Adverse Interactions Between Pregnancy and a New Model of Systemic Hypertension Produced by Chronic Blockade of Endothelial Derived Relaxing Factor (EDRF) in the Rat

Abstract

Chronic blockade of the endogenous EDRF system has previously been reported to produce a model of hypertension and renal damage in rats. chronically catheterized rats to compare the renal hemodynamic and blood pressure responses to pregnancy in normal rats and during chronic EDRF blockade. produced by EDRF blockade, the normal late gestational fall in blood pressure is absent and blood pressure remains elevated at term. There was no midterm renal vasodilation or increase in GFR in the chronically hypertensive rats, also proteinuria developed close to term in hypertensive animals. The normal pregnant rat shows a marked plasma volume expansion as evidenced by significant falls in hematocrit close to term. This was suppressed in the hypertensive animals, particularly in the more severely hypertensive group. The chronically EDRF blocked hypertensive animals had a relatively poor maternal and fetal outcome compared to normal rats. The present studies were conducted in consciousIn both moderate and severe hypertension INTRODUCTION Pregnancies complicated by hypertension carry an increased risk of maternal and fetal morbidity and mortality and when under-117 Copyright 0 1992 by Marcel Dekker, Inc. Hypertens Pregnancy Downloaded from informahealthcare.com by University of Otago on 07/23/15 For personal use only.

Animal models of preeclampsia

“…The chronically NOS-inhibited pregnant rat also exhibited renal vasoconstriction leading to a decrease in GFR (Fig. 1), proteinuria, suppression of the normal volume expansion, and increased maternal and fetal morbidity and mortality 46 in a pattern that resembled preeclampsia. Many subsequent studies confirmed our initial observations.…”

“…55 In particular, studies from the laboratory of Conrad strongly suggested a primary role for NOmediated renal vasodilation that is signaled by the ovarian hormone relaxin and requires activation of the endothelin type B receptor. 56,57 Our original studies reported that NO was necessary for the midterm renal vasodilation of pregnancy, 46 although a recent publication by Danielson and Conrad 58 suggested that vasodilatory prostaglandins can be recruited to compensate and maintain the midterm increase in GFR despite chronic NOS inhibition. This suggestion raised the issue of completeness of NOS inhibition and we recently repeated the studies of Danielson and Conrad 58 but used a larger dose of NOS inhibitor, given for a longer duration, 59 and found that the midterm increase in GFR was prevented completely and acute administration of the cyclooxygenase inhibitor indomethacin produced insignificant further renal vasoconstriction.…”

Impact of Pregnancy on Underlying Renal Disease

“…Danielson and Conrad 24 have reported that low-level, acute (nonselective) NOS inhibition can reverse the pregnancy-induced rise in GFR without affecting the value in nonpregnant rats. We reported that chronic nonselective NOS inhibition prevents the gestational rise in GFR and the renal vasodilation 25 (Fig 4) and causes systemic hypertension. According to our in vivo and in vitro studies, the NOS isoform responsible has characteristics of both nNOS and iNOS.…”

“…□A difference between normal midterm or late pregnant rats versus rats receiving chronic NOS inhibition. (Data from 25 .) Impact of pregnancy on GFR during 10 pregnancies in 8 renal transplant recipients (lower curves ± 1 standard deviation).…”

“…In gentamicin-induced acute renal failure, the spontaneously hypertensive rat (SHR) and the rat subjected to chronic NOS inhibition, there is no midterm rise in GFR or renal vasodilation. 25,[42][43][44] Rats with the FX1A model of membranous glomerulonephritis (GN) respond to pregnancy with renal vasoconstriction by an unknown mechanism and GFR falls, but because the rise in RVR is localized at R A , the P GC actually goes down. 45 In this situation, pregnancy acutely impairs maternal renal function.…”