Role of Oxidative Stress in High Endothelin Models of Hypertension

Hdl Handle:
http://hdl.handle.net/10675.2/345143
Title:
Role of Oxidative Stress in High Endothelin Models of Hypertension
Authors:
Elmarakby, Ahmed A.
Abstract:
Recent studies have shown that the potent vasoconstrictor peptide endothelin-1 (ET-1) stimulates superoxide production in vivo and in vitro. We hypothesized that ET-1 induced hypertension, at least in part, is due to an increase in oxidative stress. In the initial experiments, we hypothesized that ETA receptor stimulation contributes to the elevated blood pressure and superoxide production in ETB receptor deficient rats as an example of a high endothelin model of hypertension. Experiments were conducted on homozygous {si/si) ETB deficient and wild type {wt) rats fed a high salt diet for three weeks. Separate groups of rats were given normal drinking water or water containing the ETA receptor antagonist, ABT 627. On a normal salt diet, sl/sl rats had a significantly elevated systolic blood pressure (SBP) compared to wt. High salt caused a significant increase in SBP in sl/sl compared with wt rats. ETA receptor blockade decreased SBP in sl/sl rats on high salt without affecting the blood pressure in wt rats. Plasma 8-isoprostane levels, an indirect measure of oxidative stress, were significantly higher in sl/sl rats compared with the wt. ETa receptor blockade significantly attenuated the elevation in plasma 8- isoprostane levels in sl/sl rats'. These findings suggest that ET-1, through the ETA receptor, contributes to salt-induced hypertension and superoxide production in ETB deficient rats. We hypothesized that ET-1 increases superoxide production via the stimulation of the NADPH oxidase system. Chronic ET-1 infused rats were fed a high salt diet and either allowed to drink tap water, water containing the SOD mimetic, tempol, or the NADPH oxidase inhibitor, apocynin, for two weeks. Infusion of ET-1 increased mean arterial pressure (MAP) when compared to baseline values. Neither tempol nor apocynin treatment had any effect on the increase in MAP produced by ET 1. Plasma 8-isoprostane was increased significantly in ET-1 infused rats compared to rats on a high salt diet alone. Both tempol and apocynin treatment significantly attenuated the ET-1 induced increase in plasma 8-isoprostane. These data provide evidence that chronic ET-1 infusion increases vascular NADPH oxidase dependent superoxide production, but does not account for chronic ET-1-induced hypertension. Finally, experiments were performed to determine if increased kinins and/or decreased superoxide attenuates the elevation in blood pressure in chronic Ang II hypertensive rats. Four groups of rats, all given Ang II, were studied and allowed to drink tap water, water containing enalapril, tempol, or both for two weeks. Ang II infusion significantly increased SBP when compared with the baseline. Neither enalapril nor tempol treatment alone was able to attenuate the elevation in SBP. Combined administration of tempol and enalapril prevented the increase in SBP. Plasma 8-isoprostane was elevated significantly in Ang II infused rats when compared with control untreated rats. Tempol treatment alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane. These studies support the hypothesis that an antioxidant alone is not effective in preventing Ang II hypertension. However, administration of an ACE inhibitor with an antioxidant enhances antioxidant efficiency in preventing Ang II hypertension. Overall, these studies showed that ETA receptor stimulation participates in superoxide production via the stimulation of NADPH oxidase and that antioxidant treatment alone is not sufficient to lower blood pressure in high endothelin models of hypertension.
Affiliation:
Department of Medicine
Issue Date:
Jul-2004
URI:
http://hdl.handle.net/10675.2/345143
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/305098711?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorElmarakby, Ahmed A.en
dc.date.accessioned2015-02-24T02:37:15Z-
dc.date.available2015-02-24T02:37:15Z-
dc.date.issued2004-07-
dc.identifier.urihttp://hdl.handle.net/10675.2/345143-
dc.description.abstractRecent studies have shown that the potent vasoconstrictor peptide endothelin-1 (ET-1) stimulates superoxide production in vivo and in vitro. We hypothesized that ET-1 induced hypertension, at least in part, is due to an increase in oxidative stress. In the initial experiments, we hypothesized that ETA receptor stimulation contributes to the elevated blood pressure and superoxide production in ETB receptor deficient rats as an example of a high endothelin model of hypertension. Experiments were conducted on homozygous {si/si) ETB deficient and wild type {wt) rats fed a high salt diet for three weeks. Separate groups of rats were given normal drinking water or water containing the ETA receptor antagonist, ABT 627. On a normal salt diet, sl/sl rats had a significantly elevated systolic blood pressure (SBP) compared to wt. High salt caused a significant increase in SBP in sl/sl compared with wt rats. ETA receptor blockade decreased SBP in sl/sl rats on high salt without affecting the blood pressure in wt rats. Plasma 8-isoprostane levels, an indirect measure of oxidative stress, were significantly higher in sl/sl rats compared with the wt. ETa receptor blockade significantly attenuated the elevation in plasma 8- isoprostane levels in sl/sl rats'. These findings suggest that ET-1, through the ETA receptor, contributes to salt-induced hypertension and superoxide production in ETB deficient rats. We hypothesized that ET-1 increases superoxide production via the stimulation of the NADPH oxidase system. Chronic ET-1 infused rats were fed a high salt diet and either allowed to drink tap water, water containing the SOD mimetic, tempol, or the NADPH oxidase inhibitor, apocynin, for two weeks. Infusion of ET-1 increased mean arterial pressure (MAP) when compared to baseline values. Neither tempol nor apocynin treatment had any effect on the increase in MAP produced by ET 1. Plasma 8-isoprostane was increased significantly in ET-1 infused rats compared to rats on a high salt diet alone. Both tempol and apocynin treatment significantly attenuated the ET-1 induced increase in plasma 8-isoprostane. These data provide evidence that chronic ET-1 infusion increases vascular NADPH oxidase dependent superoxide production, but does not account for chronic ET-1-induced hypertension. Finally, experiments were performed to determine if increased kinins and/or decreased superoxide attenuates the elevation in blood pressure in chronic Ang II hypertensive rats. Four groups of rats, all given Ang II, were studied and allowed to drink tap water, water containing enalapril, tempol, or both for two weeks. Ang II infusion significantly increased SBP when compared with the baseline. Neither enalapril nor tempol treatment alone was able to attenuate the elevation in SBP. Combined administration of tempol and enalapril prevented the increase in SBP. Plasma 8-isoprostane was elevated significantly in Ang II infused rats when compared with control untreated rats. Tempol treatment alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane. These studies support the hypothesis that an antioxidant alone is not effective in preventing Ang II hypertension. However, administration of an ACE inhibitor with an antioxidant enhances antioxidant efficiency in preventing Ang II hypertension. Overall, these studies showed that ETA receptor stimulation participates in superoxide production via the stimulation of NADPH oxidase and that antioxidant treatment alone is not sufficient to lower blood pressure in high endothelin models of hypertension.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/305098711?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectendothelinen
dc.subjectEndothelin B Receptoren
dc.subjectEndothelin A Receptoren
dc.subjectOxidative stressen
dc.subjectNADPHen
dc.subjectSOD mimeticen
dc.subjectAngiotensin IIen
dc.subjectACE inhibitoren
dc.subjectHypertensionen
dc.titleRole of Oxidative Stress in High Endothelin Models of Hypertensionen
dc.typeDissertationen
dc.contributor.departmentDepartment of Medicineen
dc.description.advisorPollock, David M.en
dc.description.committeeCatravas, John; Marrero, Mario; Brands, Michaelen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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