Unlike related diuretics indapamide has been found by some investigators to be associated with a mild reduction in heart rate during its use as an antihypertensive agent. This investigation concerns the attempt to duplicate this phenomenon in animals and to elucidate possible mechanisms. In isolated frog hearts, high concentrations (0.3 mM) of indapamide decreased contractions 21.7 +/- 1.2% and rate 9.1 +/- 1.0%. This effect was not observed with chlorothiazide, acetazolamide, or furosemide and was not altered by atropine. Also in the frog heart, 0.03 mM indapamide reduced the stimulatory effects of isoproterenol and calcium ion and enhanced the inhibitory action of acetylcholine. In open-chest cats, after 30 min, indapamide (3 mg/kg, i.v.) elicited minor decreases in heart rate, aortic flow, and mean carotid pressure. When arterial pressure was rapidly reduced by acetylcholine (5 microgram/kg, i.v.) the resultant rise in aortic flow was significantly diminished by indapamide pre-treatment. Antifibrillatory activity was measured in the open-chest cat by determining the minimum electrical current, delivered to the right atrium, required to induce atrial fibrillation. Quinidine (5 mg/kg, i.v.) and chlorothiazide (10 mg/kg, i.v.) raised the fibrillatory threshold 94.3 +/- 10.1 % and 45.1 +/- 4.0 % respectively while indapamide displayed minimal activity.