Functional role of endogenous endothelin-1 in congestive heart failure treated with angiotensin II receptor antagonist

Interactions between angiotensin (ANG) II and endothelin (ET)-1 receptor transduction pathways have been unclear in congestive heart failure (CHF). Therefore the objects of this study are, in CHF, whether production of ET-1 is modulated by ANG II and/or whether hemodynamic effects of endogenous ET-1 are modulated by ANG II. Twelve dogs were randomly assigned to two groups: untreated (n=6) and treated with ANG II type 1 (AT1) receptor antagonist (TCV116, 1.5 mg/kg/d) (n=6). After rapid ventricular pacing (240 bpm) for 4 weeks, plasma and cardiac ET-1 levels were compared between the two groups. Acute hemodynamic effects of a nonspecific ETA&B receptor antagonist, TAK044 (3 mg/kg plus 3 mg/kg/h I.V.) were examined in both groups by a conductance catheter and a micromanometer. After 4 weeks of pacing, plasma and cardiac tissue ET-1 levels were elevated in both groups to a similar degree. In the group treated with TCV116, TAK044 produced an increase in stroke volume and a decrease in total systemic resistance; heart rate was unchanged. The time constant of left ventricular (LV) relaxation was significantly decreased. The slope of LV end-systolic pressure-volume relation (E-ES) was increased (p <0.05), indicating an increased LV contractility. Thus endogenous ET-1 produces an arterial vasoconstriction and impairs LV contractility and relaxation in CHF with AT1 receptor antagonism. These hemodynamic responses to TAK044 in CHF treated with TCV116 were similar in untreated CHF. These results suggest that the production of ET-1 and the cardiac effects of endogenous ET-1 in CHF may be unaffected by ANG II acting through AT1 receptors.