Key result
High-dose insulin increased the vasoconstrictor response to norepinephrine in 12-week-old spontaneously hypertensive rats, an effect abolished by antihypertensive treatment.
Why the study?
Does insulin exposure alter norepinephrine-induced vasoconstriction in spontaneously hypertensive rats, and is this effect modified by antihypertensive treatment?
Does insulin exposure alter norepinephrine-induced vasoconstriction in spontaneously hypertensive rats, and is this effect modified by antihypertensive treatment?
High-dose insulin potentiates norepinephrine-induced vasoconstriction in hypertensive rats via an endothelin-1 mediated mechanism, which can be normalized by treatment with ACE inhibitors or ARBs.
Does not support changes to insulin therapy in hypertension; hypothesis-generating for endothelin-mediated effects modifiable by antihypertensives.
The effect of insulin on the vasoconstriction induced by norepinephrine is presently controversial. Therefore, the aims of our study were: (1) to evaluate the effect of low- and high-dose insulin on the concentration-response curve to norepinephrine in small resistance arteries of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) before and after the development of hypertension, and (2) to evaluate the effects of antihypertensive treatment on vascular response to insulin and norepinephrine. Fifty-six rats were included in the study. Six SHR were treated with enalapril and 6 with 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 and 10 WKY were killed at 4 weeks of age, in a prehypertensive phase. Mesenteric small arteries were dissected and mounted on a micromyograph. A dose-response curve to norepinephrine was performed at cumulative concentrations in the presence or absence of low- and high-dose insulin. We found that only 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 increased responsiveness to norepinephrine disappeared after preincubation of the vessels with a selective inhibitor of endothelin-1 type A receptors. After antihypertensive treatment with enalapril or candesartan cilexetil, the potentiation of the vasoconstrictor response to norepinephrine was abolished. In conclusion, insulin at high, nonphysiological doses seems to induce an increase in the reactivity to norepinephrine in mesenteric small arteries of SHR, possibly mediated by a local production of endothelin-1. Antihypertensive 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.
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Rizzoni et al. (1999) studied Hypertension (n=56). High-dose insulin and antihypertensive treatment (enalapril or candesartan cilexetil) vs. Low-dose insulin, untreated rats, WKY rats was evaluated on Vascular response to norepinephrine in mesenteric small arteries. High-dose insulin increased the vasoconstrictor response to norepinephrine in 12-week-old spontaneously hypertensive rats, an effect abolished by antihypertensive treatment.
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