A long-term goal of the principal investigator's research program is to determine the role of the kidneys in the regulation of arterial pressure during pathophysiological conditions such as salt-sensitive hypertension. A common defect that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension, is a hypertensive shift in the pressure natriuresis relationship. A major objective of the current proposal is to examine the role of the renal medullary endothelin system in modulating pressure natriuresis and blood pressure. Data from our laboratory indicates that the production of endothelin is enhanced specifically in the renal medulla by chronic sodium loading. Moreover, data from our laboratory indicate that chronic blockade of ETB receptors within the renal medulla results in significant hypertension in rats on a high sodium intake. The exact mechanisms involved in mediating the hypertension, however, are unknown. Compelling evidence indicates a potential interaction between the renal medullary endothelin and cytochrome P450 enzyme /20-Hydroxyeicosatetraenoic acid (20-HETE) systems. Thus, the goal of this proposal is to test the central hypothesis that chronic blockade of renal medullary ETB receptors causes salt-sensitive hypertension by impairing pressure natriuresis. Attenuated pressure natriuresis occurs as a result of a direct influence of ETB receptors on sodium excretion and/or indirectly by decreased synthesis of renal medullary 20-HETE. Furthermore, we propose that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats. A wide range of molecular, biochemical, pharmacological, and physiological techniques will be used to test our hypothesis.
Specific aims to be addressed are: 1) To test the hypothesis that the renal medullary endothelin system plays a greater role in regulating sodium excretion and blood pressure as dietary sodium intake is increased; 2) To test the hypothesis that the reduction in sodium excretion and elevation in arterial pressure during renal medullary ETB receptor blockade is due to a decrease in renal medullary production of 20-HETE; 3) To test the hypothesis that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038499-16
Application #
7185124
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Barouch, Winifred
Project Start
1990-07-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
16
Fiscal Year
2007
Total Cost
$179,635
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
Gilbert, Jeffrey S; Verzwyvelt, Joseph; Colson, Drew et al. (2010) Recombinant vascular endothelial growth factor 121 infusion lowers blood pressure and improves renal function in rats with placentalischemia-induced hypertension. Hypertension 55:380-5
Gilbert, Jeffrey S; Gilbert, Sara A B; Arany, Marietta et al. (2009) Hypertension produced by placental ischemia in pregnant rats is associated with increased soluble endoglin expression. Hypertension 53:399-403
Vera, Trinity; Granger, Joey P; Stec, David E (2009) Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice. Am J Physiol Regul Integr Comp Physiol 297:R738-43
Veillon Jr, Edward W; Keiser, Sharon D; Parrish, Marc R et al. (2009) 17-Hydroxyprogesterone blunts the hypertensive response associated with reductions in uterine perfusion pressure in pregnant rats. Am J Obstet Gynecol 201:324.e1-6
Granger, Joey P (2009) Vascular endothelial growth factor inhibitors and hypertension: a central role for the kidney and endothelial factors? Hypertension 54:465-7
Sedeek, Mona; Gilbert, Jeffrey S; LaMarca, Babbette B et al. (2008) Role of reactive oxygen species in hypertension produced by reduced uterine perfusion in pregnant rats. Am J Hypertens 21:1152-6
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
Gilbert, Jeffrey; Dukes, Matt; LaMarca, Babbette et al. (2007) Effects of reduced uterine perfusion pressure on blood pressure and metabolic factors in pregnant rats. Am J Hypertens 20:686-91
Ai, Z; Fischer, A; Spray, D C et al. (2000) Wnt-1 regulation of connexin43 in cardiac myocytes. J Clin Invest 105:161-71