Disparate effects of antidiabetic drugs on arterial contraction

Type II diabetic patients and others with insulin resistance are at risk for development of hypertension characterized by elevated peripheral vascular resistance and loss of insulin's normal vasodilating activity. Oral antidiabetic drugs have recently been recognized to have disparate effects on arterial pressure in such patients and in related rodent models. Sulfonylureas (e.g., glyburide), which stimulate insulin secretion, have been reported either to increase or not to affect arterial pressure, whereas nonsulfonylurea agents with insulin-sensitizing properties, the biguanide metformin and various thiazolidinediones (eg, pioglitazone), have been reported to decrease arterial pressure in humans and rodents. To help elucidate these disparate effects, we investigated these agents for direct actions on arterial vascular contractility and its sensitivity to insulin. Preincubation of intact rat tail arterial tissue rings for 2 hours with known therapeutically effective antidiabetic concentrations of metformin and pioglitazone significantly attenuated the force of contractions produced by either potassium (membrane depolarization) or norepinephrine ([NE] adrenergic receptor activation). Glyburide did not influence these contractions. Preincubation with metformin also induced an attenuating (vasodilating-like) action of insulin on arterial tissue rings contracted by potassium. Conversely, glyburide induced an accentuating action of insulin on potassium-mediated contractions. These results are consistent with measures of vascular function obtained in the past after oral administration of the drugs, which suggested but did not prove that they may exert direct effects on arterial vascular contractility. Thus, metformin and thiazolidinediones may decrease arterial pressure partly by direct vasorelaxant mechanisms, with metformin having an additional effect of inducing vasorelaxation by insulin. In contrast, sulfonylureas may directly induce a paradoxical vasoconstrictor response to insulin.