Abstract
Aim:
To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs).
Methods:
Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states.
Results:
(1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1–10 μmol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg·kg−1·d−1, for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2–4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg·kg−1·d−1, for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level.
Conclusion:
These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- KATP:
-
ATP-sensitive potassium channel
- IR:
-
insulin resistance
- SHR:
-
spontaneously hypertensive rat
- FFR:
-
fructose-fed rat
- GIR:
-
glucose infusion rate
- SBP:
-
systolic blood pressure
- HUVEC:
-
human umbilical vein endothelial cells
- NO:
-
nitric oxide
- ET-1:
-
endothelin-1
- Ang II:
-
angiotensin II
- ACEI:
-
angiotensin-converting enzyme inhibitor
- 6-Keto-PGF1α:
-
6-Ketoprostaglandin-F1α
- PAI-1:
-
plasminogen activator inhibitor-1
- PPARγ:
-
γ peroxisome proliferator-activated receptors
References
Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350–7.
Reddy KJ, Singh M, Bangit JR, Batsell RR . The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review. J Cardiovasc Med (Hagerstown) 2010; 11: 633–47.
Penesova A, Cizmarova E, Belan V, Blazicek P, Imrich R, Vlcek M, et al. Insulin resistance in young, lean male subjects with essential hypertension. J Hum Hypertens 2011; 25: 391–400.
Perticone F, Sciacqua A, Maio R, Perticone M, Galiano Leone G, Bruni R, et al. Endothelial dysfunction, ADMA and insulin resistance in essential hypertension. Int J Cardiol 2010; 142: 236–41.
Higashiura K, Ura N, Takada T, Li Y, Torii T, Togashi N, et al. The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats. Am J Hypertens 2000; 13: 290–7.
Umeda M, Kanda T, Murakami M . Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats. Hypertens Res 2003; 26: 485–92.
Pahor M, Psaty BM, Furberg CD . Treatment of hypertensive patients with diabetes. Lancet 1998; 32: s18–23.
Duncan ER, Crossey PA, Walker S, Anilkumar N, Poston L, Douglas G, et al. Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes 2008; 57: 3307–14.
Katakam PV, Ujhelyi MR, Hoenig ME, Miller AW . Endothelial dysfunction precedes hypertension in diet-induced insulin resistance. Am J Physiol 1998; 275: R788–92.
Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP . Endothelial dysfunction in metabolic syndrome: prevalence, pathogenesis and management. Nutr Metab Cardiovasc Dis 2010; 20: 140–6.
Kim JA, Montagnani M, Koh KK, Quon MJ . Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888–904.
Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol 2005; 289: H813–22.
Minamino T, Hori M . Protecting endothelial function: a novel therapeutic target of ATP-sensitive potassium channel openers. Cardiovasc Res 2007; 73: 448–9.
Pan Z, Huang J, Cui W, Long C, Zhang Y, Wang H . Targeting hypertension with a new ATP sensitive potassium channel opener iptakalim. J Cardiovasc Pharmacol 2010; 56: 215–28.
Duan RF, Cui WY, Wang H . Association of the antihypertensive response of iptakalim with KCNJ11 (Kir6.2 gene) polymorphisms in Chinese Han hypertensive patients. Acta Pharmacol Sin 2011; 32: 1078–84.
Wang H, Long C, Duan Z, Shi C, Jia G, Zhang Y . A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells. Cardiovasc Res 2007; 73: 497–503.
Gao S, Long CL, Wang RH, Wang H . KATP activation prevents progression of cardiac hypertrophy to failure induced by pressure overload via protecting endothelial function. Cardiovasc Res 2009; 83: 444–56.
Tang Y, Long CL, Wang RH, Cui W, Wang H . Activation of SUR2B/Kir6.1 subtype of adenosine triphosphate-sensitive potassium channel improves pressure overload induced cardiac remodeling via protecting endothelial function. J Cardiovasc Pharmacol 2010; 56: 345–53.
Zhao RJ, Wang H . Chemerin/ChemR23 signaling axis is involved in the endothelial protection by KATP channel opener iptakalim. Acta Pharmacol Sin 2011; 32: 573–80.
Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002; 277: 1794–9.
