Date of Award

2012

Publisher

North Dakota State University

Document Type

Dissertation

Degree Awarded

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Department

School of Pharmacy

College

Health Professions

Faculty Advisor

O'Rourke, Stephen

Description

This research represents an effort to bridge a critical gap in the understanding of the local effects of melatonin on the coronary circulation. The first objective was designed to identify the specific melatonin receptor mediating the inhibitory effect of melatonin on nitric oxide (NO)-induced relaxation of porcine coronary arteries. Based on current data, one can conclude that the melatonin (MT) type-2 receptor mediates the inhibitory effect of melatonin on coronary arterial relaxation induced by either exogenous or endogenous NO. I have also tested the hypothesis that melatonin inhibits the NO-induced increase in cGMP levels by increasing the degradation of cGMP by cGMP specific phosphodiesterase (PDE). The results suggest that in coronary arteries melatonin acts via MT2-receptors and stimulates the PKG1-dependent PDE5 phosphorylation, resulting in decreased cyclic GMP accumulation in response to NO and impaired NO-induced vasorelaxation. It was further tested whether the impairment of NO-induced relaxation of porcine coronary arteries by melatonin involves inhibition of NO-activated BKCa channel activity in porcine coronary smooth muscle cells. Findings from these studies provide evidence that the impairment of coronary artery relaxation in response to NO by melatonin involves MT2-receptor coupled inhibition of NO-activated BKCa currents. The results of these studies have improved our understanding of the role of melatonin in regulation of local coronary vascular tone. Inasmuch as the NO pathway is a critical regulator of coronary arterial smooth muscle tone, inhibition of this pathway may contribute to the mechanisms by which melatonin influences coronary arterial function in health and disease.

Rights

NDSU Policy 190.6.2

Rights Link

https://www.ndsu.edu/fileadmin/policy/190.pdf

Handle Identifier

https://hdl.handle.net/10365/26653

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