High-dose, not low-dose insulin increases the vasoconstrictor effect of norepinephrine in spontaneously hypertensive rats: Effects of antihypertensive treatment

The effect of insulin on the vasoconstriction induced by norepinephrine is presently controversial. Therefore, the aims of our study were: (1) to eval uate the effect of low- and high-dose insulin on the concentration-response curve to norepinephrine in small resistance arteries of spontaneously hype rtensive rats (SHR) and Wistar Kyoto rats (WKY) before and after the develo pment of hypertension, and (2) to evaluate the effects of antihypertensive treatment on vascular response to insulin and norepinephrine. Fifty-six rat s were included in the study. Six SHR were treated with enalapril and 6 wit h candesartan cilexetil from the 4th to the 12th week of age, while 10 WKY and 14 SHR were kept untreated. Two additional groups of 10 untreated SHR a nd 16 WKY were killed at 4 weeks of age, in a prehypertensive phase. Mesent eric small arteries were dissected and mounted on a micromyograph. A dose-r esponse curve to norepinephrine was performed at cumulative concentrations in the presence or absence of low- and high-dose insulin. We found that onl y high-dose insulin increased the vascular response to norepinephrine in 12 -week-old SHR, but not in 4-week-old SHR or in age-matched WKY. The increas ed responsiveness to norepinephrine disappeared after preincubation of the vessels with a selective inhibitor of endothelin-l type A receptors. After antihypertensive treatment with enalapril or candesartan cilexetil, the pot entiation of the vasoconstrictor response to norepinephrine was abolished. in conclusion, insulin at high, nonphysiological doses seems to induce an i ncrease in the reactivity to norepinephrine in mesenteric small arteries of SHR, possibly mediated by a local production of endothelin-l. Antihyperten sive treatment with an ACE inhibitor or an angiotensin II receptor blocker may normalize this altered response. This mechanism may be relevant in the development of hypertension in SHR. Copyright (C) 1999 S. Karger AG, Basel.