Pi. Mcconnell et al., Chronic endothelin blockade in dogs with pacing-induced heart failure: Possible modulation of sympathoexcitation, J CARD FAIL, 6(1), 2000, pp. 56-65
Background: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide elabora
ted by many cell types. Plasma ET-1 levels are significantly augmented in p
atients and experimental animals with heart failure. Enhanced levels of ET-
1 may contribute to myocardial depression and alterations in sympathetic ne
rve activity in the setting of chronic heart failure. The effects of chroni
c blockade of endothelin A (ETA) receptors on the development and severity
of experimental heart failure and sympathoexcitation were evaluated in thes
e experiments using the specific ETA antagonist, PD156707.
Methods and Results: Four groups of conscious, chronically instrumented mon
grel dogs were administered either PD156707 (750 mg orally thrice daily) or
a placebo starting 1 day before ventricular pacing or a sham (nonpaced) pe
riod. Before pacing or the sham period, baseline hemodynamic and plasma nor
epinephrine (NE) measurements were made. Hemodynamic and NE measurements we
re made every 3 to 4 days for the next 28 days. All parameters were relativ
ely stable in nonpaced dogs administered placebo. Paced placebo dogs showed
classic hemodynamic and sympathoexcitatory changes indicative of heart fai
lure. Nonpaced dogs administered PD156707 showed a significant decrease in
mean arterial pressure and total peripheral resistance beginning 3 days aft
er drug administration. Myocardial function was not affected by PD156707 in
nonpaced dogs. In paced dogs, PD156707 also reduced arterial pressure and
peripheral resistance. Changes in myocardial function were small and insign
ificant. Paced dogs administered PD156707 showed an approximately 50% lower
increase in plasma NE level from days 10 to 24 compared with paced dogs ad
ministered placebo (941.8 +/- 122.8 vs 501.1 +/- 92.6 pg/mL at 17 days; P <
.01).
Conclusions: These data suggest that ET-1 contributes to the maintenance of
arterial pressure in both sham dogs and dogs paced into heart failure. ET-
1 does not appear to have a potent effect on inotropic state, but the data
strongly suggest that ET-1 may contribute to the progressive deterioration
of circulatory function in heart failure by mediating sympathoexcitation an
d enhancing plasma NE concentration.