ABSTRACT
Hypertension and insulin resistance are often part of a complex set of abnormalities including obesity, hyperlipidemia and glucose intolerance described as syndrome X. Besides a common genetic basis, insulin resistance and hypertension might be linked by excessive activity of the sympathetic nervous system. Accordingly suppression of this sympathetic overactivity might be an effective approach to reduce hypertension and the concomitant metabolic effect. Since central imidazoline receptors are currently considered to be a specific phamacological target for blood pressure reduction, a study was undertaken to determine the effects of rilmenidine, a centrally antihypertensive agent with selectivity for imidazoline I[1] receptors, in an animal model of hypertension associated with insulin resistance, i.e. rats fed on a high fructose diet. First the effect of fructose diet on body weight, blood pressure, glucose tolerance, fasting insulin level and lipid profile of experimental rats was determined and compared with those of normal rats. Then the effects of rilmenidine and/or glibenclamide were studied on these parameters. As insulin resistance is commonly a predisposing factor to endothelial dysfunction, we assessed the effect of fructose diet on the aortic reactivity to norepinephrine [NE]. The effect of that diet on the vasodilator response to acetylcholine, after NE-induced contractions, was also determined. In addition we investigated whether fructose-induced endothelial dysfunction is the result of impaired nitric oxide [NO] or prostanoid relaxing factors. This was achieved by comparing NE-evoked contraction or acetyl choline-induced relaxation of aortae, isolated from normal and fructose fed rats, before and after addition of N [G] nitro L arginine methyl ester [L-NAME] [a nitric oxide synthase inhibitor] or indomethacin [a cyclooxygenase inhibitor]. Then we assessed whether ATP sensitive K+ channels are involved in the fructose-induced endothelial dysfunction. This was done by demonstrating responses to either NE or acetyl choline before and after administration of glibenclamide [an ATP sensitive K+ cha vbnnel blocker]. Lastly, the effect of treating fructose fed rats with rilmenidine and/or glibenclamide, on the contractile response to NE and on acetyl choline-mediated relaxation of NE-induced tone, was determined. Body weight gain, hypertension. hyperinsulinemia and hyperlipidemia [significant increase in plasma cholesterol, triglycerides [TG], low density lipoprotein [LDL] level with decrease in high density lipoprotein [HDL] level] were noticed in the fructose than in normal rats. During the intraperitoneal glucose tolerance test, blood glucose levels in fructose fed rats were significantly raised relative to normal rats. Rilmenidine treatment not only lowered blood pressure, but also reduced body weight and decreased the plasma cholesterol level compared to fructose non-treated group. Moreover, the glucose tolerance was improved in the fructose rilmenidine-treated rats. No significant alterations in the insulin level or the other lipid profiles were elicited by rilmenidinc. In contrast glibenclamide pretreatment reduced glucose tolerance and increased plasma high density lipoproteins; otherwise all other aspects, studied in this work, were not significantly modified by the drug. Combined administration of rilmenidine and glibenclaniide did not show significant changes than those noticed with rilmenidine treatment alone except on glucose level. Improvement of the glucose tolerance in fructose fed rats treated with both rilmenidine and glibenclamide was found to be better than that observed in rilmenidine treated group alone. By examining the aortic endothelial functions, we observed that the contractile response to NE and the mean percentage relaxation to acetyl choline were decreased in the fructose fed rats than in normal animals. Administration of L-NAME augmented the NE-induced contraction and attenuated acetyl choline mediated relaxation in both groups [being more in the normal group than in the fructose fed group]. This suggests attenuation of both the spontaneously released NO and that released by acetyl choline in the fructose fed group, as a result of impairment of endothelial cell functions. Addition of indomethacin to aortae, isolated from normal and fructose fed rats, did not produce any difference in either NE contractile response or acetyl choline-induced relaxation of both groups; suggesting that prostanoids do not play a role in the fructose-induced endothelial dysfunction. In contrast when gibenclamide was added to NE or acetyl choline in the normal aortic preparations an increase of NE-induced contraction or a reduction in acetyl choline relaxant effect was observed. However glibenclarnide had no effect on aortic preparations isolated from fructose fed rats in response to either NE or acetyl choline. This indicates impairement of the ATP-activated K+ channels in the fructose mediated endothelial dysfunction. When fructose fed rats were treated with rilmenidine, whether administered alone [group 3] or combined with glibenciamide [group 4], a significant decrease in the contractile response to NE and a significant increase of acetyl cholineinduced relaxation was observed when compared to fructose fed non treated rats. The difference between both treated groups was found to be statistically insignificant. These results indicate that dlmenidine and not glibenclamide improved endothelial dysfunction. In contrast glibenclamide treated rats showed no significant improvement in the fructose-induced endothelial dysfunction. These data demonstrate that rilmenidine can ameliorate the deleterious effects of a high fructose diet. The beneficial effect of the drug is probably a result of reducing the sympathetic overactivity associated with insulin resistant syndrome, improving the metabolic effects accompanying the fructose diet as well as releasing endothelial derived relaxing factors as a result of alpha[2] adrenoceptor stimulation. Accordingly rilmenidine should be considered for the treatment of hypertension associated with metabolic disorders such as syndrome X. In addition glibenclainide therapy didn't modulate the effects of rilmenidine on the parameters studied in this work. So rilmenidine nay be of benefit in the treatment of insulin resistant hypertensive patients taking glibenclamide. However clinical investigations should be done before the assurance of this combination safety