Skip to main content

Advertisement

SpringerLink
Log in

Reduction of myocardial infarct size by SM-198110, a novel Na+/H+ exchange inhibitor, in rabbits

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The effects of 3-[2-({[amino(imino)methyl]amino}carbonyl)-4-chloro-1H-indol-1-yl]-1-propanesulphonic acid monohydrate (SM-198110), a novel potent Na+/H+ exchange inhibitor, and cariporide (Hoe642), another Na+/H+ exchange inhibitor, were studied in a myocardial ischaemia and reperfusion injury model. Anaesthetized rabbits were subjected to occlusion of the coronary artery for 30 min followed by reperfusion for 5 h. SM-198110 or cariporide was administered before ischaemia and before reperfusion. We also assessed the anti-necrotic effect of SM-198110 when given before reperfusion, both alone and together with glibenclamide, a KATP channel blocker, 5-hydroxydecanoate (5-HD), a mitochondrial KATP channel-selective blocker and 8-(p-sulphophenyl)-theophylline (8-SPT), an adenosine receptor blocker. The infarct size was reduced dose-dependently by i.v. administration of SM-198110 before ischaemia, with a significant reduction in serum creatine phosphokinase activity. Infarct sizes, normalized to the size of the area-at-risk (means±SE) were: vehicle 56.6±3.7%; low-dose SM-198110 39.2±6.3%; mid-dose 32.8±7.4% (P<0.05); high-dose 22.1±6.7% (P<0.01). This anti-necrotic effect of SM-198110 was achieved without significant haemodynamic changes. Cariporide given before ischaemia also reduced infarct size significantly and dose-dependently. SM-198110 administered before reperfusion also resulted in a dose-dependent reduction in the infarct size. Infarct sizes were: vehicle 56.6±3.7%; low-dose SM-198110 44.5±5.7%; mid-dose 36.3±6.6% (P<0.01); high-dose 34.7±3.8% (P<0.01). In contrast, cariporide given before reperfusion did not reduce infarct sizes significantly. The anti-necrotic effect of SM-198110 was observed even when given 10 min after the beginning of reperfusion. Glibenclamide and 5-HD abolished the anti-necrotic effect of treatment before reperfusion with SM-198110. However, the co-administration of 8-SPT with SM-198110 did not affect infarct size. These results suggest that, in addition to Na+/H+ exchange inhibition, mitochondrial and/or sarcolemmal KATP channels contribute to the anti-necrotic effect of SM-198110 when the latter is given before reperfusion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2a,b
Fig. 3
Fig. 4a,b
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Allain CC, Henson CP, Nadel MK, Knoblesdorff AJ (1973) Rapid single-step kinetic colorimetric assay for lactate dehydrogenase in serum. Clin Chem 19:223–227

    CAS  PubMed  Google Scholar 

  • Allen DG, Xiao X-H (2003) Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion. Cardiovasc Res 57:934–941

    Article  CAS  PubMed  Google Scholar 

  • Avkiran M (1996) Sodium-hydrogen exchange in myocardial ischemia and reperfusion: a critical determinant of injury? In: Karmazyn M (ed) Myocardial ischemia: mechanism, reperfusion, protection. Birkhäuser, Switzerland, pp 299–311

    Google Scholar 

  • Boyce SW, Bartels C, Bolli R, Chaitman B, Chen JC, Chi E, Jessel A, Kereiakes D, Knight J, Thulin L, Theroux P (2003) Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: results of the CABG surgery cohort of the GUARDIAN study. J Thorac Cardiovasc Surg 126:420–427

    Article  CAS  PubMed  Google Scholar 

  • Bugge E, Munch-Ellingsen J, Ytrehus K (1996) Reduced infarct size in the rabbit heart in vivo by ethylisopropyl-amiloride. A role for Na+/H+ exchange. Basic Res Cardiol 91:203–209

    Article  CAS  PubMed  Google Scholar 

  • Cingolani HE, Ennis IL, Mosca SM (2003) NHE-1 and NHE-6 activities: ischemic and reperfusion injury. Circ Res 93:694–696

    Article  CAS  PubMed  Google Scholar 

  • Ganote CE, Armstrong SC (2000) Adenosine and preconditioning in the rat heart. Cardiovasc Res 45:134–140

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Dorado D, Gonzaláz MA, Barrabés JA, Ruiz-Meana M, Solares J, Lidon R-M, Blanco J, Puigfel Y, Piper HM, Soler-Soler J (1997) Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na+-H+ exchange. Cardiovasc Res 35:80–89

