Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats.
The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to 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 cardiac 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 cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.
Rosenkranz
S
S
Klinik III für Innere Medizin der Universität zu Köln, Lindethal, Germany.
Nickenig
G
G
Flesch
M
M
Cremers
B
B
Schnabel
P
P
Lenz
O
O
Krause
T
T
Ganten
D
D
Hoffmann
S
S
Böhm
M
M
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D016275:Atrial Function; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000502:physiology; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000302:isolation & purification; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D015059:1-Sarcosine-8-Isoleucine Angiotensin II