Date of Award

5-1-2005

Degree Type

Restricted Access Thesis

Degree Name

Master of Science

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

James L. Caffrey

Second Advisor

H. Fred Downey

Third Advisor

Glenn Dillon

Abstract

Barlow, Matthew A., Vagotonic Effects of Enkephalin are not Mediated by Sympatholytic Mechanisms. Master of Science (Biomedical Sciences), May, 2005, 50pp. 1 table, 10 illustrations, bibliography. This study examined the hypothesis that the vagotonic and sympatholytic effects of cardiac enkephalins are independently mediated by different receptors. In study one, the heart rate response to increasing doses of the δ-receptor opioid, MEAP was determined during nerve stimulation. MEAP was administered by microdialysis into the interstitium of the canine sinoatrial node during sympathetic (right ansa subclavia) and parasympathetic (right cervical vagus) stimulation. This protocol was conducted to illustrate that the vagotonic effect of MEAP was independent of any simultaneous sympatholytic activity that might be intrinsic to MEAP. The right cardiac sympathetic nerves were isolated as they exited the stellate ganglion and were stimulated at frequencies selected to produce an intermediate increase in heart rate (HR) of approximately 35 bpm. The cervical vagi were ligated and the right vagus nerve was stimulated at frequencies related to produce a two-step decline in heart rate of approximately 25 and 50 bpm. Dose response relationships were constructed by recording the change in heart rate during nerve stimulation as the dose of MEAP was increased in 5-min steps from 0.05 pmoles/min to 1500 pmoles/min. A significant increase in vagal transmission was observed during the administration of δ-agonist, MEAP at 0.5 pmoles/min as evident by a greater decline in heart rate. The sympathetically mediated tachycardia was unaltered at this or any other dose of MEAP. In study two, a similar dose response relationship was constructed with the κ-opioid receptor agonist, U-50488H to illustrate an independent sympatholytic effect and to verify its κ-receptor character. U-50488H gradually suppressed the sympathetic tachycardia with a significant effect obtained at the highest dose (1500 pmoles/min). U-50488H had no effect on vagally mediated decreases in heart rate. Surprisingly the sympatholytic effect of U-50488H was not reversed by withdrawal of the agonist or by addition of the κ-antagonist, norBNI. Study three was conducted to determine whether the sympatholytic effect to U-50488H could be prevented by co-administration of norBNI. NorBNI blocked the sympatholytic effect of the U-50488H throughout 90 min of exposure. When norBNI was discontinued after 90 min and U-50488H was continued alone, its sympathetic effect reappeared within 30 min. Collectively these observations support the hypothesis that the vagotonic influence of MEAP was independent of sympathetic transmission and sympathetic transmission was unaltered by MEAP. Furthermore the observed sympatholytic effect of U-50488H was mediated independently by κ-receptors. The sympatholytic effect of sustained κ-receptor stimulation appears to evolve gradually into a functional state not easily reversed.

Comments

Barlow, Matthew A., Vagotonic Effects of Enkephalin are not Mediated by Sympatholytic Mechanisms. Master of Science (Biomedical Sciences), May, 2005, 50pp. 1 table, 10 illustrations, bibliography. W 4.5 B2579V 2005

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