Table of Contents  
Year : 2012  |  Volume : 3  |  Issue : 1  |  Page : 12-14  

Iptakalim: A novel multi-utility potassium channel opener

1 Department of Pharmacology, LLRM Medical College, Meerut, Uttar Pradesh, India
2 Department of Oral Pathology and Microbiology, ITS -CDSR, Murad Nagar, Ghaziabad, Uttar Pradesh, India
3 Department of Medicine, IDST, Meerut, Uttar Pradesh, India

Date of Web Publication3-Feb-2012

Correspondence Address:
Pranav Sikka
Department of Pharamacology, LLRM Medical College, Meerut, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0976-500X.92495

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How to cite this article:
Sikka P, Kapoor S, Bindra V K, Saini M, Saxena K K. Iptakalim: A novel multi-utility potassium channel opener. J Pharmacol Pharmacother 2012;3:12-4

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Sikka P, Kapoor S, Bindra V K, Saini M, Saxena K K. Iptakalim: A novel multi-utility potassium channel opener. J Pharmacol Pharmacother [serial online] 2012 [cited 2020 Jun 4];3:12-4. Available from:

Hypertension is a multifactorial disorder, and effective blood pressure control is not achieved in most individuals. According to the most recent report of the American Heart Association, for 2010, the estimated direct and indirect financial burden for managing hypertension is estimated to be $76.6 billion. Overall, almost 75% of adults with cardiovascular diseases/comorbidities have hypertension, which is associated with a shorter overall life expectancy. [1] Alarmingly, rates of prehypertension and hypertension are increasing among children and adolescents due, in part, to the obesity epidemic we currently face. There is also the problem of an aging population and the growing rates of diabetes and obesity in adults, all factors that are associated with high blood pressure. [2] Thus, the need is great for novel drugs that target the various contributing causes of hypertension and the processes leading to end organ damage.

Iptakalim (IPT), chemically 2, 3-dimethyl-N-(1-methylethyl)-2-butanamine hydrochloride, is novel adenosine triphosphate-sensitive potassium (K ATP ) channel opener. K ATP channels are composed of discrete pore-forming inward rectifier subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR). [3] IPT shows high selectivity for cardiac K ATP (SUR2A/Kir6.2) and vascular K ATP (SUR2B/Kir6.1 or SUR6B/Kir6.2). Because of this high selectivity, IPT does not exhibit the adverse side effects associated with the older nonspecific K + channel openers, which limit their use to the treatment of severe or refractory hypertension. IPT produces arteriolar and small artery vasodilatation, with no significant effect on capacitance vessels or large arteries. Vasodilatation is induced by causing cellular hyperpolarization via the opening of K + channels, which in turn decreases the opening probability of L-type Ca 2+ channels. Of particular note, IPT is very effective in lowering the blood pressure of hypertensive humans but not of those with normal blood pressure. [4]

Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen/proliferation factor for vascular smooth muscle. Wang et al. (2005) have shown that IPT reduces ET-1-induced arterial contraction and decreases ET-induced hypertension in rats. [5] They hypothesized that activation of endothelial K ATP channels might result in protection against endothelial dysfunction. The mechanism behind endothelial dysfunction, an early risk factor for cardiovascular disease and hypertension, includes reduced nitric oxide (NO) generation and increased ET-1 generation. Wang et al. (2007) first reported that the K ATP channel opener, IPT, promotes NO synthase (NOS) activity and NO release; inhibits ET-1 synthesis, and suppresses ET-1 and endothelin converting enzyme (ECE) mRNA expression. [6] Also, Zhao and Wang (2011) have suggested that IPT, via opening K ATP channels, enhances the endothelial chemerin/ChemR23 axis and NO production and thus improves endothelial function. [7]

Gao et al. (2009) showed that IPT possesses antihypertrophic properties, preventing the progression of left ventricular hypertrophy (LVH) to heart failure induced by pressure overload. Additionally, IPT reduces myocardial and perivascular fibrosis as well as mRNA expression of two important molecular markers of heart failure, viz, atrial natriuretic peptide and B-type natriuretic peptide. The results suggest that IPT's effects on hypertrophy induced by pressure overload occurs through maintenance of the balance between the NO and endothelin signaling systems. [8]

