Nitroxyl anion as a novel relaxant molecule in the rat pudendal artery and metformin as treatment for angiotensin II-induced erectile dysfunction

Hdl Handle:
http://hdl.handle.net/10675.2/317510
Title:
Nitroxyl anion as a novel relaxant molecule in the rat pudendal artery and metformin as treatment for angiotensin II-induced erectile dysfunction
Authors:
Labazi, Hicham
Abstract:
Cardiovascular diseases, which are the leading cause of illness and death in the United States, frequently share similar risk factors (hypertension, smoking, aging, etc…) as erectile dysfunction (ED). Hypertension is an important risk factor for both heart failure and ED; hypertension and ED are closely intertwined diseases, which have vascular and endothelial dysfunction as a common cause. Recently it has been shown that ED is an independent predictor of cardiovascular diseases (CVD). Thus, studying mechanisms of erectile function and ED will be of great importance for developing treatments for ED, as well as reducing the burden of CVD. In this dissertation, the mechanisms of angiotensin II (AngII)-induced ED was investigated. In addition, we also investigated the effect of metformin on erectile function in an AngII-hypertensive model of ED. We hypothesized that AngII infusion for 4 weeks results in ED and treatment with metformin improves erectile function in the AngII-infused rats. We observed that AngII infusion resulted in ED, which was accompanied by an increased contraction and decreased relaxation response of the corpus cavernosum and pudendal arteries. Furthermore, it was observed that ERK1/2 activation contributes to ED in the AngIIhypertensive model of ED. Treatment with metformin restored erectile function in AngIIhypertensive rats, with a reversal of the increased contractility and decreased relaxation seen in both the corpus cavernosum and pudendal arteries of the hypertensive rats. Our data suggest that metformin may have potential therapeutic effects in ED, independent of its anti-diabetic effects. Additionally we investigated the contribution of nitroxyl anion (HNO), a NO congener, to erectile function. We observed that the endothelium mediated relaxation in pudendal arteries was partially mediated through HNO, and that this relaxation was soluble guanylyl cyclase-dependent (sGC), resulting in activation of voltage-dependent potassium channels (KV +) and large conductance calcium-activated potassium channel (BKCa). The identification of this novel pathway will enhance our understanding of erectile function and possibly allow for development of therapeutic agents for the treatment of ED.
Affiliation:
Department of Physiology
Issue Date:
2012
URI:
http://hdl.handle.net/10675.2/317510
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1267746864?accountid=12365
Type:
Dissertation
Language:
en_US
Appears in Collections:
Theses and Dissertations; Department of Physiology Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorLabazi, Hichamen
dc.date.accessioned2014-05-27T19:01:00Z-
dc.date.available2014-05-27T19:01:00Z-
dc.date.issued2012-
dc.identifier.urihttp://hdl.handle.net/10675.2/317510-
dc.description.abstractCardiovascular diseases, which are the leading cause of illness and death in the United States, frequently share similar risk factors (hypertension, smoking, aging, etc…) as erectile dysfunction (ED). Hypertension is an important risk factor for both heart failure and ED; hypertension and ED are closely intertwined diseases, which have vascular and endothelial dysfunction as a common cause. Recently it has been shown that ED is an independent predictor of cardiovascular diseases (CVD). Thus, studying mechanisms of erectile function and ED will be of great importance for developing treatments for ED, as well as reducing the burden of CVD. In this dissertation, the mechanisms of angiotensin II (AngII)-induced ED was investigated. In addition, we also investigated the effect of metformin on erectile function in an AngII-hypertensive model of ED. We hypothesized that AngII infusion for 4 weeks results in ED and treatment with metformin improves erectile function in the AngII-infused rats. We observed that AngII infusion resulted in ED, which was accompanied by an increased contraction and decreased relaxation response of the corpus cavernosum and pudendal arteries. Furthermore, it was observed that ERK1/2 activation contributes to ED in the AngIIhypertensive model of ED. Treatment with metformin restored erectile function in AngIIhypertensive rats, with a reversal of the increased contractility and decreased relaxation seen in both the corpus cavernosum and pudendal arteries of the hypertensive rats. Our data suggest that metformin may have potential therapeutic effects in ED, independent of its anti-diabetic effects. Additionally we investigated the contribution of nitroxyl anion (HNO), a NO congener, to erectile function. We observed that the endothelium mediated relaxation in pudendal arteries was partially mediated through HNO, and that this relaxation was soluble guanylyl cyclase-dependent (sGC), resulting in activation of voltage-dependent potassium channels (KV +) and large conductance calcium-activated potassium channel (BKCa). The identification of this novel pathway will enhance our understanding of erectile function and possibly allow for development of therapeutic agents for the treatment of ED.en
dc.language.isoen_USen
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1267746864?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.-
dc.titleNitroxyl anion as a novel relaxant molecule in the rat pudendal artery and metformin as treatment for angiotensin II-induced erectile dysfunctionen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorWebb, Clinton-
dc.description.committeeErgul, Adviye; Bollag; Mong; Dong, Zheng-
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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