Relaxin is a potent renal vasodilator in conscious rats

Abstract

The hormone relaxin (RLX) has a molecular weight of approximately 5,000-6,000 and is a member of the insulin-growth factor family. In humans and rats, the ovary is the major, if not sole, source of circulating RLX. In pregnant rats, RLX promotes growth and softening of the cervix and vagina, promotes growth of the mammary nipples, and inhibits spontaneous uterine contractility (reviewed in ref. 1).During early pregnancy in humans, rats, and other mammals, vasodilation of nonreproductive organs leads to a marked decline in total peripheral vascular resistance (2). The kidneys contribute to this fall in peripheral resistance; a nadir in renal vascular resistance and a reciprocal peak in renal blood flow and glomerular filtration rate of 40%-80% above nonpregnant levels are reached by the end of the first trimester in women (reviewed in ref.3). Maximal changes, albeit of a lesser magnitude (20%-40% from nonpregnant levels), are observed in the renal circulation of conscious rats by gestational day 12 (3).The "pregnancy hormones" that cause renal vasodilation and hyperfiltration have not been identified. For several reasons, we hypothesized that RLX contributes. First, the plasma concentration of RLX increases rapidly after conception in women (reviewed in ref. 1), corresponding with the marked increase in both glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during the first trimester (3). The stimulus for secretion of RLX by the corpus luteum is human chorionic gonadotrophin (hCG), which rises in parallel (1). Second, circulating RLX also increases during the luteal phase of the menstrual cycle (1, 4-6), coinciding with a transient 20% increase in GFR and ERPF (7-12). Third, the gestational rise in RLX corresponds with another early physiological adaptation in human pregnancy, namely, osmoregulatory changes (13). Chronic administration of recombinant human RLX 2 (rhRLX) to ovariectomized rats reduced plasma osmolality and the osmotic threshold for arginine vasopressin release to levels comparable to the gravid condition (14). Fourth, the osmoregulatory changes of pregnancy were mimicked by administering hCG to women in the luteal phase of the menstrual cycle and intact female rats, but not to men or ovariectomized rats, suggesting the intermediary role of an ovarian hormone (15-17). Associated with the osmoregulatory changes observed in women after administration of hCG was a 15%-20% rise in GFR, which again was not observed in men administered the hormone (Davison, J.M., personal communication). Fifth, although renal vasodilation and hyperfiltration are observed in gravid rats as early as day 5 of gestation, before detectable increases in ovarian and plasma RLX occur, there is a marked jump in GFR and ERPF between gestational days 8 and 12 (18) Received for publication October 27, 1998, and accepted in revised form January 4, 1999. Relaxin is a potent renal vasodilator in conscious ratsThe kidneys and other nonreproductive organs vasodilate during early gestation; however, the "pregnancy h...

New Aspects in the Pathophysiology of Preeclampsia

“…This renal vasodilatory effect does not require the presence of the ovaries (25) and is also observed during relaxin administration to male rats (26). Relaxin administration to nonpregnant female rats also diminishes the renal vasoconstrictor response to angiotensin II, similar to the dampening influence of rat gestation (25,27,28). Moreover, reduced myogenic reactivity of small renal arteries is observed after relaxin administration, analogous to vessels isolated from midterm pregnant rats (29,30).…”

“…Chronic administration of relaxin to conscious female rats increases GFR and effective renal plasma flow, thereby mimicking the changes in the renal circulation during pregnancy (24,25). This renal vasodilatory effect does not require the presence of the ovaries (25) and is also observed during relaxin administration to male rats (26). Relaxin administration to nonpregnant female rats also diminishes the renal vasoconstrictor response to angiotensin II, similar to the dampening influence of rat gestation (25,27,28).…”

“…Human chorionic gonadotrophin produced by the placenta is a major stimulus for relaxin secretion during pregnancy in women. Chronic administration of relaxin to conscious female rats increases GFR and effective renal plasma flow, thereby mimicking the changes in the renal circulation during pregnancy (24,25). This renal vasodilatory effect does not require the presence of the ovaries (25) and is also observed during relaxin administration to male rats (26).…”

Impact of Pregnancy on Underlying Renal Disease

“…Relaxin release is stimulated by pregnancy (via chorionic gonadotrophin), and relaxin has a selective renal vasodilatory action in nonpregnant female rats that is NO dependent. 30 No direct link, however, has yet been established between relaxin and renal vasodilation in pregnancy.…”

“…Relaxin release is stimulated by pregnancy (via chorionic gonadotrophin), and relaxin has a selective renal vasodilatory action in nonpregnant female rats that is NO dependent. 30 No direct link, however, has yet been established between relaxin and renal vasodilation in pregnancy.In summary, the animal literature suggests that NO plays an important role in mediating the gestational rise in GFR, although there are no data currently available in normal women. Whether or not defects in the renal NO system are involved in situations in which pregnancy has an adverse effect on renal function also remains to be determined.…”