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

Conrad, Kirk P.; Gandley, Robin E.; Ogawa, Tatsuhiro; Nakanishi, Satoshi; Danielson, Lee A.

doi:10.1152/ajprenal.1999.276.5.f767

Cited by 62 publications

(68 citation statements)

References 34 publications

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“…Because RLX is a functional AngII antagonist in the vasculature (16,19), perhaps it also antagonizes AngII-induced secretion of aldosterone or the influence of AngII on renal tubular sodium absorption. Moreover, RLX has been shown to exert its renal vasodilatory influence ultimately through ET and ET B stimulation of NO production (6,15,16,26). Conceivably, RLX may influence sodium reabsorption and potassium secretion in the collecting duct through ET activation of ET B receptors, thereby inhibiting Na ϩ -K ϩ -ATPase activity (27 and citations therein).…”

Section: Discussionmentioning

confidence: 99%

Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers

Smith¹,

Danielson²,

Conrad³

et al. 2006

Journal of the American Society of Nephrology

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Maternal renal hemodynamic adaptation to human pregnancy is one of the most dramatic of all physiologic changes, but the factors that are responsible have remained elusive. In rat pregnancy, there are comparable renal hemodynamic changes, and in this species there is comprehensive evidence that the ovarian hormone relaxin (RLX) is responsible. This study investigated the renal effects of recombinant human RLX (rhRLX) in humans. Eleven volunteers (six male, five female) received intravenous infusions of rhRLX over 5 h at an infusion rate that was chosen to sustain serum concentrations that are comparable to early pregnancy. The renal clearances of inulin and para-aminohippurate were used to measure GFR and renal plasma flow, respectively. Irrespective of gender, renal plasma flow was increased by 47% compared with baseline levels (P < 0.0001), but no significant change was observed in GFR. There were no side effects or adverse reactions of rhRLX given as an intravenous infusion, and the data suggest that RLX indeed may be one of the elusive renal vasodilatory factors in human pregnancy. Further work is necessary to elucidate the complimentary factors that permit the concomitant increase in GFR during pregnancy. T he renal response to pregnancy is characterized by a substantially increased GFR. Micropuncture studies in rats have shown that vasodilation of both the afferent and the efferent arterioles is responsible for augmented renal plasma flow (RPF), which in turn is the main cause of the gestational increase in GFR (1). Indirect evidence indicates that comparable mechanisms are operational in human pregnancy (2-4). There is comprehensive evidence that the ovarian hormone relaxin (RLX) is an essential mediator of the renal vasodilation and hyperfiltration (as well as osmoregulatory changes) in midterm pregnant rats (5), and current evidence supports a mechanism whereby RLX upregulates vascular gelatinase, matrix metalloproteinase 2, promoting cleavage of big endothelin (ET) into ET 1-32 , which then causes nitric oxide (NO)-mediated vasodilation via endothelial ET B receptors (6,7). Until now, the investigation of the vasoactive properties of RLX in the human kidney has been hampered by difficulties that are encountered in pharmacologic stimulation of RLX secretion outside pregnancy (8) and by the absence of an exogenous RLX product for human administration. We have previously investigated, however, women with ovarian failure who became pregnant through egg donation. These RLX-deficient pregnancies had a significantly subdued increase in GFR and reduction in plasma osmolality in early pregnancy (9).The recent availability of recombinant human RLX (rhRLX) has allowed us to test the renal vasoactive properties of this protein hormone. Using the renal clearances of inulin and para-aminohippurate (PAH) to measure GFR and RPF, respectively, we describe the renal response to infusions of rhRLX that attained serum RLX levels comparable to early gestation (10). RLX, which is secreted by the corpus luteum in pregnancy, ...

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Section: Discussionmentioning

confidence: 99%

Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers

Smith¹,

Danielson²,

Conrad³

et al. 2006

Journal of the American Society of Nephrology

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“…NO mediates the renal circulatory changes of pregnancy in the gravid rat model (28), as well as the reduced myogenic reactivity of small renal arteries isolated from gravid rats in vitro (15). Endothelin (ET) via the ET B receptor subtype on the endothelium drives the NO-dependent renal vasodilation and hyperfiltration in pregnant rats (29), as well as the NO-dependent reductions in myogenic reactivity of small renal arteries in vitro (15).…”

