Abstract
The cardioprotective effects of KR-31762, a newly synthesized K+ ATP opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, KR-31762 (3 and 10 μM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate × LVDP) after 30-min referfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 μM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 μM), a nonselective blocker of K+ ATP channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK+ ATP channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC50: 23.5 μM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal KATP channel in rat hearts with the minimal vasorelaxant effects.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Armstrong, S. C., Liu, G. S., Downey, J. M., and Ganote, C. E., Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. J. Mol. Cell. Cardiol., 27, 1765–1774 (1995).
Atwal, K. S., Pharmacology and structure-activity relationships for KATP modulators: tissue-selective KATP openers. J. Cardiovasc. Pharmacol., 24, S12–S17 (1994).
Coghlan, M. J., Carroll, W. A., and Gopalakrishnan, M., Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J. Med. Chem., 44, 1627–1653 (2001).
Cole, W.C., McPherson, C. D., and Sontag, D., ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ. Res., 69, 571–581 (1991).
Crawford, R. M., Budas, G. R., Jovanoviæ, S, Ranki, H. J., Wilson, T. J., Davies, A. M., and Jovanoviæ, A., M-LDH serves as a sarcolemmal KATP channel subunit essential for cell protection against ischemia. EMBO. J. 21, 3936–3948 (2002).
D’Alonzo, A. J., Grover, G. J., Darbenzio, R. B., Sewter, J. C., Hess, T. A., Dzwonczyk, S., and Sleph, P. G., Hemodynamic and cardiac effects of BMS-180448, a novel K+ ATP opener, in anesthetized dogs and isolated rat hearts. Pharmacology 52, 101–112 (1996).
Ding, C. Z., Rovnyak, G. C., Misra, R. N., Grover, G. J., Miller, A. V., Ahmed, S. Z., Kelly, Y., Normandin, D. E., Sleph, P. G., and Atwal, K. S., Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 6. Effect of modifications at C6 of benzopyranyl cyanoguanidines. J. Med. Chem., 42, 3711–3717 (1999).
Ghosh, S., Standen, N. B., and Galinanes, M., Evidence for mitochondrial KATP channels as effectors of human myocardial preconditioning. Cardiovasc. Res., 45, 934–940 (2000).
Gomoll, A. W., Roth, R. A., Swillo, R. E., Baird, A. J., Sargent, C. S., Behling, R. W., Malone, H. J., and Grover, G. J., Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448. J. Pharmacol. Exp. Ther., 281, 24–33 (1997).
Grover, G. J., D’Alonzo, A. J., Garlid, K. D., Bajgar, R., Lodge, N. J., Sleph, P. G., Darbenzio, R. B., Hess, T. A., Smith, M. A., Paucek, P., and Atwal, K. S., Pharmacologic characterization of BMS-191095, a mitochondrial KATP opener with no peripheral vasodilator or cardiac action potential shortening activity. J. Pharmacol. Exp. Ther., 297, 1184–1192 (2001).
Grover, G. J., D’Alonzo, A. J., Hess, T., Sleph, P. G., and Darbenzio, R. B., Glyburide-reversible cardioprotective effect of BMS-180448 is independent of action potential shortening. Cardiovasc. Res., 30, 731–738 (1995).
Hwang, G. S., Oh, K. S., Koo, H. N., Seo, H. W., You, K. H., and Lee, B. H., Effects of KR-31378, a novel ATP-sensitive potassium channel activator, on hypertrophy of H9c2 cells and on cardiac dysfunction in rats with congestive heart failure. Eur. J. Pharmacol. 540, 131–138 (2006).
Lee, J. H., Jung, I. S., Lee, S. H., Yang, M. K., Hwang, J. H., Lee, H. D., Cho, Y. S., Song, M. J., Yi, K. Y., Yoo, S. E., Kwon, S. H., Kim, B., Lee, C. S., and Shin, H. S., Cardioprotective effects of BMS-180448, a prototype mitoKATP channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury. Arch. Pharm. Res., 30, 634–640 (2007).
