ET-1 vasoconstricts in the skin microcirculation and it appears that endothelin converting enzyme (ECE) activity is present as big ET-1 also vasoconstricts. ECE and neutral endopeptidase (NEP) blockade both cause vasodilatation suggesting skin basal resting ET tone. ET-1 _(1-31) is also a vasoconstrictor in the skin microcirculation. Plasma concentrations of ET-1_(1-31) are not elevated in patients with CHF. ET_ARA improves systemic haemodynamics in patients with CHF while concomitant ET_BRA attenuates this effect. In the isolated human myocardium ET is positively inotropic but there is no resting ET inotropy with no effect on basal twitch force with ETRA. In addition, ET attenuates beta-adrenergic activation in isolated human myocardium. In hypercholesterolaemia, forearm vascular effects are similar to those previously reported in healthy volunteers. Treatment with statin therapy for 8 weeks caused a trend towards an increase in ET_A mediated vasodilatation. Conclusions: The novel finding that ET_(1-31) is a vasoconstrictor in the skin microcirculation may represent a novel pathway of ET production. The haemodynamic benefits of selective ET_ARA over dual ET_A/BRA is a unique finding with considerable importance and supports the development of selective ET_ARAs as clinical therapies in CHF. The finding of antagonism between the ET system and the beta-adrenergic stimulation may represent a protective adaptation in conditions where there beta-adrenergic stimulation is detrimental and there is activation of the ET system, such as CHF.