Previous studies suggest that the renal kallikrein-kinin system (KKS) functions as a renal paracrine system, locally modulating fluid and electrolyte homeostasis and blood pressure regulation. Recently the applicant has developed novel methods to sample renal interstitial fluid (RIF) and monitor changes in renal regional blood flow. The development of the conscious animal model is essential to the investigation of the physiological role of the renal kallikrein-kinin system. Our preliminary studies utilizing the renal interstitial microdialysis technique demonstrated our ability to measure both renal cortical and medullary interstitial bradykinin, prostaglandin E/2, cyclic GMP, cyclic AMP and angiotensin II. RIF bradykinin increases during chronic low sodium intake and in response to acute salt loading. The increase in bradykinin may be essential in protection against the harmful effects of high salt intake (e.g., hypertension). However it is not clear why bradykinin, a natriuretic substance, increases during chronic salt depletion. It is possible that bradykinin counteracts the vasoconstrictor action of hormones (e.g., angiotensin II) induced by sodium depletion. This proposal examines the hypothesis that the renal actions of the KKS are mediated by endothelium-derived relaxing factor (EDRF) and eicosanoids, and investigates the relationship between the KKS and the renin-angiotensin system in the kidney.
Three specific aims will be addressed: (1) to determine the paracrine action and renal compartmentalization of the KKS and its mediators in the kidney, (2) to ascertain the interaction between the intrarenal KKS and renin-angiotensin system and (3) to determine the role of intrarenal KKS and its mediators in the regulation of blood pressure. The proposed studies are related to the long-term goal of increasing our understanding of the pathophysiology of fluid/electrolyte disorders and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL047669-04
Application #
2223853
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1992-07-07
Project End
1998-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Siragy, Helmy M; Awad, Alaa; Abadir, Peter et al. (2003) The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-alpha in diabetic rats. Endocrinology 144:2229-33
Millatt, Lesley J; Whitley, Guy StJ; Li, Dechun et al. (2003) Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 108:1493-8
Siragy, Helmy M; El-Kersh, Mohamed A; De Gasparo, Marc et al. (2002) Differences in AT2 -receptor stimulation between AT1 -receptor blockers valsartan and losartan quantified by renal interstitial fluid cGMP. J Hypertens 20:1157-63
Siragy, H M; de Gasparo, M; El-Kersh, M et al. (2001) Angiotensin-converting enzyme inhibition potentiates angiotensin II type 1 receptor effects on renal bradykinin and cGMP. Hypertension 38:183-6
Millatt, L J; Siragy, H M (2000) Renal cyclic 3',5'-guanosine monophosphate and sodium excretion in Dahl salt-resistant and Dahl salt-sensitive rats: comparison of the roles of bradykinin and nitric oxide. J Hypertens 18:1491-6
Millatt, L J; Siragy, H M (2000) Age-related changes in renal cyclic nucleotides and eicosanoids in response to sodium intake. Hypertension 35:643-7
Siragy, H M; de Gasparo, M; Carey, R M (2000) Angiotensin type 2 receptor mediates valsartan-induced hypotension in conscious rats. Hypertension 35:1074-7
Siragy, H M; Bedigian, M (1999) Mechanism of action of angiotensin-receptor blocking agents. Curr Hypertens Rep 1:289-95
Siragy, H M; Senbonmatsu, T; Ichiki, T et al. (1999) Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor. J Clin Invest 104:181-8
Siragy, H M; Carey, R M (1999) Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension 33:1237-42

Showing the most recent 10 out of 21 publications