Changes in K + channel function may represent a universal mechanism by which Ca 2+ signals are targeted toward the activation of gene expression and cell growth. [9] Furthermore, activation of K + channels can induce apoptosis in vascular smooth muscle cells (SMCs) in proliferative conditions of vessels. [10] Thus, K ATP channels can be potential targets to regulate proliferative vascular disorders in diseases such as pulmonary hypertension. [11] Pan et al. (2010) and Zhu et al. (2008) have shown that IPT inhibits the ET-1-induced proliferation of human pulmonary arterial smooth muscle cells (PASMCs). [4],[12]

A study in the spontaneous hypertensive rat (SHR) model by Xue et al. (2005) indicated that IPT not only effectively reduces blood pressure but also ameliorates the pathological changes in the glomerular filtration membrane and the glomerular and renal interstitia, reverses renal arteriolar remodeling, decreases proteinuria, and improves renal function. Furthermore, long-term antihypertensive therapy with IPT decreases the circulating and intrarenal concentrations of ET-1 and transforming growth factor (TGF)-b1; downregulates the elevated expression of ET-1, ECE-1, and TGF-b1 mRNA; and corrects the matrix metalloproteinase-9 (MMP-9)/MMP tissue inhibitor-1 (TIMP-1) imbalance; all of which is evidence of the renoprotective effect of IPT. [13] IPT is also a potential alternative antihypertensive in cases where angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor antagonists are either ineffective or contraindicated.

Because the K ATP channels are widely distributed throughout the mammalian brain [14],[15] and are found in the neural circuits that are implicated in the pathophysiology of schizophrenia, IPT might broadly impact brain functions by opening these K ATP channels and modulating glutamate and dopamine release when the brain is under stress. Sun and colleagues (2009) who are the pioneers in exploring the antipsychotic activity of IPT, found that the drug is effective in reducing both amphetamine- and phencyclidine-induced locomotor activity, as well as in suppressing avoidance responding, a behavioral profile shared with all currently used antipsychotics. [16],[17] Neuroanatomically, IPT also exhibits an antipsychotic profile. It dose-dependently increases c-Fos expression in the nucleus accumbens, medial prefrontal cortex, and lateral septal nucleus, but not in the dorsolateral striatum. All these findings are consistent with the behavioral and molecular profiles of antipsychotics. IPT, by opening K ATP channels located on the ventral tegmental area (VTA) dopamine neurons, inhibits dopamine and glutamate release [18],[19] and attenuates the behavioral and c-Fos expression effects induced by amphetamine, phencyclidine, or conditioned stimulus. Hence, it can be concluded that IPT is a potential antipsychotic drug, with distinct mechanisms of action. [20]

Tests in a variety of in vivo and in vitro ischemia and Parkinson disease models indicate that IPT also has neuroprotective effects. [21],[22],[23],[24] Furthermore, IPT has potential in the prevention of drug addiction because it inhibits cocaine challenge-induced enhancement of dopamine release in the rat nucleus accumbens. [25]

Although, IPT opens up new avenues in medicine, large randomized controlled trials are required to establish its efficacy.