Section: Discussionmentioning

confidence: 99%

Relaxin is essential for renal vasodilation during pregnancy in conscious rats

Novak¹,

Danielson²,

Kerchner³

et al. 2001

J. Clin. Invest.

205

171

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IntroductionAmong the most striking changes seen in biology are those associated with pregnancy. In particular, profound vasodilation of nonreproductive organs including the kidney epitomizes the maternal cardiovascular adaptation to early gestation in women. Cardiac output, global arterial compliance, effective renal plasma flow (ERPF), and GFR rise from 30% to 80%, while vascular resistances plummet and blood pressure declines modestly (refs. 1, 2; and reviewed in ref. 3). These alterations begin immediately after conception, peak by the end of the first or beginning of the second trimester, and persist throughout gestation. It is likely that the circulations of nonreproductive organs such as the kidney serve as arteriovenous shunts during early gestation. Thus, ventricular afterload falls, which initiates the enormous increase in cardiac output and, subsequently, the expansion of plasma volume -maternal adaptations associated with healthy pregnancies. Furthermore, pressor response to administration of angiotensin II and vascular reactivity to infusion of norepinephrine become attenuated. Insight into the mechanisms responsible for these vasodilatory phenomena may be particularly critical, since in preeclampsia, the attenuation of pressor responsiveness to angiotensin II, the reduced vascular reactivity to norepinephrine, and the systemic and renal vasodilation are compromised (3).Although 17β-estradiol has been traditionally viewed as the uterine and systemic vasodilator of pregnancy (4, 5), this hormone has little, if any, effect on the renal circulation (5-8), which markedly vasodilates so early in pregnancy. Progesterone may have limited capacity to vasodilate the renal circulation (6, 9, 10); however, an alternative possibility is that the pregnancy protein hormones are involved. Relaxin is an approximately 6-kDa protein secreted by the corpus luteum during human gestation (reviewed in ref. 11). Stimulated by the luteotrophic hormone human chorionic gonadotrophin, serum levels of relaxin increase immediately after conception (11) corresponding to the gestational rise in ERPF and GFR (3). Relaxin also circulates, albeit at lower levels, in the luteal phase of the menstrual cycle (11) and is associated with a 20% increase in ERPF and GFR at that time (e.g., see ref. 12). The hormone is temporally linked to another early pregnancy adaptationosmoregulatory changes (13). In gravid rats, relaxin is secreted by the corpora lutea with serum levels first detectable on gestational day 8 (11). Marked vasodilation in the kidney and other nonreproductive organs is one of the earliest maternal adaptations to occur during pregnancy. Despite the recognition of this extraordinary physiology for over four decades, the gestational hormone responsible has remained elusive. Here we demonstrate a key role for relaxin, a member of the IGF family that is secreted by the corpus luteum in humans and rodents. Using a gravid rodent model, we employ two approaches to eliminate relaxin or its biological activity from the circulation:...

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“…4 Ang II has vasopressor effects, increasing systemic vascular resistance through central and peripheral actions. The RAAS is activated in early pregnancy to maintain blood pressure as maternal peripheral blood flow increases, particularly in the skin, 5 kidneys 6 and uterus. 7 A rise in glomerular filtration rate (GFR) 8 and an increase in progesterone levels 9 occur early in pregnancy and would promote salt excretion if not offset by an activated RAAS.…”

Section: Introductionmentioning

confidence: 99%

The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex

Sykes

Pringle

Zhou

et al. 2013

J Renin Angiotensin Aldosterone Syst

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Hypothesis: There are fetal sex-associated differences in the circulating maternal renin-angiotensin system (RAS) in early pregnancy. Methods: Plasma prorenin, angiotensin (Ang) II, Ang 1-7 and angiotensin-converting enzyme (ACE) concentrations were measured at 15 weeks' gestation in 131 women with uncomplicated pregnancies from the Adelaide SCOPE cohort. Uterine and umbilical artery Doppler sonography was performed at 20 weeks' gestation. Results: At 15 weeks, women bearing female fetuses had higher maternal Ang II concentrations (p = 0.017) and lower Ang 1-7 to Ang II ratios (p = 0.016) than women bearing males. In women with male fetuses, Ang II positively correlated with birth weight (p = 0.028) and prorenin negatively correlated with placental weight (p = 0.014). Female fetuses had higher umbilical artery resistance indices (p = 0.019) that were related to maternal prorenin concentrations (p = 0.007). Conclusions: In early human pregnancy, the maternal RAS is influenced by fetal sex. The lower Ang 1-7 to Ang II ratios in women with female fetuses may contribute to the lower maternal peripheral microvascular flow as described previously and the lack of any positive effect of Ang II on fetal growth, as seen in women with male fetuses.

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

Cited by 62 publications

References 34 publications

Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers

Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers

Relaxin is essential for renal vasodilation during pregnancy in conscious rats

The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex

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