S. Rosenkranz et al., CARDIAC ANGIOTENSIN-II RECEPTORS - STUDIES ON FUNCTIONAL COUPLING IN SPRAGUE-DAWLEY RATS AND TGR(ALPHA-MHC-HAT(1)) TRANSGENIC RATS, European journal of pharmacology, 330(1), 1997, pp. 35-46
The renin-angiotensin system plays an important role in the pathogenes
is of cardiac hypertrophy and chronic heart failure as angiotensin II
has been shown to induce cardiac hypertrophy and fibrosis. Besides the
se structural alterations, functional effects on cardiomyocytes have b
een reported in different mammalian species. Angiotensin II is known t
o produce a positive inotropic effect in some species, and differences
in atrial and ventricular myocardium have been described. So far, the
molecular events which govern angiotensin II-mediated changes in card
iac contractility are not completely understood. In order to study the
dependency of the angiotensin II-induced positive inotropic effect on
receptor density, we examined the effect of angiotensin II on cardiac
function in atria, papillary muscles and isolated ventricular cardiom
yocytes from adult Sprague-Dawley rats and TGR(alpha MHC-hAT(1)) trans
genic rats, which expressed the human angiotensin AT(1) receptor (hAT(
1)) specifically in the heart. In atrial myocardium from adult Sprague
-Dawley rats, angiotensin II (30 mu mol/l) produced an AT(1)-mediated
positive inotropic effect (38.5% of control), whereas in papillary mus
cles and isolated ventricular myocytes, no inotropic response was obse
rved. As shown by polymerase chain reaction (PCR) and radioligand bind
ing, the human angiotensin AT(1) receptor was exclusively expressed in
transgenic animals, which markedly overexpressed the angiotensin AT(1
) receptor. However, in transgenic rats the positive inotropic effect
in atrial preparations was similar to the controls, and neither in pap
illary muscles nor in isolated cardiomyocytes the increase in receptor
density led to an inotropic effect induced by angiotensin II. These d
ata suggest that the existence of functionally uncoupled receptors rat
her than the low density of receptors at the ventricular site is respo
nsible for the inability of ventricular myocardium to respond to angio
tensin II. (C) 1997 Elsevier Science B.V.