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http://dx.doi.org/10.4196/kjpp.2009.13.6.437

Diclofenac, a Non-steroidal Anti-inflammatory Drug, Inhibits L-type $Ca^{2+}$ Channels in Neonatal Rat Ventricular Cardiomyocytes  

Yarishkin, Oleg V. (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Hwang, Eun-Mi (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Kim, Dong-Gyu (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Yoo, Jae-Cheal (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Kang, Sang-Soo (Department of Anatomy, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Kim, Deok-Ryoung (Department of Biochemistry, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Shin, Jae-Hee-Jung (Division of Molecular Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Chung, Hye-Joo (Division of Molecular Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Jeong, Ho-Sang (Division of Molecular Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration)
Kang, Da-Won (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Han, Jae-Hee (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Park, Jae-Yong (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Hong, Seong-Geun (Department of Physiology, Institute of Health Sciences, and Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.13, no.6, 2009 , pp. 437-442 More about this Journal
Abstract
A non-steroidal anti-inflammatory drug (NSAID) has many adverse effects including cardiovascular (CV) risk. Diclofenac among the nonselective NSAIDs has the highest CV risk such as congestive heart failure, which resulted commonly from the impaired cardiac pumping due to a disrupted excitationcontraction (E-C) coupling. We investigated the effects of diclofenac on the L-type calcium channels which are essential to the E-C coupling at the level of single ventricular myocytes isolated from neonatal rat heart, using the whole-cell voltage-clamp technique. Only diclofenac of three NSAIDs, including naproxen and ibuprofen, significantly reduced inward whole cell currents. At concentrations higher than $3\;{\mu}M$, diclofenac inhibited reversibly the $Na^+$ current and did irreversibly the L-type $Ca^{2+}$ channels-mediated inward current $(IC_{50}=12.89\pm0.43\;{\mu}M)$ in a dose-dependent manner. However, nifedipine, a well-known L-type channel blocker, effectively inhibited the L-type $Ca^{2+}$ currents but not the $Na^+$ current. Our finding may explain that diclofenac causes the CV risk by the inhibition of L-type $Ca^{2+}$ channel, leading to the impairment of E-C coupling in cardiac myocytes.
Keywords
Diclofenac; L-type $Ca^{2+}$ current; Rat cardiac myocytes; NSAID;
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1 Ferrier GR, Howlett SE. Contractions in guinea-pig ventricular myocytes triggered by a calcium-release mechanism separate from $Na^+$ and L-currents. J Physiol 484: 107-122, 1995   PUBMED
2 Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense. J Am Med Assoc 296: 1653-1656, 2006   DOI   PUBMED   ScienceOn
3 Howlett SE, Zhu JQ, Ferrier GR. Contribution of a voltage- sensitive calcium release mechanism to contraction in cardiac ventricular myocytes. Am J Physiol 274: H155-H170, 1998
4 Larsen JK, Mitchell JW, Best PM. Quantitative analysis of the expression and distribution of calcium channel $\alpha$1 subunit mRNA in the atria and ventricles of the rat heart. J Mol Cell Cardiol 34: 519-532, 2002   DOI   ScienceOn
5 McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systemic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase-2. J Am Med Assoc 296: 1633-1644, 2006   DOI   ScienceOn
6 Nawrath H, Klein G, Rupp J, Wegener JRW, Shainberg A. Open state block by fendiline of L-type $Ca^{2+}$ channels in ventricular myocytes from rat heart. J Pharmacol Exp Ther 285: 546-552, 1998   ScienceOn
7 Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort- Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR. A sodium channel mutation causes isolated cardiac conduction disease. Nature 409: 1043-1047, 2001   DOI   ScienceOn
8 Waksman JC, Brody A, Phillips SD. Nonselective nonsteroidal anti-inflammatory drugs and cardiovascular risk: are they safe? Ann Pharmacother 41: 1163-1173, 2007   DOI   ScienceOn
9 Hobai IA, Howarth FC, Pabbathi VK, Dalton GR, Hancox JC, Zhu JQ, Howlett SE, Ferrier GR, Levi AJ. Voltage-activated $Ca^{2+}$ release in rabbit, rat and guinea-pig cardiac myocytes, and modulation by internal cAMP. Pflugers Arch 435: 164-173, 1997   DOI   ScienceOn
10 Brater DC. Renal effects of cyclooxygyenase-2-selective inhibitors. J Pain Sympt Management 23: S15-S20, 2002   DOI   PUBMED   ScienceOn
11 Hombach V. Electrocardiography of the failing heart. Cardiol Clin 24: 413-426, 2006   DOI   PUBMED   ScienceOn
12 Pieske B, Maier LS, Bers DM, Hasenfuss G. $Ca^{2+}$ handling and sarcoplasmic reticulum $Ca^{2+}$ content in isolated failing and nonfailing human myocardium. Circ Res 85: 38-46, 1999   PUBMED   ScienceOn
13 Lee JH, Gomora JC, Cribbs LL, Perez-Reyes E. Nickel block of three cloned T-type calcium channels: low concentrations selectively block a1H. Biophys J 77: 3034-3042, 1999   DOI   PUBMED   ScienceOn
