EFFECT OF CAPTOPRIL AND ANGIOTENSIN-II RECEPTOR BLOCKADE ON PRESSURE NATRIURESIS IN TRANSGENIC TGR(MREN-2)27 RATS

The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4+/-1.2 to 10.1+/-0.5 mu mol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1+/-0.7 to 4.4+/-0.5 mL/min per gram kidney weight and increased (P<.05) with both captopril and CV 11974 to ranges from 4.8+/-0.9 to 6.8+/-0.6 or from 4.5+/-0.7 to 6.9+/-1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis. These results suggest that the hypertensive, rightward shift in the transgenic pressure-natriuresis curve is largely due to angiotensin II-dependent renal effects. Altered renal structure may also play a role in shifting the renal function curve rightward.