Date of Award

2011

Degree Type

Thesis

Department

Biological, Geological and Environmental Sciences

First Advisor

Moravec, Christine S.

Subject Headings

Parasympathetic nervous system, Muscarinic receptors, Heart failure, Heart -- Left ventricle, parasympathetic nervous system, muscarinic receptors, heart failure, left ventricular assist device

Abstract

Heart failure (HF) affects 5.8 million Americans and is characterized by an inability of the heart to pump blood throughout the body. In a non-diseased state, the sympathetic (SNS) and parasympathetic nervous systems (PNS) innervate the heart to regulate rate and force of contraction. Actions of the PNS on the cardiovascular system are mediated via the vagus nerve, releasing acetylcholine which binds muscarinic receptors on cardiomyocytes. The SNS has been found to be overstimulated in HF, with the role of the PNS in HF unclear. We hypothesized that the PNS is dysregulated in HF, resulting in a change of muscarinic receptor densities. We measured total muscarinic receptor density on non-failing and failing human heart samples, and determined if demonstrated differences were reversed through mechanical unloading with a left ventricular assist device (LVAD). Through radioligand binding assays, we found a significant increase in receptor density in failing human heart samples compared to control (275.8 ± 177 11.9 versus 194.1 ± 177 17.3 fmol/mg protein p We also measured M1-M4 receptor subtypes on a subset of these samples. While the percent of M1, M2, and M4 receptor subtypes did not significantly change between non-failing, failing, and failing with LVAD support samples, the percent of M3 was significantly decreased in failure (8.61 ± 177 1.65 versus 13.56 ± 177 2.16 p Muscle function analysis was also performed. Acetylcholine and isoproterenol were used to determine if a change in total muscarinic receptor density in groups related to a change in functional response on fresh trabecular muscles with and without SNS stimulation. Recovery in contractile parameters without SNS stimulation on ACh-treated muscles, and greater negative inotropic and chronotropic effects on ACh-treated muscles with SNS stimulation provide evidence that total muscarinic receptor density changes elicit different responses on the failing human heart

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