Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene.

Abstract

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%, N umerous genetic rat models of hypertension show abnormalities of the renin-angiotensin system. 1 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. 2TG 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.2 -3 The finding of exaggerated natriuresis both in hypertensive patients with low plasma renin activity but high aldosterone concentrations 4 and in TG rats 5 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 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 trans...

Enalapril and Pressure-Diuresis in Hypertensive Rats Transgenic for Mouse Renin Gene

“…We and oth ers have previously found similar glomerular filtration rates in TGR(mRen2)27 and Hannover Sprague-Dawley rats [7,12]. The ability of EL to lower blood pressure and alter pressure-diuresis-natriuresis responses of both CON and TGR rats could relate to differences in experimental conditions that favored fluid retention and enhanced angiotensin II (Ang II) production during the present study.…”

Roles of AT 1 and AT 2 Receptors in the Hypertensive Ren -2 Gene Transgenic Rat Kidney

“…These observations are in good agreement with previous studies in the contralateral kidney of 2-kidney, 1 clip Goldblatt hypertensive rats 26 and in the kidney of TGR rats, in which antidiuresis and antinatriuresis occurred, or GFR fell, after captopril or losartan treatment. 4,27 Because GFR and sodium and water excretion fell in parallel with a marked fall in MAP, these effects were most likely pressure-dependent in TGR rats. 5,9 Similarly, the observed higher basal renal hemodynamic and excretory function in TGR rats than in SD rats (Table) was also probably the result of severe hypertension and increased renal perfusion pressure.…”

Acute Effects of Cyclooxygenase-2 Inhibition on Renal Function in Heterozygous Ren-2-Transgenic Rats on Normal or Low Sodium Intake

“…Although hypertension that occurs in this model is clearly a result of insertion of the mouse Ren-2 renin gene into the genome of the Hannover Sprague-Dawley (HanSD) rat, the exact pathophysiological mechanism responsible for the development of hypertension remains unknown [1]. Previous studies have implicated that the hypertension in TGR is angiotensin II (ANG II) dependent and that activation of the ANG II receptor subtype 1 is mainly responsible for the development of hypertension in this model [2][3][4][5]. However, it has been recently found that plasma and kidney ANG II concentrations are not elevated during the prehypertensive phase and during the developmental phase of hypertension in TGR [6].…”