Vaziri ND, Wang XQ . cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide. Hypertension 1999; 34: 1237–41.
Furukawa LN, Kushiro T, Asagami T, Takahashi A, Kanmatsuse K, Ishikawa K . Variations in insulin sensitivity in spontaneously hypertensive rats from different sources. Metabolism 1998; 47: 493–6.
Katakam PV, Ujhelyi MR, Hoenig M, Miller AW . Metformin improves vascular function in insulin-resistant rats. Hypertension 2000; 35: 108–12.
Li R, Zhang H, Wang W, Wang X, Huang Y, Huang C, et al. Vascular insulin resistance in prehypertensive rats: role of PI3-kinase/Akt/eNOS signaling. Eur J Pharmacol 2010; 628: 140–7.
Xue H, Zhang YL, Liu GS, Wang H . A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in experimental hypertension. J Pharmacol Exp Ther 2005; 315: 501–9.
Long CL, Qin XC, Pan ZY, Chen K, Zhang YF, Cui WY, et al. Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. J Hyperten 2008; 26: 2326–38.
Pollare T, Lithell H, Berne C . Insulin resistance is a characteristic feature of primary hypertension in dependent of obesity. Metabolism 1990; 39: 167–74.
Oron-Herman M, Sela BA, Rosenthal T . Risk reduction therapy for syndrome X: comparison of several treatments. Am J Hypertens 2005; 18: 372–8.
Modon CE, Reaven GM . Evidence of abnormalities of insulin metabolism in rats with spontaneously hypertension. J Metabolism 1988; 37: 303–5.
Verma S, Yao L, Stewart DJ, Dumont AS, Anderson TJ, McNeill JH . Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension 2001; 37: 328–33.
Misurski DA, Wu SQ, McNeill JR, Wilson TW, Gopalakrishnan V . Insulin-induced biphasic response in rat mesenteric vascular bed: role of endothelin. Hypertension 2001; 37: 1298–302.
Verma S, Bhanot S, McNeill JH . Effects of chronic endothelin blockade in hyperinsulinemia hypertensive rats. Am J Physiol 1995; 269: H2017–21.
Kurtz TW . Recent advances in genetics of the spontaneously hypertensive rat. Curr Hypertens Rep 2010; 12: 5–9.
Tran LT, Yuen VG, McNeill JH . The fructose-fed rats: a review on the mechanism of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 2009; 332: 145–59.
Potenza MA, Marasciulo FL, Tarquinio M, Quon MJ, Montagnani M . Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance. Diabetes 2006; 55: 3594–603.
Katakam PV, Ujhelyi MR, Hoenig ME, Miller AW . Endothelial dysfunction precedes hypertension in diet-induced insulin resistance. Am J Physiol 1998; 275: R788–92.
Hwang IS, Ho H, Hoffman BB, Reaven GM . Fructose-induced insulin resistance and hypertension in rats. Hypertension 1987; 10: 512–6.
Wilkes JJ, Hevener A, Olefsky J . Chronic endothelin-1 treatment leads to insulin resistance in vivo. Diabetes 2003; 52: 1904–9.
Acknowledgements
This study was supported by grants from the National New Drug Research and Development Key Project (No 2008ZX09101-006, 2008ZXJ09004-018 and 2009ZX09301-002), the State Key Basic Research and Development from the Ministry of Science and Technology of China (No GT1998051112), the 863-High Technology Research and Development Program Plan (No 2002AA2Z3137), the National 1035 Project (No 969010101) of China and the New Drug Development of Beijing Key Project (No D0204003040721).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, Y., Zeng, Fh., Long, Cl. et al. The novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function. Acta Pharmacol Sin 32, 1466–1474 (2011). https://doi.org/10.1038/aps.2011.129
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2011.129
Keywords
This article is cited by
-
Proteomics reveals potential non-neuronal cholinergic receptor-effectors in endothelial cells
Acta Pharmacologica Sinica (2014)
-
A new antihypertensive drug ameliorate insulin resistance
Acta Pharmacologica Sinica (2012)
-
Arecoline improves vascular endothelial function in high fructose-fed rats via increasing cystathionine-γ-lyase expression and activating KATP channels
Acta Pharmacologica Sinica (2012)
