Glyburide, an insulin secretagogue and an insulin-sensitizing agent, lowers blood pressure in normal male and female dogs when administered acutely. Because insulin resistance may contribute to spontaneous hypertension in rats, we sought to determine if long-term administration of glyburide (5 mg/kg per day by diet, age 5 weeks to 5 months) would lower blood pressure in male and female stroke-prone spontaneously hypertensive rats. Arterial (aortic) rings from these rats were incubated with insulin in vitro (100 mU/mL) 1 hour before and during phenylephrine-induced contraction to determine if long-term glyburide administration improves vascular sensitivity to the intrinsic vasodilator action of insulin. Glyburide, however, significantly increased blood pressures and ratios of heart weight to body weight in 5 -month-old female rats (+20 mm Hg diastolic, P<.05), with no significant change noted in male rats (+4 mm Hg diastolic). Glyburide increased plasma insulin levels (twofold, P<.04) in female but not in male rats. Glyburide did not affect plasma glucose or catecholamine levels. After incubation with insulin, aortic rings from glyburide-treated female rats demonstrated more than 40% greater contractile responsiveness to phenylephrine compared with aortic rings from control female rats (/*<.O4). This insulin-dependent increase in phenylephrine-induced contraction consisted of a reversal in the in vitro action of insulin, from attenuation to accentuation of such contraction (P<.05). This change was not seen in male rats. Neither gender, glyburide, nor insulin influenced acetylcholine-induced relaxation of phenylephrineinduced contraction. Insulin in vitro slightly increased nitroprusside-induced relaxation (P<.05) of aortic rings from female but not from male rats, and glyburide administration abolished this increase. Thus, long-term glyburide administration aggravates hypertension selectively in female stroke-prone spontaneously hypertensive rats. This aggravation may be due to a sustained increase in circulating insulin accompanied by emergence of a paradoxical vasoconstrictor sensitivity to insulin in vascular smooth muscle. (Hypertension 1993^2:214-220) KEY WORDS • vascular resistance • insulin • sulfonylurea compounds • catecholamines • glucose • gender T here is considerable evidence that the insulin resistance and hyperinsulinemia of diabetes also exists in essential hypertension 1 and in various genetic models of hypertension such as Zucker obese, Dahl salt-sensitive, and spontaneously hypertensive rats (SHR).2 -4 Recently, two separate classes of antidiabetic, insulin-sensitizing agents (biguanides and thiazolidinediones) were reported to attenuate hypertension in these animal models.57 Glyburide (a secondgeneration sulfonylurea antidiabetic agent) has been reported to decrease blood pressure when administered acutely to normal male and female dogs. 8 -9 Sulfonylurea agents are insulin secretagogues 10 but have also been reported to sensitize peripheral tissues to insulin actions.11 ' 12 We sought to de...

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The pharmacodynamic effects of single oral doses of atenolol (100 mg), labetalol (300 mg), and propranolol (80 mg) were compared with those of placebo in a randomized, double-blind, Latin square design in 12 patients with hypertension. Atenolol and propranolol both significantly reduced cardiac output (-0.55 vs. -0.31 L/min) and heart rate (-8.0 vs. -6.6 bpm), whereas labetalol had no effect on either parameter (-0.08 L/min; + 1.0 bpm). Labetalol significantly reduced vascular resistance (-339 dynes X cm/sec5), but atenolol and propranolol did not (147 vs. 62 dynes X cm/sec5). Only labetalol significantly reduced the systolic (-15.3 mm Hg), diastolic (-11.5 mm Hg), and mean blood pressures (-12.8 mm Hg). Atenolol significantly reduced only diastolic blood pressure (-5.20 mm Hg), whereas propranolol failed to lower these parameters significantly. These data indicate that the hemodynamic profile of labetalol differs from that of selective and nonselective beta-blockers. Labetalol lowered blood pressure primarily by reducing vascular resistance, whereas reductions in heart rate and cardiac output were the predominant effects of atenolol and propranolol.