   References Top

1.Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics-2010 update: A report from the American Heart Association. Circulation 2010;121:e46-e215.  Back to cited text no. 1
2.Feig PU, Roy S, Cody RJ. Antihypertensive drug development: current challenges and future opportunities. J Am Soc Hypertens 2010;4:163-73.  Back to cited text no. 2
3.Zhou F, Wu JY, Yao HH, Ding JH, Hu G. Iptakalim alleviates rotenone-induced degeneration of dopaminergic neurons through inhibiting microglia-mediated neuroinflammation. Neuropsychopharmacology 2007;32:2570-80.   Back to cited text no. 3
4.Pan Z, Huang J, Cui W, Long C, Zhang Y, Wang H. Targeting hypertension with a new adenosine triphosphate-sensitive potassium channel opener iptakalim. J Cardiovasc Pharmacol 2010;56:215-28.  Back to cited text no. 4
5.Wang H, Xie WP, Wang H, Hu G. Effects of iptakalim on endothelin-1- induced pulmonary hypertension in rats. Chin J Clin Pharmacol Ther 2005;10:9-14.   Back to cited text no. 5
6.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.  Back to cited text no. 6
7.Zhao RJ, Wang H. Chemerin/ChemR23 signaling axis is involved in the endothelial protection by K ATP channel opener iptakalim. Acta Pharmacol Sin 2011;32:573-80.   Back to cited text no. 7
8.Gao S, Long CL, Wang RH, Wang H. K ATP activation prevents progression of cardiac hypertrophy to failure induced by pressure overload via protecting endothelial function. Cardiovasc Res 2009;83:444-56.   Back to cited text no. 8
9.Neylon CB. Potassium channels and vascular proliferation. Vascul Pharmacol 2002;38:35-41.   Back to cited text no. 9
10.Brevnova EE, Platoshyn O, Zhang S, Yuan JX. Overexpression of human KCNA5 increases IKV and enhances apoptosis. Am J Physiol Cell Physiol 2004;287:C715-22.  Back to cited text no. 10
11.Cole WC, Clement-Chomienne O. ATP-sensitive K + channels of vascular smooth muscle cells. J Cardiovasc Electrophysiol 2003;14:94-103.  Back to cited text no. 11
12.Zhu Y, Zhang S, Xie W, Li Q, Zhou Y, Wang H. Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of K (ATP) channel. Vascul Pharmacol 2008;48:92-9.  Back to cited text no. 12
13.Xue H, Zhang YL, Liu GS, Wang H. A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in spontaneously hypertensive rats. J Pharmacol Exp Ther 2005;315:501-9.   Back to cited text no. 13
14.Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP-sensitive K + channel in rat brain. Brain Res 1998;814:41-54.  Back to cited text no. 14
15.Thomzig A, Laube G, Pruss H, Veh RW. Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. J Comp Neurol 2005;484:313-30.  Back to cited text no. 15
16.Abekawa T, Ito K, Koyama T. Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short- and long-term withdrawal from this antipsychotic. Naunyn Schmiedebergs Arch Pharmacol 2007;375:261-71.   Back to cited text no. 16
17.Sun T, Hu G, Li M. Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidineinduced hyperlocomotion, but attenuates inhibition on amphetamine- induced hyperlocomotion: Relevance to animal models of antipsychotic drugs. Eur J Pharmacol 2009;602:334-42.  Back to cited text no. 17
18.Wang S, Hu LF, Zhang Y, Sun T, Sun YH, Liu SY, et al. Effects of systemic administration of iptakalim on extracellular neurotransmitter levels in the striatum of unilateral 6-hydroxydopamine-lesioned rats. Neuropsychopharmacology2006;31:933-40.   Back to cited text no. 18
19.Yang YJ, Wang QM, Hu LF, Sun XL, Ding JH, Hu G. Iptakalim alleviated the increase of extracellular dopamine and glutamate induced by 1-methyl-4-phenylpyridinium ion in rat striatum. Neurosci Lett 2006;404:187-90.   Back to cited text no. 19
20.Sun T, Zhao C, Hu G, Li M. Iptakalim: A Potential Antipsychotic Drug with Novel Mechanisms? Eur J Pharmacol 2010;634:68-76.   Back to cited text no. 20
21.Wang H, Zhang YL, Tang XC, Feng HS, and Hu G. Targeting ischemic stroke with a novel opener of ATP-sensitive potassium channels in the brain. Mol Pharmacol 2004;66:1160-8.   Back to cited text no. 21
22.Wang S, Hu LF, Yang Y, Ding JH, Hu G. Studies of ATP-sensitive potassium channels on 6-hydroxydopamine and haloperidol rat models of Parkinson's disease: implications for treating Parkinson's disease? Neuropharmacology 2005;48:984-92.   Back to cited text no. 22
23.Yang Y, Liu X, Ding JH, Sun J, Long Y, Wang F, et al. Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells. Neurosci Lett 2004;366:53-7.   Back to cited text no. 23
24.Yang Y, Liu X, Long Y, Wang F, Ding JH, Liu SY, et al. Systematic administration of iptakalim, an ATP-sensitive potassium channel opener, prevents rotenone-induced motor and neurochemical alterations in rats. J Neurosci Res 2005;80:442-9.  Back to cited text no. 24
25.Liu Y, He HR, Ding JH, Gu B, Wang H, Hu G. Iptkalim inhibits cocaine challenge-induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up-regulating Kir6.1 and Kir6.2 mRNA expression. Acta Pharmacol Sin 2003;24:527-33.  Back to cited text no. 25

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