SEX-SPECIFIC EFFECTS OF AN INSULIN SECRETAGOGUE IN STROKE-PRONE HYPERTENSIVE RATS

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 (P<.04). 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 or phenylephrine-induced 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.