The kidneys play a central role in long-term regulation of extracellular fluid volume and arterial pressure. Several lines of evidence also support an important role for the kidneys in the pathogenesis of hypertension. A common defect that has been found in all forms of hypertension examined to date is a hypertensive shift in the pressure natriuresis relationship. In the current proposal, a major objective is to examine the role of endothelin and nitric oxide in mediating the reduction in renal- pressure natriuresis in a specific form of hypertension associated with endothelial dysfunction--pregnancy-induced hypertension (PIH). Despite being the leading cause of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PIH are unclear. Our current working hypothesis is that reduced uteroplacental perfusion causes hypertension by impairing renal- pressure natriuresis. Attenuated pressure natriuresis occurs as a result of placental factor(s) causing endothelial cell dysfunction leading to enhanced formation of vasoconstrictors (endothelin and thromboxane) and decreased formation of vasodilators (nitric oxide and prostacyclin). These endothelial abnormalities, in turn, reduce renal plasma flow and glomerular filtration rate or enhance tubular reabsorption, thereby decreasing renal sodium excretory function. To test this hypothesis, an integrated analysis of arterial pressure, renal, hormonal, and endothelial regulation will be conducted in a conscious, chronically-instrumented rat model of reduced uterine perfusion pressure (RUPP). Preliminary data in this model indicate that the hypertension produced by decreased perfusion pressure to the uteroplacental unit is associated with proteinuria, significant reductions in renal plasma flow and GFR, a hypertensive shift in the pressure natriuresis relationship, and endothelial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010137-02
Application #
6151281
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Bishop, Terry Rogers
Project Start
2000-02-01
Project End
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$37,516
Indirect Cost
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A et al. (2016) Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring. Am J Physiol Renal Physiol 311:F312-9
Intapad, Suttira; Ojeda, Norma B; Varney, Elliott et al. (2015) Sex-Specific Effect of Endothelin in the Blood Pressure Response to Acute Angiotensin II in Growth-Restricted Rats. Hypertension 66:1260-6
Hennington, Bettye Sue; Alexander, Barbara T (2013) Linking intrauterine growth restriction and blood pressure: insight into the human origins of cardiovascular disease. Circulation 128:2179-80
Intapad, Suttira; Alexander, Barbara T (2013) Pregnancy Complications and Later Development of Hypertension. Curr Cardiovasc Risk Rep 7:183-189
Campbell, Leigh R; Pang, Yi; Ojeda, Norma B et al. (2012) Intracerebral lipopolysaccharide induces neuroinflammatory change and augmented brain injury in growth-restricted neonatal rats. Pediatr Res 71:645-52
LaMarca, Babbette D; Alexander, Barbara T; Gilbert, Jeffery S et al. (2008) Pathophysiology of hypertension in response to placental ischemia during pregnancy: a central role for endothelin? Gend Med 5 Suppl A:S133-8
Llinas, Maria T; Alexander, Barbara T; Capparelli, Maria F et al. (2004) Cytochrome P-450 inhibition attenuates hypertension induced by reductions in uterine perfusion pressure in pregnant rats. Hypertension 43:623-8
Alexander, Barbara T (2003) Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 41:457-62
Llinas, Maria T; Alexander, Barbara T; Seedek, Mona et al. (2002) Enhanced thromboxane synthesis during chronic reductions in uterine perfusion pressure in pregnant rats. Am J Hypertens 15:793-7

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