14 Doering CJ, Zamponi GW. Molecular pharmacology of high voltage- activated calcium channels. J Bioenerg and Biomem 35: 491-505, 2003   DOI   ScienceOn
15 Alves D, Duarte I. Involvement of ATP-sensitive $K^+$ channels in the peripheral antinociceptive effect induced by dipyrone. Eur J Pharmacol 444: 47-52, 2002   DOI   PUBMED   ScienceOn
16 Maltsev VA, Sabbab HN, Undrovinas AI. Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvediol. Cell Mol Life Sci 59: 1561-1568, 2002   DOI   ScienceOn
17 Asomoza-Espinosa R, Alonso-Lopez R. Mixcoatl-Zecuatl T, Aguirre- Banuelos P, Torres-Lopez JE, Granados-Soto V. Sildenafil increases diclofenac antinociception in the formalin test. Eur J Pharmacol 418: 195-200, 2001   DOI   ScienceOn
18 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Br Med J 332: 1302-1308, 2006   DOI   ScienceOn
19 Pinto JM, Boyden PA. Electrical remodeling in ischemia and infarction. Cardiovasc Res 42: 284-297, 1999   DOI   ScienceOn
20 Katsube Y, Yokoshiki H, Nguyen L, Yamamoto M, Sperelakis N. L-type $Ca^{2+}$ currents in ventricular myocytes from neonatal and adult rats. Can J Physiol Pharmacol 76: 873-881, 1998   DOI   ScienceOn
21 Ferrier GR, Redondo IM, Mason CA, Mapplebeck C, Howlett SE. Regulation of contraction and relaxation by membrane potential in cardiac ventricular myocytes. Am J Physiol 278: H1618-H1626, 2000
22 Dalla Libera L, Vescovo G, Volterrani M. Physiological basis for contractile dysfunction in the heart failure. Curr Pharm Design 14: 2572-2581, 2008   DOI   ScienceOn
23 Fu J, Gao J, Pi R, Liu P. An optimized protocol for culture of cardiomyocytes from neonatal rat. Cytotechnol 49: 109-116, 2005   DOI   ScienceOn
24 Liu LY, Fei XW, Li ZM, Zhang ZH, Mei YA. Diclofenac, a nonsteroidal anti-inflammatory drug, activates the transient outward $K^+$ current in rat cerebellar granule cells. Neuropharmacol 48: 918-926, 2005   DOI   ScienceOn
25 Morales MA, Salazar T, Paeile C. Effects of flunixin and mefenamic acid on cardiac pacemaker cells. Structure-activity relationship and comparison with clonixin. Gen Pharmacol 24: 775-780, 1993   PUBMED   ScienceOn
26 Perez-Reyes E, Lee JH, Cribbs LL. Molecular characterization of two members of the T-type calcium channel family. Ann N Y Acad Sci 868: 131-143, 1999   DOI   PUBMED
27 Fei XW, Liu LY, Xu JG, Zhang ZH, Mei YA. The non-steroidal anti-inflammatory drug, diclofenac, inhibits $Na^+$ current in rat myoblasts. Biochem Biophys Res Commun 346: 1275-1283, 2006   DOI   ScienceOn
28 Lee HM, Kim HI, Shin YK, Lee CS, Park M, Song JH. Diclofenac inhibition of sodium currents in rat dorsal root ganglion neurons. Brain Research 992: 120-127, 2003   DOI   ScienceOn
29 Leucuta A, Vlase L, Farcau D, Nanulescu M. No effect of short term ranitidine intake on diclofenac pharmakinetics. Rom J Gastroenterol 13: 306-308, 2004   PUBMED   ScienceOn
30 Lindner M, Erdmann E, Beuckelmann DJ. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol 30: 743-749, 1998   DOI   ScienceOn
31 Ortiz MI, Torres-Lopez JE, Castaneda-Hernandez G, Rosas R, Vidal-Cantu GC, Granados-Soto V. Pharmacological evidence for the activation of $K^+$ channels by diclofenac. Eur J Pharmacol 438: 85-91, 2002   DOI   ScienceOn
32 Perez-Reyes E. Molecular characterization of a novel family of low voltage-activated, T-type, calcium channels. J Bioenerg Biomem 30: 313-318, 1998   DOI   PUBMED   ScienceOn
33 Zhu JQ, Ferrier GR. Regulation of a voltage-sensitive release mechanism by $Ca^{2+}$-calmodulin dependent kinase in cardiac myocytes. Am J Physiol 279: H2104-H2115, 2000
34 Willis JV, Kendall MJ, Flinn RM, Thornhill DP, Welling PG. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol 16: 405-410, 1979   DOI   ScienceOn
35 Hudson M, Rahme E, Richard H, Pilote L. Risk of congestive heart failure with nonsteroidal anti-inflammatory drugs and selective cyclooxygenase 2 inhibitors: a class effect? Arthritis and Rheumatism 57: 516-523, 2007   DOI   ScienceOn
36 Tonussi CR, Ferreira SH. Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. Eur J Pharmacol 251: 173-179, 1994   DOI   PUBMED   ScienceOn
37 Bort R, Ponsoda X, Jover R, Gomez-Lechon MJ, Castell JV. Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J Pharmacol Exp Ther 288: 65-72, 1998   ScienceOn
38 Yang YC, Kuo CC. An inactivation stabilizer of the $Na^+$ channel acts as an opportunistic pore blocker modulated by external $Na^+$. J Gen Physiol 125: 465-481, 2005   DOI   ScienceOn
39 Bodi I, Mikala G, Koch SE, Akhter SA, Schwartz A. The L-type calcium channel in the heart: the beat goes on. J Clin Invest 115: 3306-3317, 2005   DOI   ScienceOn
40 Morales MA, Inostroza L, Salazar T, Paeile C. Effects of clonixin on the electrical activity of cardiac pacemaker cells. Gen Pharmacol 23: 515-521, 1992   DOI   PUBMED   ScienceOn
41 Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, Nattel S. Dissociation between remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure. Circulation 109: 412-418, 2004   DOI   ScienceOn