| A great many of clinical and epidemiological studies have demonstrated that hyperuricemia is closely associated with the development of hypertension and renal disease. The incidence of hypertension is significantly higher in the populations with hyperuricemia than that in the populatons with normal serum uric acid. However, it is present in 25% of untreated hypertensive subjects. There is an increased risk of cardiovascular and cerebrovascular events in patients with hypertension companied by hyperuricemia. Hyperuricemia can induce, aggravate, and predict the renal injury, and it can result in the development of hypertension. It has been demonstrated that hyperuricemia may induce endothelial dysfunction by inhibiting the production of nitric oxide(NO), which may be one of the pathogenic mechanisms causing reno-cardiovascular damage.Iptakalim is a new ATP-sensitive potassium (Katp) channel opener with antihypertensive property. Iptakalim not only has definite, stable, and lasting antihypertensive effects, but also can reverse the remodeling of structure and function of heart, blood vessel, and kidney damage induced by hypertension. It may enhance NO production in the endothelial cells and prevent pathological elevation of plasma endothelin-l(ET-l) via different pathways to block the biological function of ET-1, as well as, iptakalim has an protective effects on the impaired endothelium induced by homocysteineamia. Therefore, based on previous findings, we investigated the effects of iptakalim on hypertension and renal injury induced by hyperuricemia and further explore the protective effects of it on the impaired endothelium induced by hyperuricemia in the hyperuricemic rat model, in order to provide the theoretical evidence to support iptakalim which was applied to clinical treat hypertensive patients combine with hyperuricemia.According to the theory of increasing uric acid supplements and blocking uric acid breakdown by inhibiting uricase. Hyperuricemia was induced in male Sprague-Dawley rats with an uricase inhibitor, 2% oxonic acid, by gavage at dose of 2.5ml/100g per time for three time per day, and combine with o.lmmol/L uric acid added in drinking water. Rats were randomly divided into five groups: normal control(control);hyperuricemia model(model);iptakalim-treated hyperuricemia with a dose of 0.5mg/kg (iptakalim-0.5-treated group);iptakalim-treated hyperuricemia with a dose of 1.5mg/kg (iptakalim-1.5-treated group);iptakalim-treated hyperuricemia with a dose of 4.5mg/kg (iptakalim-4.5-treated group). Iptakalim were administered by gavage at doses of 0.5, 1.5, or 4.5mg/kg/d for 5 weeks when hyperuricemia were induced. We investigated effects of iptakalim on changes of systolic blood pressure, heart rate, urine, renal function, renal histopathology, vascular morphology, serum NO, plasm ET-1, plasm PGt, plasm angiotensin II (Angll), and plasm renin activity in rats with hyperuricemia. We observed effects of iptakalim on the impaired endothelium induced by hyperuricemia in rat isolated aortic rings;and we also detected effects of iptakalim on changes of both ET-lmRNA and eNOSmRNA expressions in aortic tissue, and in intrarenal tissue, respectively.The present study comes to the following results:1. Serum uric acid level was significantly increased at 2 weeks and maintained at higher level during the whole study period in hyperuricemic rats model induced by 2%oxonic acid plused O.lmmol/L uric acid. Systolic blood pressure was also markedly evaluated, and renal function was impaired. Level of serum uric acid was positive correlated with systolic blood pressure.2. Iptakalim dose-dependently decreased or prevented increase in systolic blood pressure caused by hyperuricemia.3. Hyperuricemia caused dysfunction of kidney with increased urinary excretion of urinary protein, N-aceto-beto-amino-glucosidase(NAG) leveland 24h urine volume. Decrease in urine osmotic pressure and elevation of serum of BUN and Cr in hyperuricemic rats was significantly attenuated when iptakalim was used. On histopathology, iptakalim attenuated pathological changes in the glomerular and renal interstitia.4. Hyperuricemia was found to reduce the relaxation-induced by Ach in the isolated aortic rings, caused the smooth muscle cell proliferation and the resistance arterial thickening, such as the tail arterioles, and the renal arterioles. Iptakalim ameliorated the impairment of the endothelial vasodilator function, inhibited the smooth muscle cell proliferation, arterial thickening and stenosis.5. Hyperuricemic rats had a remarkable increase in blood levels of ET-1 and Angll and in blood renin activity. There was a decrease in plasma NO and PGI2 in hyperuricemic rats. Meanwhile, hyperuricemia up-regulated the expression of ET-lmRNA and down-regulated the expression of eNOS mRNA in aortic tissue and in intrarenal tissue. Iptakalim dose-dependently reduced plasma ET-1 , increased blood levels of NO and PGI2, accompanied by inhibiting the expression of ET-lmRNA and enhancing the expression of eNOS mRNA in the aortic and intrarenal tissue. There was no effects of iptakalim on plasma AngH and blood renin activity.In summary, our study indicates that hyperuricemic rat model may be induced successfully by oxonic acid plus uric acid. Hyperuricemia results in hypertension and renal injury, which is related to increase level of ET-1 and decrease levels of NO and PGI2. Thus, hyperuricemia induces endothelial dysfunction by which impaired blood vessel. Iptakalim reduces increasing blood pressure and attenuated renal injury, which may benefit from decreasing level of ET-1 and increasing levels of NO and PGI2. These siuggest that iptakalim may protect the endothelial function and ameliorate impaired blood vessel induced by hyperuricemia.
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