Down-regulation of aortic and cardiac AT₁ receptor gene expression in transgenic (mRen-2) 27 rats

Abstract

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 B_max in the left atrium was 1.3±0.08 fmol mg⁻¹ protein in control rats (K_D 1.1±0.18 nmol l⁻¹) and 0.94±0.15 fmol mg⁻¹ protein (K_D 2.1±0.3 nmol l⁻¹. In the aorta B_max values were 15.1±0.5 fmol mg⁻¹ protein (K_D 1.9±0.27 nmol l⁻¹) for control rats and 11.3±0.76 fmol mg⁻¹ protein (K_D 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.

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