Xl. Qi et al., Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: Effects of chronic quinapril, J MOL CEL C, 33(11), 2001, pp. 2023-2035
Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased
in congestive heart failure (CHF). In order to determine whether this resu
lts in increased responsiveness of ET-A or ET-B receptors to ET-1, we evalu
ated the contractile effects of ET-1 in isolated papillary muscles isolated
from hearts of control rats and from rats 4 weeks post myocardial infarcti
on (MI) having received no therapy or chronic quinapril therapy, The ET-1 d
ose-response was biphasic in normal muscles. The use of the selective ET-A
receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788
revealed that the initial decrease in tension was the result of ET-B recept
or stimulation. Blockade of nitric oxide (NO) production with L-NAME abolis
hed the initial decrease in tension. MI resulted in CHF that was partially
reversed by quinapril. In MI, the positive inotropic effects of ET-1 were e
nhanced due to the loss of the initial ET-B receptor mediated decrease in t
ension, as well as an increase in the positive inotropic effects of ET-A re
ceptors. This was associated with an increase in ET-A and ET-B receptor mRN
A and a decrease in cardiac ecNOS protein. Four weeks of therapy with quina
pril attenuated the positive inotropic effects of ET-1 and prevented the in
crease in ET-A receptor mRNA. Although quinapril did not restore the effect
s of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did
restore cardiac ecNOS protein expression. Thus, the inotropic response to
ET-1 is biphasic due to an overall positive inotropic effect of ET-A recept
or stimulation and an ET-B receptor mediated decrease in contractility at l
ow ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO).
In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B med
iated negative inotropic response is lost despite an increase in both recep
tor subtypes. Quinapril therapy attenuates these effects and normalises car
diac ecNOS protein. (C) 2001 Academic Press.