H. Leskinen et al., COMBINED INHIBITION OF ENDOTHELIN AND ANGIOTENSIN-II RECEPTORS BLOCKSVOLUME LOAD-INDUCED CARDIAC HORMONE-RELEASE, Circulation research, 80(1), 1997, pp. 114-123
Volume expansion has been shown to increase plasma atrial natriuretic
peptide (ANP) levels, but the precise role of paracrine and autocrine
factors in stretch-induced cardiac hormone release is not clear. In th
e present study, we report the effects of endothelin (ET) and angioten
sin receptor (AT receptor) antagonists on baseline and atrial stretch-
induced immunoreactive ANP (IR-ANP) and immunoreactive N-terminal ANP
(IR-NT-ANP) release in vivo by using BQ-123 (ET(A) receptor antagonist
), bosentan (ET(A) and ET(B) receptor antagonist), and losartan (AT(1)
receptor antagonist). Intravenous administration of BQ-123 had no sig
nificant effect on baseline hemodynamics in conscious rats, whereas bo
sentan (10 mg/kg) and losartan (10 mg/kg) decreased slightly (4 to 7 m
m Hg, P<.05 to .001) the mean arterial pressure. Both the ET(A) recept
or antagonist BQ-123 and ET(A)/ET(B) receptor antagonist bosentan decr
eased plasma ANP and NT-ANP responses to volume load (P<.05 to .001),
whereas the ATI receptor antagonist losartan had no significant effect
on this response. The relative increase in plasma IR-ANP correspondin
g to a 3 mm Hg increase in right atrial pressure was 2.7-fold in the v
ehicle-treated group. BQ-123 (0.3 and 1.0 mg/kg) decreased this respon
se 2.5- and 2.1-fold (P<.05); bosentan (3 and 10 mg/kg), 1.7-fold (P<.
001) and 1.9-fold (P<.05); and bosentan (10 mg/kg)+losartan (10 mg/kg)
, 1.6-fold (P<.001). The responses in plasma IR-NT-ANP decreased simul
taneously. These results indicate that combined inhibition of ET(A/B)
and AT(1) receptors almost completely blocks ANP response to acute vol
ume load. Therefore, our study shows that endogenous paracrine and/or
autocrine factors liberated in response to atrial wall stretch rather
than myocyte stretch itself are responsible for the activation of ANP
peptide secretion in response to acute volume load. Our results also s
how that ET(A) receptors are more important in the regulation of mecha
nical stretch-induced changes in cardiac hormone secretion than AT(1)
receptors.