Date of Award

7-1-2007

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Integrative Physiology

Department

Graduate School of Biomedical Sciences

First Advisor

James L. Caffrey

Second Advisor

H. Fred Downey

Third Advisor

Michael Smith

Abstract

Deo, Shekhar H., Delta Opioid Receptor: Parasympathetic Location and Changing Phenotypes in Canine Heart. Doctor of Philosophy (Integrative Physiology), July 23, 112 pp, 4 tables, 24 figures. Delta opioid receptors (DOR) have long been implicated in the complex mechanism of ischemic preconditioning (IPC). Repeated arterial occlusion of the SA node artery in IPC protocol progressively raised the nodal encephalin concentrations and improved vagal transmission during a subsequent extended occlusion. This vagatonic effect was reversed by the DOR-1 antagonist, BNTX. The present thesis tested whether the IPC protocol, the prolonged occlusion or a combination of both was required to demonstrate the vagotonic effect. The study also tested whether the evolution of the vagotonic effect during occlusion might be attributed to erosion of completing vagolytic effects. A progressive improvement in vagal transmission was observed during the IPC protocol. The vagotonic effect was not observed during sham occlusions or during occlusions in animals pretreated with a DOR-1 antagonist. Following the IPC protocol, exogenous MEAP reduced vagal transmission under both normal and occluded conditions. The magnitude of the vagolytic effects was however significantly reduced and eroded further over time compared to time matched shams. The loss of the response was not altered by prior DOR-1. The magnitude of the vagolytic effects was however significantly reduced and eroded further over time compared to time matched shams, however the failure of DOR-1 blockade to slow that process suggests that the PC mediated erosion is independent of receptor activation by DOR-1 agonists. Although DORs are associated with IPC, their precise location remains unconfirmed. DOR and autonomic markers vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH) were labeled in tissue sections and synaptosomes from canine atrium and SA node. Synapsin I verified the neural character of labeled structures. Acetylcholine and norepinephrine content indicated both cholinergic and adrenergic synaptosomes are present. VAChT and TH signals indicated more than 80% of synapsin positive synaptosomes were cholinergic and less than 8% were adrenergic. Western blots of synaptosomal extracts confirmed by two DOR bands at molecular weights corresponding to reports for DOR monomers and dimmers. The preferential association of DORs with cholinergic nerve terminals supports the hypothesis that post-ganglionic prejunctional DORs regulate local vagal transmission within the heart.

Comments

Deo, Shekhar H., Delta Opioid Receptor: Parasympathetic Location and Changing Phenotypes in Canine Heart. Doctor of Philosophy (Integrative Physiology), July 23, 2007, 112 pp, 4 tables, 24 figures. W 4 D418d 2007

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