Date of Defense

Fall 9-9-1990

Department

Biological Sciences

First Advisor

Kaush Meisheri, Upjohn Company

Second Advisor

William Jackson, Biological Sciences

Third Advisor

Leonard Beuving, Biological Sciences

Abstract

The vascular pharmacology of ATP-sensitive K+ channels was studied in isolated rabbit mesenteric artery. Using the drugs glyburide, a K[ATP] channel blocker, and pinacidil, a K[ATP] channel opener, studies were carried out involving dose-reponse relationships and time of action requirements. The intention of the study was to use the data to further elucidate the functional interaction between the agonist and an antagonist working on the same K+ channel. In addition pH studies were conducted on pinacidil, glyburide and other vasodilators to test for the specificity of the pH effect on K[ATP] channels. A final investigation was made into the area of temperature effects on pinacidil as compared to other vasodilators. It was found that glyburide inhibits pinacidil relaxation in a dose-dependent manner and requires a minimum time period of 10-15 minutes to exert its optimal effect. In addition, lyburide was shown to reverse pre-existing relaxation by pinacidil, independent of the degree of relaxation that had occurred. The data suggest the mechanism and site of action of pinacidil on ATP-sensitive K+ channels compared to those of glyburide may be quite different. Investigations of pH showed that lowering the pH decreases the effectiveness of pinacidil, but not the vasodilator D600. Since D600 does not work through K+ channels as pinacidil does the pH effect may be specific for these channels. Consistent with these findings, it was also found that acidic pH increases the effectiveness of the glyburide blockade. Investigations of temperature effects on pinacidil and other vasodilators showed these effects to be non-specific, probably affecting general cell functioning. In summary, the results obtained in this study should provide a basis for further experimental understanding of the ATP-sensitive K+ channel pharmacology in vascular smooth muscle.

Access Setting

Honors Thesis-Campus Only

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