Attenuation of hypertension by insulin-sensitizing agents

The observation that pharmacologically diverse insulin-sensitizing agents and lipid-lowering drugs decrease blood pressure lends credence to the hypothesis that insulin resistance causes an elevation of arterial pressure. However, these agents may lower blood pressure by different mechanisms. On the basis of the physiological and metabolic effects of these drugs, we hypothesize that hypertension induced by insulin resistance may be mediated by one or more of the following: (1) stimulation of vascular smooth muscle growth and possibly renal sodium retention by compensatory hyperinsulinemia; (2) augmented vasoconstriction in response to norepinephrine and angiotensin II, possibly as a consequence of enhanced calcium influx across vascular muscle membranes; and (3) impaired endothelium-dependent vasodilation as a consequence of hyperglycemia and hyperlipidemia. Finally, other than thiazide diuretics and β-blockers, which decrease insulin sensitivity, insulin sensitivity is increased by several different classes of antihypertensive agents, including calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and peripheral α-adrenergic antagonists. The capacity of these drugs to increase insulin sensitivity may be a consequence of vasodilation and hence increased blood flow to insulin-sensitive tissues. On the basis of these observations, it is tempting to speculate that some common mechanism contributes to both vasoconstriction and resistance to insulin-stimulated glucose uptake, eg, increased intracellular free calcium concentrations in vascular smooth muscle and in insulin-sensitive tissues. A cycle may be established by which insulin resistance results in vasoconstriction and vasoconstriction in turn results in decreased blood flow to insulin-sensitive tissues and hence insulin resistance. Conceivably, the cycle may be interrupted by pharmacological agents that increase insulin sensitivity or alternatively by agents that increase blood flow to insulin- sensitive tissues as their primary action. Whatever mechanisms may be involved, the observation that a single agent may have the capacity to increase insulin sensitivity and attenuate the development of hypertension is potentially of considerable clinical significance. Furthermore, sufficient data may be available from animal studies to justify a controlled clinical trial of the effects of insulin-sensitizing agents, particularly thiazolidinediones, on blood pressure in hypertensive insulin-resistant humans.