    Article  CAS  PubMed  Google Scholar 

  • Gomoll AW (1996) Cardioprotection associated with preconditioning in the anesthetized ferret. Basic Res Cardiol 91:433–443

    Article  CAS  PubMed  Google Scholar 

  • Gumina RJ, Mizumura, Beier N, Schelling P, Schultz JJ, Gross GJ (1998) A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmacol Exp Ther 286:175–183

    CAS  PubMed  Google Scholar 

  • Gumina RJ, Beier N, Schelling P, Gross GJ (2000) Inhibitors of ischemic preconditioning do not attenuate Na+/H+ exchange inhibitor mediated cardioprotection. J Cardiovasc Pharmacol 35:949–953

    Article  CAS  PubMed  Google Scholar 

  • Hanley PJ, Gopalan KV, Lareau RA, Srivastava DK, von Meltzer M, Daut J (2003) Beta-oxidation of 5-hydroxydecanoate, a putative blocker of mitochondrial ATP-sensitive potassium channels. J Physiol (Lond) 547:387–393

    Google Scholar 

  • Hotta Y, Nishimaki H, Takeo T, Itoh G, Yajima M, Otsuka-Murakami H, Ishikawa N, Kawai N, Huang L, Yamada K, Yamamoto S, Matsui K, Ohashi N (2004a) Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts. Eur J Pharmacol 503:109–122

    CAS  PubMed  Google Scholar 

  • Hotta Y, Yajima M, Ishikawa N, Matsui K (2004b) The participation of mitochondrial permeability transition pores (MPTP) against post-ischemic myocardial dysfunction. J Pharmacol Sci 94 (Suppl I):159

    Google Scholar 

  • Hu H, Sato T, Seharaseyon J, Liu Y, Johns DC, O’Rourke B, Marban E (1999) Pharmacological and histochemical distinctions between molecularly defined sarcolemmal KATP channels and native cardiac mitochondrial KATP channels. Mol Pharmacol 55:1000–1005

    CAS  PubMed  Google Scholar 

  • Imahashi K, Hashimoto K, Yamaguchi H, Nishimura T, Kusuoka H (1998) Alteration of intracellular Na+ during ischemia in diabetic rat hearts: the role of reduced activity in Na+/H+ exchange against stunning. J Mol Cell Cardiol 30:509–517

    Article  CAS  PubMed  Google Scholar 

  • Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid K (1998) State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate. J Biol Chem 29:13578–13582

    Google Scholar 

  • Klein HH, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber J, Nebendahl K (1997) Time delay of cell death by Na+/H+-exchange inhibition in regionally ischemic, reperfused porcine hearts. J Cardiovasc Pharmacol 30:235–240

    Article  CAS  PubMed  Google Scholar 

  • Klein HH, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber J, Schade-Brittinger C, Nebendahl K (1998) Time-dependent protection by Na+/H+ exchange inhibition in a regionally ischemic, reperfused porcine heart preparation with low residual blood flow. J Mol Cell Cardiol 30:795–801

    Article  CAS  PubMed  Google Scholar 

  • Kouchi I, Murakami T, Nawada R, Akao M, Sasayama S (1998) KATP channels are common mediators of ischemic and calcium preconditioning in rabbits. Am J Physiol 274:H1106–H1112

    CAS  PubMed  Google Scholar 

  • Lim KH, Javadov SA, Das M, Clarke SJ, Suleiman MS, Halestrap AP (2002) The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration. J Physiol (Lond) 545:961–974

    Article  CAS  Google Scholar 

  • Miura T, Ogawa T, Suzuki K, Goto M, Simamoto K (1997) Infarct size limitation by a new Na+-H+ exchange inhibitor, HOE642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol 29:693–701

    Article  CAS  PubMed  Google Scholar 

  • Miura T, Miura T, Kawamura S, Goto M, Sakamoto J, Tsuchida A, Matsuzaki M, Shimamoto K (1998) Effect of protein kinase C inhibitors on cardioprotection by ischemic preconditioning depends on the number of preconditioning episodes. Cardiovasc Res 37:700–709

    Article  CAS  PubMed  Google Scholar 

  • Miura T, Liu Y, Goto M, Tsuchida A, Miki T, Nakano A, Nishino Y, Ohnuma Y, Shimamoto K (2001) Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury. J Am Coll Cardiol 37:957–963

