High salt diet is often associated with increased vascular resistance and arterial pressure in salt-sensitive individuals. In normal individuals, however, high salt diet does not increase the arterial pressure significantly, suggesting possible vascular protective mechanisms. Endothelin-1 (ET-1) activates ETA and ETa receptors. Although the role of ETA receptors in vascular contraction and hypertension has been studied extensively, the importance of ETa receptors in modulating the vascular function and arterial pressure particularly during high salt diet is less clear. Preliminary data suggest that ET-1 production is enhanced during high sodium intake. Data also suggest that chronic blockade of ETa receptors results in a salt-sensitive form of hypertension; however, the vascular and cellular mechanisms involved are unclear. The overall objective of this proposal is to test the hypothesis that normally during high salt diet an increase in ET-1 production and enhancement of its ETA-mediated vascular contraction pathways are counterbalanced by enhanced ETa-mediated vascular relaxation pathways, thus preventing excessive increases in vascular resistance and arterial pressure. Accordingly, chronic blockade of Eta receptors during high salt diet will not only decrease vascular relaxation, but also enhance vascular reactivity leading to increased vascular resistance and salt-sensitive hypertension. The decreased vascular relaxation occurs as a result of inhibition of the endothelium-dependent nitric oxide-cGMP, prostacyclincAMP and/or hyperpolarizing factor pathway. The increased vascular reactivity occurs as a result of increased [Ca2+]i and protein kinase C activity in vascular smooth muscle. The increases in vascular reactivity, [Ca2+]i and PKC activity during chronic blockade of ETa receptors and high salt diet occur as a result of unbalanced stimulation of ETA receptors. To test this hypothesis chronically-instrumented rats on normal and high sodium diets and nontreated or treated with ETa and ETA receptor antagonists will be used. Integrated analysis will be used to investigate the relation between ETa-mediated vascular relaxation and ETA-mediated vascular contraction in isolated renal vessels, and the arterial pressure in vivo. These studies should help understand better the vascular protective mechanisms during high salt diet in normal individuals and the pathophysiological basis of the increased vascular resistance in salt-sensitive hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070659-04
Application #
6913600
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$350,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Raffetto, Joseph D; Yu, Peng; Reslan, Ossama M et al. (2012) Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava. J Vasc Surg 55:1716-25
Gencel, V B; Benjamin, M M; Bahou, S N et al. (2012) Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease. Mini Rev Med Chem 12:149-74
Lim, Chung S; Qiao, Xiaoying; Reslan, Ossama M et al. (2011) Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava. J Vasc Surg 53:764-73
Raffetto, Joseph D; Khalil, Raouf A (2011) Ca(2+)-dependent contraction by the saponoside escin in rat vena cava: implications in venotonic treatment of varicose veins. J Vasc Surg 54:489-96
Khalil, Raouf A (2011) Modulators of the vascular endothelin receptor in blood pressure regulation and hypertension. Curr Mol Pharmacol 4:176-86
Sheppard, Stephanie J; Khalil, Raouf A (2010) Risk factors and mediators of the vascular dysfunction associated with hypertension in pregnancy. Cardiovasc Hematol Disord Drug Targets 10:33-52
Raffetto, Joseph D; Qiao, Xiaoying; Beauregard, Katie G et al. (2010) Estrogen receptor-mediated enhancement of venous relaxation in female rat: implications in sex-related differences in varicose veins. J Vasc Surg 51:972-81
Raffetto, Joseph D; Qiao, Xiaoying; Beauregard, Katie G et al. (2010) Functional adaptation of venous smooth muscle response to vasoconstriction in proximal, distal, and varix segments of varicose veins. J Vasc Surg 51:962-71
Khalil, Raouf A (2010) Potential approaches to enhance the effects of estrogen on senescent blood vessels and postmenopausal cardiovascular disease. Cardiovasc Hematol Agents Med Chem 8:29-46
Tanbe, Alain F; Khalil, Raouf A (2010) Circulating and Vascular Bioactive Factors during Hypertension in Pregnancy. Curr Bioact Compd 6:60-75

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