DISPARATE EFFECTS OF ANTIDIABETIC DRUGS ON ARTERIAL CONTRACTION

Type II diabetic patients and others with insulin resistance are at ri sk for development of hypertension characterized by elevated periphera l Vascular resistance and loss of insulin's normal vasodilating activi ty. Oral antidiabetic drugs have recently been recognized to have disp arate effects on arterial pressure in such patients and in related rod ent models. Sulfonylureas leg, glyburide), which stimulate insulin sec retion, have been reported either to increase or not to affect arteria l pressure, whereas nonsulfonylurea agents with insulin-sensitizing pr operties, the biguanide metformin and various thiazolidinediones leg, pioglitazone), have been reported to decrease arterial pressure in hum ans and rodents. To help elucidate these disparate effects, we investi gated these agents far direct actions on arterial vascular contractili ty and its sensitivity to insulin. Preincubation of intact rat tail ar terial tissue rings for 2 hours with known therapeutically effective a ntidiabetic concentrations of metformin and pioglitazone significantly attenuated the force of contractions produced by either potassium (me mbrane depolarization) or norepinephrine ([NE] adrenergic receptor act ivation). Glyburide did not influence these contractions. Preincubatio n with metformin also induced an attenuating (vasodilating-like) actio n of insulin on arterial tissue rings contracted by potassium. Convers ely, glyburide induced an accentuating action of insulin on potassium- mediated contractions. These results are consistent with measures of v ascular function obtained in the past after oral administration of the drugs, which suggested but did not prove that they may exert direct e ffects on arterial vascular contractility. Thus, metformin and thiazol idinediones may decrease arterial pressure partly by direct vasorelaxa nt mechanisms, with metformin having an additional effect of inducing vasorelaxation by insulin. In contrast, sulfonylureas may directly ind uce a paradoxical vasoconstrictor response to insulin. Copyright (C) 1 997 by W.B. Saunders Company.