There is a high incidence of diuretic use among patients who develop exaggerated QT prolongation and polymorphic ventricular tachycardia (torsade de pointes) during treatment with action potential-prolonging agents. Diureticinduced hypokalemia is thought to be the usual mechanism, but a direct effect of diuretic drugs on repolarizing currents is an additional possibility. Therefore, in this study, we examined the effects of the diuretic agents chlorthalidone and indapamide on the cardiac delayed rectifier current. In guinea pig ventricular myocytes, this current is made up of two components: 1Kr, a rapidly activating, inwardly rectifying current blocked by most action potential-prolonging antiarrhythmics, and IKC, a slowly activating component. In this preparation, indapamide blocked outward current in a time-, voltage-and concentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was without effect. The following features of the effect of indapamide strongly suggest selective block of IK,: (1) Indapamide block was significantly greater with 5000-millisec-S elective prolongation of cardiac repolarization was proposed as a mechanism of antiarrhythmic drug action over 20 years ago.' This "class III" action has become a major focus in antiarrhythmic drug development, because of the perceived liabilities of Na+ channel blockers2,3 and the theoretical advantages of class III therapy.4 1 Compounds that selectively prolong cardiac repolarization, unlike Na' channel blockers, improve survival in an animal model of ischemic ventricular fibrillation,4-6 facilitate ventricular defibrillation,7 and may augment cardiac contractility.8 However, in clinical trials, the action potential prolongation produced by antiarrhythmic drugs can also be associated with polymorphic ventricular tachycardia, the torsade de pointes syndrome.9-12 Available information indicates that this side effect is facilitated by slow heart rates and electrolyte disturbances, most commonly hypokalemia and/or hypomagnesemia. The latter are often provoked by concomitant therapy with K'-wasting diuretics.'0,'2,13Action potential prolongation by antiarrhythmic drugs is a result of either an increase in inward currents or, more commonly, a decrease in outward currents. MultiReceived July 12, 1993; accepted August 29, 1994. From the Departments of Pharmacology and Medicine (P.B.B., S.SW., L.S., D.M.R.), Vanderbilt University, Nashville, Tenn, and the Qu6bec (Canada) Heart Institute (J.T., P.D.), Hopital Laval.Presented in part in abstract form (Biophys J. 1991;59:278a with minK, a cRNA encoding an IK,-like current, induced current was blocked by indapamide. These studies demonstrate that indapamide is a K+ channel blocker but, unlike most antiarrhythmics, targets IKS. (Circ Res. 1994;75:879-886.) Key Words * indapamide * diuretics * K' current ple outward current phenotypes have been identified in mammalian tissues; these include time-independent currents such as 'K1I, 1c14 or I ,"15 inactivating currents such as ITO16 or 1Ca_,317 and the de...

A prevalence study was designed to evaluate host and seasonal risk factors associated with three systemic mycoses in dogs: blastomycosis, coccidioidomycosis, and histoplasmosis. Histoplasmosis was the most commonly diagnosed of the three diseases. All three of the mycoses occurred more frequently in male than female dogs. Compared to dogs less than 2 years of age, those 4--7 years of age were at increased risk of developing coccidioidomycosis whereas dogs 2--7 years of age were at increased risk of developing histoplasmosis. Three breeds, i.e., Pointer, Weimaraner and Brittany Spaniel, had increased risk of having histoplasmosis infections. Seasonal analysis with an epidemiologic trend model indicated that all three systemic mycoses have different but strong seasonal trends.

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Arsenic poisoning is one of the more important causes of heavy metal poisoning in domestic animals. Two speciedogs and cattle-are intoxicated more frequently than other animals; yet sporadic instances of poisoning have been observed in cats, horses, and pigs. Cases observed by veterinary dinicians are either peracute, acute, or chronic intoxications. Frequently the initial and only indication that a severe problem exists with peracute poisoning in a cattle herd is dead animals. Chronic intoxications are also observed in cattle. Acute intoxication is the most common form of arsenic poisoning observed and documented in the dog. Also intoxicated dogs were younger, i.e., 2-6 months of age. Arsenic is a severe alimentary tract irritant in domestic animals, and treatment in most instances consists mainly of symptomatic and supportive treatment. The source of intoxication, when it can be determined, is usually dips, sprays, powders, or vegetation contaminated by pesticides containing arsenic.