The Observation Of Therapeutic Effects On Insulin Resistance In Spontaneously Hypertensive Rats By A New ATP-Sensitive Potassium Channel Opener: Iptakalim Hydrochloride

[Background] Insulin resistance is important mechanism of etiology and the basement of pathphsiology of metabolism syndrome(MS); such as coronary heart disease, hypertention, diabetes. Acording to the Hypertention League of China, 18% of adult over 15years old in china have hypertention, 3.5million patients were newly diagonised every year, the sum of patients were 160 million and the incidence would be rising more higher. Preventing IR may reduced the incidence of cardiac and cerebrovascular diseases. Present anti-hypertensive agents can effectively decrease blood pressure, but little effect on IR, so studying new effective and safe anti-hypertensive agents with improving IR effects has important meaning.ATP-sensitive potassium (K_ATP)channels are the main target proteins of antihypertensive agents. In vascular smooth muscle,K_ATP channel opening can induce membrane hyperpolarization and decrease intracellular Ca⁺ levels, thereby leading to peripheral vasodilatation and a reduction in blood pressure. Iptakalim( Ipt) , which belongs to a novel chemical type of KCO, possesses unique pharmacological properties. It selectively relaxes small arteries in vitro and also has selective antihypertensive activity that is more potent in the hypertensive state than in the normotensive state. As it decreases blood pressure, iptakalim also reverses hypertensive vascular remodeling and cardiac remodeling and prevents ischemic stroke. However, it is unclear whether iptakalim has effect on IR. Under previous research basis, using of Hyperinsulinemic Euglycemic Clamp Technique(HECT) , we study the experimental therapeutic effects and protective mechanism of iptakalim on IR in the spontaneously hypertensive rat (SHR) model. [Objective] Investigated the effects of Ipt on SHR IR forming, pancreas K_ATP geneexpression and the change of pancreas,heart,liver,kindy in pathyology. [Method] Rats were respectively entered into experiment at 1 month-old, 2 months-old,3 months-old, 4 months-old. SHR were randomly divided into 5 groups, SHR control group(n=5), iptakalim-treated SHR with a dose of 1 mg kg^-1 day^-1 (iptakalim-1-treated group) (n=6); iptakalim-treated SHR with a dose of 3 mg kg^-1 day^-1 (iptakalim-3-treated group) (n = 6); and iptakalim-treated SHR with a dose of 9 mg kg^-1 day^-1 (iptakalim-9-treated group) (n =6); benazepril-treated WKY with a dose of 6mg kg^-1 day^-1 (benazepril-treated group) (n =6); WKY rats (n = 5) was the normotensive control group. Iptakalim was administered by gastric lavage at doses of 1, 3, or 9 mg kg^-1 day^-1 for 8 weeks, benazepril was administered at doses of 6 mg kg^-1 day^-1 for 8 weeks; Using Hyperinsulinemic Euglycemic Clamp Technique (HECT) as diagnosis standard,which was golden standard of IR dignosis; Oberserve blood pressure(Bp),heart rate(HR), blood lipid ,kindy function ,Glucose, plasma Insulin ,hs-CRP, TNF-a ,IL-6 was measured by radioimmunoassay technique; Pancrease K_ATP genes expression were measured by reverse transcription-polymerase chain reaction( RT-PCR); At the same time, we observe the improvement of Ipt on pancreas,heart,liver,kindy of SHR by pathology examination.[Results] compare to WKY, the Bp of SHR increased significantly at 2- months-old and was steadly high at 4-months-old (194±13.3mmHg) (P<0.05);Compare to SHR control, different dose of Ipt- and benazepril-treated group all significantly decreasd Bp (P<0.05); HR of SHR increasd than that of WKY. After Ipt 3,9 mg ? kg^-1? d^-1 Were given, HR significantly decreased than SHR control group (P<0.05),whereas HR of Ipt-1 mg ? kg^-1? d^-1and benazepril-treated group had no change; The body weight (BW)of WKY and SHR increased quikly in the first to fifth month, the BW of every month had significance than that of previous month and was steady from the fifth month. Different dose Ipt and benazeprilhad no influence on BW; Compare to the same month-old WKY, The Bun and Cr of SHR increased than that of WKY,glucose and blood lipid had no significance. The plasma Insulin , hs-CRP , TNF-a and IL-6 of SHR increased significantly than those of WKY. After Ipt 3,9 mg ? kg^-1 ?d^-1 was administrated, the indexes above significantly decreased compare to SHR. Ipt 1 mg ? kg^-1? d^-1 and benazepril-treated grouphad no change;Glucose infusion rate (GIR) of SHRhad no significance than that of WKY before 4 month,with month increased, GIR of SHR decreased significance than that of WKY and persist 24 months. After Ipt 3,9 mg ? kg^-1? d^-1 was administrated, the GIR of 4,5,6 month-old SHR increasd significantly than that of SHR, and had no significance than WKY. Ipt 1 mg ? kg^-1 ? d^-1 and benazepril-treated grouphad no significance and decreased than WKY; Some subtype of K_ATP mRNA expression in SHR pancrea were changed, such as Transcript levels of SUR2, Kir6.1, and Kir6.2 were elevated, IRS-1, Glut-4, PI-3K p85 mRNA were decreased. After Ipt, Transcript levels of Kir6.1, and Kir6.2 were decreased, IRS-1, Glut-4, PI-3K p85 mRNA were elevated, SUR2 mRNA had no change; In pathology, pacrea epithelia of SHR were dilated,profile not clear, extracellular struction edema and fibrosis,much inflammatory cells soakage, extracellular capillary hyperplasia, luminal diameter occlusion; the luminal diameter of the afferent arteriole,arcuate artery, and interlobular artery were narrowed, wall of above blood vessel was thick ,so liminal/wall was smaller. After Ipt, pacrea epithelia' dilation lessened,profile being clear, extracellular struction edema and fibrosis alleviated, inflammatory cells soakage lessened, extracellular capillary hyperplasia and luminal diameter occlusion both lessen; the luminal diameter of the afferent arteriole, arcuate artery, and interlobular artery were increased, wall of above blood vessel was thin ,so liminal/wall was increasd.No obvious damage were found in heart and Liver. [Conclusion] Ipt can effectively decrease SHR Bp, HR, improve kindy function, decrease blood insulin, TNF-a, IL-6, hs-CRP,ameliorate IR, which perhaps has correlation with decreasing blood insulin,KTNF-a; Ipt has effect on Kir6.1,Kir6.2, IRS-2, Glut-4, PI-3K p85 gene expression,which can has correlation with target organ Protection; The pancreas, kidney histocyte and extracelluar pathology.and vascularwall had all damagement. Ipt can reversed thedamag of pancreas and kindyofSHR.