Transgenic Rats With an Extra Renin Gene

We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hypertensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR(mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90% in the 6 hours after administration, whereas equally antihypertensive dsses of nitrendipine increased sodium excretion by approximately 100%. The antinatriuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%, Numerous genetic rat models of hypertension show abnormalities of the renin-angiotensin system. However, primary and secondary changes cannot be easily distinguished in these models, which makes it difficult to establish cause and effect. Transgenic (TG) rats carry an additional mouse renin gene [TGR(mRen-2)27]. They provide a new model of hypertension with a well-defined genetic background. TG rats are characterized by high transcription rates of the transgene in the adrenal glands, high plasma aldosterone concentrations, suppression of renal renin production, and low plasma renin activity.The finding of exaggerated natriuresis both in hypertensive patients with low plasma renin activity but high aldosterone concentrations and in TG rats suggests a clinical relevance for this new hypertension model. We therefore investigated the renal effects of antihypertensive drugs with both renin-angiotensin system-dependent and renin-angiotensin system-independent mechanisms of action in TG rats. In particular, we compared the antihypertensive and renal sodium handling effects of the angiotensin-converting enzyme inhibitor captopril and the calcium antagonist nitrendipine in TG rats. Nitrendipine was chosen because its vasodilator action is independent of the renin-angiotensin system. Both angiotensin-converting enzyme inhibitors and calcium Received August 2, 1993; accepted in revised form February 9, 1994. From the Institut fur Herzkreislauf-und Arterioskleroseforschung, Bayer AG, Wuppertal (C.H.-D., J.-P.S.), and the Franz Volhard Clinic, Rudolf Virchow University Hospital at the Max Delbruck Center for Molecular Medicine, Berlin-Buch (D.G., F.C.L.), FRG. Correspondence to Dr Claudia Hirth-Dietrich, Bayer AG, Institut fur Herzkreislauf-und Arterioskleroseforschung, D-42096 Wuppertal, Germany. and nitrendipine slightly increased sodium excretion. In control Sprague-Dawley rats the effects were opposite; namely, captopril tended to increase natriuresis, and nitrendipine caused a small but distinct decrease in sodium excretion. Intravenous captopril in anesthetized transgenic rats caused an antinatriuresis with a decrease in inulin clearance but not in Sprague-Dawley rats. To control for non-renin-related effects of captopril, we gave transgenic rats oral losartan. Losartan also decreased urinary sodium excretion. The results suggest a role for the renin-angiotensin system in the maintenance of glomerular filtration rate and sodium excretion in transgenic TGR(mRen-2)27 rats. (Hypertension. 1994^3:626-631.)