    Article  CAS  PubMed  Google Scholar 

  • Piper HM, Basler C, Ladilov YV, Schäfer M, Siegmund B, Ruiz-Meana M, Garcia-Dorado D (1996) The role of Na+/H+ exchange in ischemia-reperfusion. Basic Res Cardiol 91:191–202

    Article  CAS  PubMed  Google Scholar 

  • Rupprecht HJ, Dahl JV, Terres W, Seyfarth KM, Richardt G, Schultheiß HP, Buerke M, Sheehan FH, Drexler H (2000) Cardioprotective effects of the Na+/H+ exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA. Circulation 101:2902–2908

    CAS  PubMed  Google Scholar 

  • Sato T, O’Rourke B, Marban E (1998) Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res 83:110–114

    CAS  PubMed  Google Scholar 

  • Scholz W, Albus U (1993) Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion. Basic Res Cardiol 88:443–455

    Article  CAS  PubMed  Google Scholar 

  • Scholz W, Albus U, Counillon L, Gögelein H, Lang HJ, Linz W, Weichert A, Schölkens BA (1995) Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 29:260–268

    Article  CAS  PubMed  Google Scholar 

  • Takeo S, Nasa Y (1999) Role of energy metabolism in the preconditioned heart—a possible contribution of mitochondria. Cardiovasc Res 43:32–43

    Article  CAS  PubMed  Google Scholar 

  • Tani M, Neely JR (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts: possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res 65:1045–1056

    CAS  PubMed  Google Scholar 

  • Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A (2000) Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation 102:3032–3038

    CAS  PubMed  Google Scholar 

  • Xiao XH, Allen DG (2003) The cardioprotective effects of Na+/H+ exchange inhibition and mitochondrial KATP channel activation are additive in the isolated rat heart. Pflugers Arch 447:272–279

    Article  CAS  PubMed  Google Scholar 

  • Yamada K, Tojo SJ, Hayashi M, Morooka S (1998) The role of P-selectin, sialyl Lewis X and sulfatide in myocardial ischemia and reperfusion injury. Eur J Pharmacol 346:217–225

    Article  CAS  PubMed  Google Scholar 

  • Yamada K, Matsui K, Satoh K, Kitano M, Yamamoto S, Ohashi N (2000) Reduction of myocardial infarct size by SM-20550, a novel Na+/H+ exchange inhibitor, in rabbits. Eur J Pharmacol 404:201–212

    Article  CAS  PubMed  Google Scholar 

  • Yamada K, Sasabe M, Matsui K, Yamamoto S, Ohashi N (2002a) Effects of SM-20550, a new Na+/H+ exchange inhibitor, on survival and infarct size in rat myocardial infarction. Pharmacology 64:176–181

    Article  CAS  PubMed  Google Scholar 

  • Yamada K, Matsui K, Yamamoto S, Kitano M, Ohashi N (2002b) Effect of an Na+/H+ exchange inhibitor, SM-20550, on ischemic preconditioning in rabbits. Int J Tissue React 24:1–10

    CAS  PubMed  Google Scholar 

  • Yamamoto S, Matsui K, Kitano M, Ohashi N (2000) SM-20550, a new Na+/H+ exchange inhibitor and its cardioprotective effect in ischemic-reperfused isolated rat hearts by preventing Ca2+-overload. J Cardiovasc Pharmacol 35:855–862

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Masako Toda and Kenji Miyazaki for excellent technical assistance during the course of this study. We are grateful to other members of Cardiovascular Group for their contribution to this work and for valuable discussion.

Author information

Authors and Affiliations

  1. Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-0022, Japan

    Kazuto Yamada, Kazuki Matsui, Shoji Ogawa, Setsuko Yamamoto, Masaya Mori & Masahumi Kitano

  2. Corporate Planning and Coordination Office, Sumitomo Pharmaceuticals Co., Ltd., 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka, 554-0022, Japan

    Naohito Ohashi

Authors
  1. Kazuto Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuki Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shoji Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Setsuko Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masaya Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahumi Kitano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naohito Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuto Yamada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamada, K., Matsui, K., Ogawa, S. et al. Reduction of myocardial infarct size by SM-198110, a novel Na+/H+ exchange inhibitor, in rabbits. Naunyn Schmied Arch Pharmacol 371, 408–419 (2005). https://doi.org/10.1007/s00210-005-1062-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-005-1062-6

Keywords

Search

Navigation