The effects of first generation sulphonylurea compounds carbutamide, gliclazide and tolbutamide as well as second generation compounds glibenclamide and glipizide on the cardiovascular system were investigated in dogs. Six dogs received each compound intravenously at cumulative dose levels of 74, 296, 1184 mumol/kg of carbutamide and tolbutamide, 0.4, 2.0, 10.0 mumol/kg of glibenclamide and glipizide, and 16, 48 and 144 mumol/kg of gliclazide. Mean arterial blood pressure, myocardial contractile force, cardiac output and heart rate were measured. The rate of change of myocardial contractile force development (positive dF/dt), as well as of myocardial relaxation (negative dF/dt) were measured. The first generation sulphonylureas were found, in dogs, to exert a positive inotropic effect in contrast to second generation compounds. The clinical importance of our findings may be in the potential for the malfunction of the cardiovascular system (based on cardiopathy, neuropathy, atherosclerosis, and obesity), developing in diabetes, to be further impaired by the first generation sulphonylureas. Therefore, second generation sulphonylureas should be preferred in the therapy of type 2 diabetics, if satisfactory metabolic control cannot be achieved by dietary management alone and sulphonylurea treatment becomes necessary.