Potassium channels play an important role in the physiology of diverse tissues, including pancreatic beta-cells, vascular smooth muscle, and the heart. Drugs which inhibit or activate potassium egress through these channels are increasingly being applied in the treatment of common human diseases such as diabetes, hypertension, and cardiac arrhythmias. The overall goal of this Project is to determine factors which account for variability in response to potassium channel modulators in humans. In vitro data indicate that the effects of inhibitors such as quinidine or glyburide can be blunted by activators such as minoxidil or pinacidil; clinical studies will assess the consequences of such combinations in modulating these compounds' antihypertensive, hypoglycemic or electrophysiologic effects. A risk with potassium channel blocking (Class III) antiarrhythmics is unpredictable and excessive QT interval prolongation and induction of the polymorphic tachycardia, torsades de pointes. The hypothesis, derived from cellular studies, that sympathetic activation will blunt the QT interval prolonging actions of Class III agents, will be tested in normal volunteers and in patients undergoing pharmacologic conversion of atrial fibrillation. Torsades de pointes is also a well-recognized complication of treatment with a number of compounds not generally thought to have electrophysiologic activity; these include the very widely-used "non-sedating" antihistamines, terfenadine and astemizole, both of which are administered as racemates. To determine if enantiomer-specific therapy is justified, the electrophysiologic effects of terfenadine's enantiomers will be assessed in models predictive of torsades de pointes, and enantiomers will be administered to humans to assess the extent of racemization in vivo. This series of studies will not only provide information to increase the safety of drugs targeting potassium channels, but also will provide insights into the basic mechanisms responsible for individual variability in their desirable and undesirable actions.