The endothelium is a rich source of vasoactive factors which influence organ perfusion (blood flow), organ function, and blood pressure. We hypothesize that under normal conditions, endothelium-derived relaxing factor (EDRF) serves as a buffer against the effects of endogenous vasoconstrictors, especially angiotensin II (AII), or the endothelium- dependent constricting factor (EDCF), endoperoxide/thromboxane. We hypothesize further that under conditions resulting in increased AII, such as during sodium restriction or the development of hypertension, EDRF increases in response to elevated AII and/or increased blood pressure and counteracts vasoconstriction. Since the kidney is rich in AII, its perfusion is particularly influenced by EDRF. We will use a competitive substrate antagonist, NW-nitro-L-arginine (N-Arg), to inhibit EDRF. This will allow us to determine the influence of EDRF on the control of blood pressure and organ perfusion in normotensive rats as well as in various models of hypertension, particularly as it relates to endogenous AII.
In specific aim #1 we hypothesize that the contribution of EDRF to vascular resistance is proportional to the basal blood pressure and/or the level of endogenous vasoconstrictors such as AII. We will examine the effect of blood pressure on the pressor response to N-Arg in normal rats. We will determine the influence of basal blood pressure on the pressor response to EDRF inhibition with N-Arg, whether EDRF increases with blood pressure, and whether inhibition of EDRF increases the pressor response to exogenous vasoconstrictors. We will determine whether chronic L-arginine administration, the substrate for EDRF, alters pressor responses, and whether inhibiting endogenous vasoconstrictors alters the systemic and renal response to N-Arg.
In specific aim #2, we hypothesize that the renal circulation is particularly responsive to EDRF inhibition. To show this, we will compare the response of the renal and mesenteric vasculatures to EDRF inhibition and determine the relative changes in resistance, particularly those influenced by AII.
In specific aim #3 we hypothesize that EDRF is increased in hypertension, particularly in AII-dependent models. We will determine whether EDRF is antihypertensive and buffers against increases in blood pressure, especially in renin-angiotensin dependent models of hypertension. We will determine whether systemic pressor and renal responses to EDRF inhibition are greater in hypertension, and whether this is a function of the dependence of different models of hypertension on AII. We will also examine whether chronic EDRF inhibition accelerates the onset of hypertension, and whether supplemental L-arginine administration retards its onset.
In specific aim #4 we will study whether agents which transiently decrease renal function, such as diagnostic contrast materials, act by poisoning endothelial cells and consequently inhibiting EDRF production. We will examine whether contrast agents added directly to isolated vessels, or given to rats decreases endothelium- dependent vasodilation or renal function. The results of these studies will help us understand how the endothelium regulates blood pressure and modulates renal perfusion and function, particularly in opposition to constrictor influences such as AII and EDCF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028982-15
Application #
5213424
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1996
Total Cost
Indirect Cost
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

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