Date of Award

10-6-2008

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Integrative Physiology

Department

Graduate School of Biomedical Sciences

First Advisor

Peter B. Raven

Second Advisor

Patricia Gwirtz

Third Advisor

Glenn H Dillon

Abstract

Barlow, Matthew A. Deltoid Opioid Receptor Phenotype Modulation of Hindlimb Vascular Conduction. Doctor of Philosophy (Integrative Physiology), Oct 6th, 2008, 136 pp, 1 table 26 figures. Hypertension, diabetes mellitus and their presumed precursor the metabolic syndrome are part of a complex disease process associated with insulin resistance. Neurovascular complications in diabetics commonly involve the lower limbs resulting in a vicious cycle of autonomic neuropathy, painful occlusive claudication and resulting immobility that precipitates inactivity and progressive disability. The fixed neural and vascular diseases evolve slowly and the early events in this progressive decline in function are poorly understood. Sympathetic vasoconstriction is a major component of blood flow regulation in muscle. Active vasoconstriction in the lower limbs depends on continued transmission of efferent vasomotor signals through the lumbar sympathetic chain ganglia. Opioid receptors actively reduce normal ganglionic transmission presumably by lowering acetylcholine release. In the heart, the subtypes of delta-opioid receptors (DORs) facilitate (DOR-1, vagotonic) and inhibit (DOR-2, vagolytic) cholinergic transmission in the heart. The DOR-2 mediated inhibitory effects in heart are alterable and can change rapidly. Diabetes impairs vascular control. Ganglionic transmission is metabolically vulnerable during high fat feeding and insulin resistance. We hypothesized that the DOR-2 stimulation significantly facilitates vasodilation by reducing cholinergic transmission within the sympathetic chain ganglion. The ability to activate DOR-1 stimulation facilitates to cause further vasoconstriction in the anesthetized and surgically instrumented state of the dog did not show dose dependent activation. The DOR-1 activity in the insulin resistant dogs appears to be decreased as the DOR-1 blockade had no effect on the dose responses in the heart or the hindlimb. Enhanced sympathetic tone through BCO by increasing and reducing cholinergic transmission in the lumbar sympathetic ganglion shows an enhanced pro-constrictor phenotype under stresses of severe hypotension possibly through a DOR-1 mediated activation.

Comments

Barlow, Matthew A. Deltoid Opioid Receptor Phenotype Modulation of Hindlimb Vascular Conduction. Doctor of Philosophy (Integrative Physiology), Oct 6th, 2008, 136 pp, 1 table 26 figures. W 4 B258d 2008

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