Tilting the balance between vasopressors and vasodepressors may result in either a significant hypertensive or antihypertensive effect. The general hypothesis to be tested is that kinins acting as paracrine hormones are an important component of the vasodepressor side of this equilibrium, regulating blood pressure both by decreasing vascular resistance and by acting as renal natriuretic hormones.
In specific aim I, we will test the hypothesis that kinins acting as paracrine hormones play a role in the long-term regulation of cardiovascular and renal function and that decreases in kinin activity facilitate the development of hypertension. We propose to study the effect of chronic blockade of kinins in experimental situations which lead to the development of hypertension and in models of low-renin hypertension, using a novel kinin receptor antagonist with more potency than those used previously.
In specific aim II we will test the effect of chronic blockade of kinins on the cardiovascular and renal actions of kininase II or angiotensin I-converting enzyme (ACE) inhibitors in various models of hypertension and heart failure in the rat. We hypothesize that ACE inhibitors tilt the balance toward antihypertensive activity, not only because they block angiotensin II formation but also because they inhibit cleavage of paracrine kinins.
In specific aim III, we will study the effect of chronic blockade of kinins on the cardiovascular, diuretic and natriuretic actions of an inhibitor of a different kininase, metalloendopeptidase-24.11 (MEP-24.11). These studies will be performed using models of low-renin hypertension and heart failure. We hypothesize that the effects of MEP-24.11 inhibitors are mediated by both ANF and kinins. Kinins appear to play an important role in the acute and pronounced hypotensive effect of an inhibitor of another kininase, metalloendopeptidase 24-15 (MEP-24.15).
In specific aim I V we propose to determine whether MEP-24.15 inhibitors have a chronic antihypertensive effect on various models of hypertension, and whether this effect is mediated by kinins and/or ANF. The studies proposed are of importance since they will improve our understanding of the role of kinins in the long-term regulation of cardiovascular and renal function and the mechanism(s) mediating the chronic effects of ACE, MEP-24.11 and MEP-24.15 inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028982-20
Application #
6495728
Study Section
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
20
Fiscal Year
2001
Total Cost
$73,467
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kumar, Nitin; Liao, Tang-Dong; Romero, Cesar A et al. (2018) Thymosin ?4 Deficiency Exacerbates Renal and Cardiac Injury in Angiotensin-II-Induced Hypertension. Hypertension 71:1133-1142
Bryson, Timothy D; Gu, Xiaosong; Khalil, Remonda M et al. (2018) Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. J Mol Cell Cardiol 118:1-12
Cerniello, Flavia M; Carretero, Oscar A; Longo Carbajosa, Nadia A et al. (2017) MAS1 Receptor Trafficking Involves ERK1/2 Activation Through a ?-Arrestin2-Dependent Pathway. Hypertension 70:982-989
Ramseyer, Vanesa D; Ortiz, Pablo A; Carretero, Oscar A et al. (2016) Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol 310:F748-F754
González, Germán E; Rhaleb, N-E; D'Ambrosio, Martin A et al. (2016) Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 311:H1287-H1296
Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9:
Kumar, Nitin; Nakagawa, Pablo; Janic, Branislava et al. (2016) The anti-inflammatory peptide Ac-SDKP is released from thymosin-?4 by renal meprin-? and prolyl oligopeptidase. Am J Physiol Renal Physiol 310:F1026-34
Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-?-induced ICAM-1 expression in endothelial cells via inhibition of I?B kinase and NF-?B activation. Am J Physiol Heart Circ Physiol 310:H1176-83
Saez, Fara; Hong, Nancy J; Garvin, Jeffrey L (2016) Luminal flow induces NADPH oxidase 4 translocation to the nuclei of thick ascending limbs. Physiol Rep 4:
Cerrato, Bruno D; Carretero, Oscar A; Janic, Brana et al. (2016) Heteromerization Between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension 68:1039-48

Showing the most recent 10 out of 381 publications