Down-regulation of aortic and cardiac AT1 receptor gene expression in transgenic (mRen-2) 27 rats.
1. Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT1 receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological effects of angiotensin II and the regulation of the AT1 receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals. 2. Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic effect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT1 receptor activation in the left atrium of control rats to a significant contraction (130 +/- 5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT1 receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39 +/- 0.2 mN mg-1 wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2 +/- 0.02 mN mg-1 wet weight). 3. These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT1 receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT1 receptor density Bmax in the left atrium was 1.3 +/- 0.08 fmol mg-1 protein in control rats (KD 1.1 +/- 0.18 nmol l-1) and 0.94 +/- 0.15 fmol mg-1 protein (KD 2.1 +/- 0.3 nmol l-1. In the aorta Bmax values were 15.1 +/- 0.5 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for control rats and 11.3 +/- 0.76 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for the TGR(mRen-2)27 rats AT1 receptor mRNA was reduced in the transgenic animals to 46 +/- 3% in the left atrium, 50 +/- 11% in the left ventricle and 40 +/- 3% in the aorta, respectively. 4. Together, the AT1 receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.
Nickenig
G
G
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Laufs
U
U
Schnabel
P
P
Knorr
A
A
Paul
M
M
Böhm
M P
MP
D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics; D015536:Down-Regulation; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000209:etiology / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II