Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Conrad, Kirk P.; Colpoys, Mary C.

doi:10.1172/jci112282

Cited by 133 publications

(58 citation statements)

References 63 publications

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“…In fact, similar attenuation of the renal vasoconstrictor action of ANG II was observed previously in midterm pregnant (22) and late gestational rats (34). In contrast to human pregnancy, reduced systemic pressor response to ANG II is not apparent until late gestation in the rat (34). Whether systemic vascular refractoriness develops earlier in rat pregnancy is unknown, because concurrent measurement of cardiac output and blood pressure has not been made during ANG II infusion in the species.…”

Section: Figuresupporting

confidence: 54%

Relaxin is a potent renal vasodilator in conscious rats

Danielson¹,

Sherwood²,

Conrad³

1999

J. Clin. Invest.

254

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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...

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Section: Figuresupporting

confidence: 54%

Relaxin is a potent renal vasodilator in conscious rats

Danielson¹,

Sherwood²,

Conrad³

1999

J. Clin. Invest.

254

View full text Add to dashboard Cite

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“…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).…”

Section: Newer Aspects On Relaxin In Pregnancy and Preeclampsiamentioning

confidence: 77%

“…However, studies in gravid humans and animal models have not shown a compelling role for vasodilatory PG in the pregnancy-induced increases in GFR and effective renal plasma flow (27,(53)(54)(55) or in the decrease of total peripheral vascular resistance (56,57). The first indi- cation of a potential role for NO came from the evaluation of guanosine 3',5'-cyclic monophosphate (cGMP), an important second messenger of NO.…”

Section: Endothelium-derived Relaxing Factors and Their Inhibitorsmentioning

confidence: 99%

New Aspects in the Pathophysiology of Preeclampsia

Davison¹,

Homuth²,

Jeyabalan³

et al. 2004

Journal of the American Society of Nephrology

171

109

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Abstract. Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.The term preeclampsia refers to the new onset of hypertension (Ͼ140/90 mmHg) and proteinuria after 20 wk of gestation in previously normotensive, nonproteinuric women (1). The condition is common and occurs in~5% of pregnancies in the United States and Europe. Eclampsia is a life-threatening complication and is characterized by grand mal seizures. The term comes from the Greek word for lightning. A severe variant of preeclampsia also features hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). This condition occurs iñ 1 per 1000 pregnancies. Predisposing factors are a positive family history, hypertension, diabetes, preexisting renal disease, multiple pregnancies, and a poor obstetric history. Nephrologists are often called on to see preeclamptic women because of the severe BP elevation and renal disease. Thus, new clinical or experimental information on this condition is important information for nephrologists. Preeclampsia and Subsequent Cardiovascular RiskThe relevance of preeclampsia to the offspring is well recognized. Children who are born to preeclamptic mothers commonly have low birth weight, and their subsequent cardiovascular risk has been a vast investigational field. The mother's outcome has attracted less interest. Chesley, the father of modern preeclampsia research, was of the opinion that once the condition was over, the mothers had no greater risk of adverse long-term outcomes than women without preeclampsia from the general population (2). This issue may prove to be the only matter in which Chesley's opinion was erroneous. Several recent studies suggest that the converse is the case. Smith et al. (3) studied the pregnancy complications and the maternal risk of ischemic cardiac death in 129,290 births. They found that delivering an infant with low birth weight for gestational age increased the hazard ratio for ischemic heart disease o...

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“…Rats that failed to habituate to the cage (< 5% of all animals) were eliminated from the study. Details of the surgical procedure have been previously described (3,4).…”

Section: Methodsmentioning

confidence: 99%

“…Although renal vasodilation in pregnancy is likely to be under endocrinologic control, the hormones or autocoids involved remain unknown. In this regard, earlier work demonstrated that vasodilatory prostaglandins are unlikely to mediate the renal hemodynamic changes of rat pregnancy (4)(5)(6).…”

Section: Introductionmentioning

confidence: 96%

Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.

Danielson¹,

Conrad²

1995

J. Clin. Invest.

Self Cite

140

102

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Because the kidneys are vasodilated and the endogenous production of nitric oxide is increased in gravid rats, we tested whether nitric oxide mediates the renal vasodilatory response to pregnancy. Chronically instrumented, conscious rats of gestational days 12-14 were studied concurrently with age-matched virgin control animals. GFR and effective renal plasma flow (ERPF) were determined by the renal clearances of inulin and para-aminohippurate before and during acute infusion of NW-nitro-L-arginine methyl ester (NAME; 2, 20, and 50 jag/min) or NG-monomethyl-L-arginine (100 jag/min). Baseline GFR and ERPF were significantly increased, and effective renal vascular resistance was decreased by 30-40% in gravid rats compared with virgin controls. During infusion of all three dosages of NAME and NG-monomethyl-L-arginine, effective renal vascular resistance, GFR, and ERPF were equalized in the pregnant and virgin rats (the only exception being GFR during the 20 jag/min NAME infusion). When compared with virgin rats, the gravid animals were more responsive to nitric oxide synthase inhibition, showing a significantly greater decline in GFR and ERPF and rise in effective renal vascular resistance at each timepoint during the infusion of inhibitor. To exclude the possibility that nonspecific renal vasoconstriction per se led to equalization of renal function in the two groups of rats, we investigated angiotensin II. In contrast to the results observed with nitric oxide synthase inhibitors, pregnant rats were less responsive to the renal vasoconstrictory effects of angiotensin II, such that the baseline differences in renal parameters measured before infusion of the hormone were increased during the infusion. To determine whether nitric oxide synthase was inhibited to a similar extent in gravid and virgin rats, aortic and renal cortical cGMP content was assayed ex vivo at the end of inhibitor infusion. The lower 2-pag/min dose of NAME consistently reduced cGMP content of these tissues to comparable levels in the two groups of rats. In conclusion, we suggest that Receivedfor publication 20 December 1994 and accepted in revised form 14 March 1995. nitric oxide mediates reduced renal vascular resistance and hyperfiltration during pregnancy in conscious rats. (J. Clin. Invest. 1995. 96:482-490.)

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Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Cited by 133 publications

References 63 publications

Relaxin is a potent renal vasodilator in conscious rats

Relaxin is a potent renal vasodilator in conscious rats

New Aspects in the Pathophysiology of Preeclampsia

Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.

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