Glyburide, an insulin secretagogue and an insulin-sensitizing agent, l
owers blood pressure in normal male and female dogs when administered
acutely. Because insulin resistance may contribute to spontaneous hype
rtension in rats, we sought to determine if long-term administration o
f glyburide (5 mg/kg per day by diet, age 5 weeks to 5 months) would l
ower blood pressure in male and female stroke-prone spontaneously hype
rtensive rats. Arterial (aortic) rings from these rats were incubated
with insulin in vitro (100 mU/mL) 1 hour before and during phenylephri
ne-induced contraction to determine if long-term glyburide administrat
ion improves vascular sensitivity to the intrinsic vasodilator action
of insulin. Glyburide, however, significantly increased blood pressure
s 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 mal
e rats (+4 mm Hg diastolic). Glyburide increased plasma insulin levels
(twofold, P<.04) in female but not in male rats. Glyburide did not af
fect plasma glucose or catecholamine levels. After incubation with ins
ulin, aortic rings from glyburide-treated female rats demonstrated mor
e than 40% greater contractile responsiveness to phenylephrine compare
d with aortic rings from control female rats (P<.04). This insulin-dep
endent increase in phenylephrine-induced contraction consisted of a re
versal in the in vitro action of insulin, from attenuation to accentua
tion of such contraction (P<.05). This change was not seen in male rat
s. Neither gender, glyburide, nor insulin influenced acetylcholine-ind
uced 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 administratio
n abolished this increase. Thus, long-term glyburide administration ag
gravates hypertension selectively in female stroke-prone spontaneously
hypertensive rats. This aggravation may be due to a sustained increas
e in circulating insulin accompanied by emergence of a paradoxical vas
oconstrictor sensitivity to insulin in vascular smooth muscle.