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Am J Physiol Renal Physiol 276: F767-F776, 1999;
0363-6127/99 $5.00
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Vol. 276, Issue 5, F767-F776, May 1999

Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats

Kirk P. Conrad1, Robin E. Gandley1, Tatsuhiro Ogawa2, Satoshi Nakanishi2, and Lee A. Danielson3

1 Departments of Obstetrics, Gynecology and Reproductive Sciences, and of Cell Biology and Physiology, University of Pittsburgh, and Magee-Womens Research Institute, Pittsburgh, Pennsylvania 15213; 2 Kyowa Hakko Kogyo, Tokyo Research Laboratories, Tokyo 194-8533, Japan; and 3 Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131

Profound vasodilation of the kidneys and other nonreproductive organs transpires during early pregnancy. Because nitric oxide (NO) was found to mediate renal vasodilation and hyperfiltration in conscious pregnant rats, and endogenous endothelin (ET) was suggested to be vasodilatory in the renal circulation of nonpregnant rats, we tested whether endothelin mediates the NO-dependent changes in the renal circulation during pregnancy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in conscious pregnant and virgin rats before and during infusion of 30 µg/min RES-701-1 (a selective ETB receptor subtype antagonist). Baseline GFR and ERPF were significantly increased by 35% in gravid rats relative to virgin controls. During infusion of RES-701-1, the pregnant rats responded more robustly, showing a greater decline in both GFR and ERPF such that renal function converged in the two groups of rats. ERPF also converged in pregnant and virgin rats during infusion of SB-209760, a nonselective ETA/B receptor subtype antagonist. Combined infusion of Nomega -nitro-L-arginine methyl ester [L-NAME, an NO synthase (NOS) inhibitor] and RES-701-1 reduced GFR and ERPF to levels comparable to those reached with either agent given alone, suggesting inhibition of a common vasodilatory pathway. RES-701-1 and SB-209670 significantly lowered the cGMP content of small renal arteries from gravid and virgin rats in vitro, strengthening the link between the renal endothelial ETB receptor subtype and NO. Importantly, we showed that RES-701-1 is not a direct inhibitor of NOS. We conclude that endothelin mediates the NO-dependent changes in the renal circulation of conscious rats during pregnancy.

nitric oxide; Nomega -nitro-L-arginine methyl ester; guanosine 3',5'-cyclic monophosphate; endothelin receptors; RES-701-1; SB-209670; glomerular filtration; renal circulation; small renal arteries


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