Publications (8) View all
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Article: L-arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats.
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ABSTRACT: While soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1) have been implicated in the pathogenesis of preeclampsia (PE), the mechanisms whereby increased sFlt-1 leads to enhanced ET-1 production and hypertension remain unclear. It is well documented that nitric oxide (NO) production is reduced in PE; however, whether a reduction in NO synthesis plays a role in increasing ET-1 and blood pressure in response to chronic increases in plasma sFlt-1 remains unclear. The purpose of this study was to determine the role of reduced NO synthesis in the increase in blood pressure and ET-1 in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg(-1)·day(-1) for 6 days beginning on day 13 of gestation) treated with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (100 mg/l for 4 days) or supplemented with 2% L-Arg (in drinking water for 6 days beginning on day 15 of gestation). Infusion of sFlt-1 into NP rats significantly elevated mean arterial pressure compared with control NP rats: 116 ± 2 vs. 103 ± 1 mmHg (P < 0.05). NO synthase inhibition had no effect on the blood pressure response in sFlt-1 hypertensive pregnant rats (121 ± 3 vs. 116 ± 2 mmHg), while it significantly increased mean arterial pressure in NP rats (128 ± 4 mmHg, P < 0.05). In addition, NO production was reduced ∼70% in isolated glomeruli from sFlt-1 hypertensive pregnant rats compared with NP rats (P < 0.05). Furthermore, prepro-ET-1 in the renal cortex was increased ∼3.5-fold in sFlt-1 hypertensive pregnant rats compared with NP rats. Supplementation with L-Arg decreased the sFlt-1 hypertension (109 ± 3 mmHg, P < 0.05) but had no effect on the blood pressure response in NP rats (109 ± 3 mmHg) and abolished the enhanced sFlt-1-induced renal cortical prepro-ET expression. In conclusion, a reduction in NO synthesis may play an important role in the enhanced ET-1 production in response to sFlt-1 hypertension in pregnant rats.AJP Regulatory Integrative and Comparative Physiology 11/2011; 302(2):R259-63. · 3.34 Impact Factor -
Article: Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in pregnant rats.
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ABSTRACT: Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5-10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14-19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.AJP Regulatory Integrative and Comparative Physiology 08/2011; 301(5):R1495-500. · 3.34 Impact Factor -
Article: Endothelin type A receptor antagonist attenuates placental ischemia-induced hypertension and uterine vascular resistance.
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ABSTRACT: We sought to determine the effect of an endothelin type A receptor antagonist (ETA) on uterine artery resistive index (UARI) and mean arterial pressure (MAP) in a placental ischemia rat model of preeclampsia produced by reduction in uterine perfusion pressure (RUPP). UARI was assessed by Doppler velocimetry in RUPP and normal pregnant controls (NP) on gestational days (GD) 12, 15, and 18. UARI was also determined on GD 18 in NP and RUPP pregnant dams after pretreatment with ETA. MAP was recorded on GD 19. The RUPP group had a higher MAP and UARI on GD 15 and 18 than the NP group. Pretreatment with ETA attenuated both the MAP and GD-18 UARI in the RUPP group without affecting these parameters in the NP group. The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ETA in pregnant dams with ischemic placentas.American journal of obstetrics and gynecology 04/2011; 204(4):330.e1-4. · 3.28 Impact Factor -
Article: Role of reactive oxygen species during hypertension in response to chronic antiangiogenic factor (sFlt-1) excess in pregnant rats.
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ABSTRACT: Preeclampsia is associated with increased levels of reactive oxygen species (ROS) and the antiangiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1). Moreover, recent studies have indicated that chronic sFlt-1 excess causes hypertension in pregnant animals. The purpose of this study was to evaluate the role of ROS in mediating sFlt-1-induced hypertension in the pregnant rat. Mean arterial pressure (MAP), and plasma sFlt-1 and tissue ROS levels were measured in the following groups: (i) pregnant controls; (ii) sFlt-1-treated pregnant rats; (iii) Tempol-treated pregnant rats; (iv) sFlt-1- and Tempol-treated pregnant rats. MAP increased from 104 ± 2 mm Hg in pregnant control rats to 118 ± 3 mm Hg (P = 0.002) in sFlt-1-infused rats. Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated levels of tissue ROS were increased in response to excess sFlt-1 during pregnancy. Pretreatment with Tempol attenuated oxidative stress and hypertension in response to sFlt-1. ROS play an important role in mediating hypertension in response to chronic sFlt-1 excess during pregnancy.American Journal of Hypertension 01/2011; 24(1):110-3. · 3.18 Impact Factor -
Article: Role of 20-hydroxyeicosatetraenoic acid in mediating hypertension in response to chronic renal medullary endothelin type B receptor blockade.
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ABSTRACT: The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production. The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor. These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla.PLoS ONE 01/2011; 6(10):e26063. · 4.09 Impact Factor
