Evidence for attenuation of myo-inositol uptake, phosphoinositide turnover and inositol phosphate production in aortic vasculature of rats during pregnancy.

Conrad, Kirk P.; Barrera, Sara; Friedman, Paul A.; Schmidt, Vera

doi:10.1172/jci115187

Cited by 23 publications

(13 citation statements)

References 42 publications

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“…A comparable attenuation of increases in cytosolic calcium by AII was observed in mesangial cells prepared from nonpregnant rats and incubated with RLN for 24 h (22). These results implicate a direct effect of pregnancy and RLN on contractile cells independent of the endothelium, an effect that is perhaps mediated through attenuation of phosphoinositide turnover (31).…”

Section: Molecular Mechanisms Of Renal Vasodilation In Pregnancymentioning

confidence: 67%

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

Conrad

Davison

2014

American Journal of Physiology-Renal Physiology

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Conrad KP, Davison JM. The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?. Am J Physiol Renal Physiol 306: F1121-F1135, 2014. First published March 19, 2014 doi:10.1152/ajprenal.00042.2014.-During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced K f and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure. renal hemodynamics; glomerular filtration; osmoregulation; relaxin; nitric oxide; assisted reproductive technology; glomerular endotheliosis; soluble vascular endothelial growth factor receptor-1; heart failure Renal Plasma Flow and Glomerular Filtration in Normal PregnancyMARKED VASODILATION OF THE MATERNAL CIRCULATION occurs in the first trimester of human pregnancy. Consequently, there is a precipitous and profound decline in systemic vascular resistance (SVR) that in turn abets a reciprocal increase in cardiac output (CO) of ϳ40% or 2 l/min lasting throughout pregnancy (23,163). Vasodilation of nonreproductive organs like the kidneys accounts mostly for the early gestational fall in SVR and rise in CO. The fall in SVR is nearly offset by the rise in CO; hence, mean arterial pressure (MAP) declines, but only modestly, by 5-10 mmHg (23,38,163). Although counterintuitive, this metamorphosis of the maternal circulation is virtually complete by the end of the first or beginning of the second trimester, when fetal crown rump length and place...

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Section: Molecular Mechanisms Of Renal Vasodilation In Pregnancymentioning

confidence: 67%

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

Conrad

Davison

2014

American Journal of Physiology-Renal Physiology

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“…On the other hand, a role for another endotheliumderived vasodilator, nitric oxide, and its second messenger, cGMP (7)(8)(9), is possible and addressed by the current investigation. Alternatively, it may not be change of endothelial function alone that mediates renal vasodilation during pregnancy but rather modification of vascular smooth muscle may contribute (28).…”

Section: Discussionmentioning

confidence: 99%

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

Danielson¹,

Conrad²

1995

J. Clin. Invest.

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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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“…Measurement of myo-inositol incorporation was conducted using the method reported by Conrad et al (1991) (Boston, MA). U46619, tetrodotoxin (TTX), cyclopiazonic acid (CPA), and U73122 were obtained from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

Nobe

Sakata²,

Nobe³

et al. 2002

J Pharmacol Exp Ther

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The effect of the thromboxane A 2 analog 9,11-dideoxy-11␣, 9␣-epoxymethanoprostaglandin F 2␣ (U46619) on spontaneous phasic contractions in the mouse portal vein was studied. U46619 induced concentration-dependent (1-100 nM) increases in amplitude, frequency, and contractile period (ONtime) of the contraction. Both amplitude and ON-time were enhanced significantly under high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation may be associated with portal vein dysfunction in diabetes. However, the mechanisms remain unclear. HG enhanced the U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed accumulation under normal conditions; however, this suppression was not observed under HG conditions. The HG-induced enhancement of U46619-induced contraction was inhibited by protein kinase C (PKC)inhibition. This finding indicated that accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed the HG-induced enhancement of contraction. Increased myo-inositol incorporation was detected under HG conditions, indicating an acceleration of phosphatidylinositol (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors. These findings indicated that HG treatments increased DG synthesis derived from incorporated glucose, PKC, and DG kinase activation. These responses induce hyperactivation of the amplitude and contractile period of contraction mediated by acceleration of PI turnover. This series of responses may be involved in the dysfunction of the portal vein under the HG conditions occurring with diabetes.The portal vein functions as the main transfer vessel from the digestive organs to the liver. To effect highly efficient transfer, the portal vein exhibits spontaneous, intermittent rhythmic contractions (Miwa et al., 1997). Dysfunction of this tissue leads not only to reduction in blood supply to the liver but also to serious diseases such as varix mediated by reflux of blood (MacMathuna, 1992). An understanding of the basic mechanisms modulating these spontaneous contractions is a prerequisite for investigation of potential pathophysiological processes. Calcium and potassium channel activity is associated with spontaneous contraction (Loirand et al., 1990;Helliwell and Large, 1997). Regulation of calcium channels is believed to occur via plasma membrane potential and/or intracellular signaling systems. However, the mechanisms involved in increased mechanical activity mediated by receptor stimulation and their related intracellular factors are poorly understood.We have previously reported that receptor-mediated contractile responses in vascular smooth muscle are altered in diabetes and the mechanisms involved change in phosphatidylinositol (PI) turnover (Nobe et al., 2002). Phosphatidylinositols, diacylglycerol (DG), protein kinase C (PKC), and DG kinase are key elements of PI turnover. Increased contractility in many smooth muscle cell ...

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Evidence for attenuation of myo-inositol uptake, phosphoinositide turnover and inositol phosphate production in aortic vasculature of rats during pregnancy.

Cited by 23 publications

References 42 publications

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

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

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

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