Lee, B. H., Seo, H. W., Yoo, S. E., Kim, S. O., Lim, H., and Shin, H. S., Differential action of KR-31378, a novel potassium channel activator, on cardioprotective and hemodynamic effects. Drug Devel. Res., 54, 182–190 (2001).
Li, Y. and Kloner, R. A., Cardioprotective effects of ischaemic preconditioning are not mediated by prostanoids. Cardiovasc. Res., 26, 226–231 (1992).
Liu, Y., Sato, T., O’Rourke, B., and Marban, E., Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97, 2463–2469 (1998).
Loussouarn, G., Pike, L. J., Ashcroft, F. M., Makhina, E. N., and Nichols, C. G., Dynamic sensitivity of ATP-sensitive K+ channels to ATP. J. Biol. Chem., 276, 29098–29103 (2001).
Mizumura, T., Nithipatikom, K., and Gross, G. J., Bimakalim, an ATP-sensitive potassium channel opener, mimics the effects of ischemic preconditioning to reduce infarct size, adenosine release, and neutrophil function in dogs. Circulation 92, 1236–1245 (1995).
Park, Y. S., Yoo, S. E., Shin, H. S., ** YR, and Yun, Y. P., Pharmacological characterization of vasorelaxant effects of BMS-180448, a novel cardioselective ATP-sensitive potassium channel opener, in rat aorta. J. Pharmacol. Sci., 92, 218–227 (2003).
Peart, J. N. and Gross, G. J., Exogenous activation of delta-and kappa-opioid receptors affords cardioprotection in isolated murine heart. Basic Res. Cardiol., 99, 29–37 (2004).
Rainbow, R. D., Lodwick, D., Hudman, D., Davies N. W., Norman, R. I., and Standen, N. B., SUR2A C-terminal fragments reduce KATP currents and ischaemic tolerance of rat cardiac myocytes. J. Physiol., 557(Pt 3):785–794 (2004).
Rohmann, S., Fuchs, C., and Schelling, P., In swine myocardium, the infarct size reduction induced by U-89232 is glibenclamide sensitive: evidence that U-89232 is a cardioselective opener of ATP-sensitive potassium channels. J. Cardiovasc. Pharmacol., 29, 69–74 (1997).
Rovnyak, G. C., Ahmed, S. Z, Ding, C. Z., Dzwonczyk, S., Ferrara, F. N., Humphreys, W. G., Grover, G. J., Santafianos, D., Atwal, K. S., Baird, A. J., McLaughlin, L. G., Normandin, D. E., Sleph, P. G., and Traeger, S. C., Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity. J. Med. Chem., 40, 24–34 (1997).
Teshima, Y., Akao, M., Li, R. A., Chong, T. H., Baumgartner, W. A., Johnston, M. V., and Marban, E., Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress. Stroke 34, 1796–1802 (2003).
Wroblewski, F. and Ladue, J. S., Lactic dehydrogenase activity in blood. Proc. Soc. Exp. Biol. Med., 90, 210–213 (1955).
Yao, Z. and Gross, G. J., The ATP-dependent potassium channel: an endogenous cardioprotective mechanism. J. Cardiovasc. Pharmacol., 24(Suppl 4), S28–S34 (1994).
Yellon, D. M., Alkhulaif, i A. M., Browne, E. E., and Pugsley, W. B., Ischaemic preconditioning limits infarct size in the rat heart. Cardiovasc. Res., 26, 983–987 (1992).
Yellon, D. M., Alkhulaifi, A. M., and Pugsley, W. B., Preconditioning the human myocardium. Lancet 342, 276–277 (1993).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, SH., Yang, MK., Lim, JH. et al. KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury. Arch. Pharm. Res. 31, 482–489 (2008). https://doi.org/10.1007/s12272-001-1182-9
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-001-1182-9