely prevented by chronic ET A receptor blockade, suggesting that endothelin modulates increased endothelium-dependent vasoconstriction in obesity.

Chagas' disease is caused by the intracellular protozoan Trypanosoma cruzi . Here we have investigated the role of endothelin-1 in T. cruzi acute infection in rats, using the orally active ET A receptor antagonist BSF-461314. Treatment with BSF-461314 markedly increased parasitaemia, but animals managed to control the infection by day 15. Histopathological analysis of heart tissue at the end of the acute phase showed greater numbers of parasite nests in BSF-461314-treated animals. The perfusion of isolated rat hearts from infected animals with bradykinin failed to induce an increase, and actually reduced, coronary blood flow. Pretreatment with BSF-461314 prevented changes in coronary flow induced by T. cruzi infection. Together these results demonstrate that endothelin-1, through ET A receptor activation, contributes to the protective immune response against acute T. cruzi infection. Moreover, these data suggest that endothelin-1 is a mediator of impaired endothelium-dependent vasomotion in the coronary microcirculation associated with acute T. cruzi infection.

In this study, we investigated the short-term effect of 17β-oestradiol on functional enzyme activity (FEA) of endothelin-converting enzymes in vitro using human internal mammary arteries ( n = 7–8) and human saphenous veins ( n = 16–17) obtained from patients undergoing coronary artery bypass graft surgery. Vascular rings were preincubated with either solvent control (0.2% ethanol) or 17β-oestradiol (1 µ M) for 30min and concentration–response curves to big ET-1 (0.1–100nM) or ET-1 (0.1–100nM) were performed. FEA for each concentration was calculated as the percentage activity [(contraction to big ET-1/contraction to ET-1)×100] normalized to KCl (100mM). In control experiments, at low concentrations FEA was lower in internal mammary arteries than in saphenous veins ( P <0.05). While FEA was suppressed in saphenous veins by 10nM (4±1 versus 22±5%, P <0.01) and 30nM (26±4 versus 48±7%, P <0.05) 17β-oestradiol, FEA was markedly enhanced in internal mammary arteries by 10nM (33±12 versus 1±1%, P <0.001) and 30nM (44±12 versus 8±3%, P <0.01) 17β-oestradiol . FEA was not affected by 100nM 17β-oestradiol. These results demonstrate for the first time that short-term exposure to 17β-oestradiol affects FEA in vitro . Human internal mammary arteries have lower FEA than the saphenous veins, but FEA is differentially affected by acute exposure to 17β-oestradiol in human arteries and veins. Whether changes in FEA play a role in the vascular effects of 17β-oestradiol in vivo remains to be determined.