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 tr ansduction pathways have been unclear in congestive heart failure (CHF). Th erefore the objects of this study are, in CHF, whether production of ET-1 i s 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, TAK0 44 (3 mg/kg plus 3 mg/kg/h I.V.) were examined in both groups by a conducta nce catheter and a micromanometer. After 4 weeks of pacing, plasma and card iac 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 volum e and a decrease in total systemic resistance; heart rate was unchanged. Th e time constant of left ventricular (LV) relaxation was significantly decre ased. The slope of LV end-systolic pressure-volume relation (E-ES) was incr eased (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 response s 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 end ogenous ET-1 in CHF may be unaffected by ANG II acting through AT1 receptor s.