(Circulation. 1995;92:1236-1245.)
© 1995 American Heart Association, Inc.
Articles |
Bimakalim, an ATP-Sensitive Potassium Channel Opener, Mimics the Effects of Ischemic Preconditioning to Reduce Infarct Size, Adenosine Release, and Neutrophil Function in Dogs
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Correspondence to Garrett J. Gross, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Background The primary goal of the present study was to determine whether the infarct size–reducing effect of preconditioning is associated with an increase in adenosine release from the ischemic myocardium during a prolonged occlusion period or the subsequent reperfusion period and by a decrease in neutrophil infiltration. A second objective was to determine whether bimakalim, a KATP channel opener, mimics the effects of ischemic preconditioning.
Methods and Results Barbital-anesthetized open-chest dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion followed by 3 hours of reperfusion. In the preconditioning group, 5 minutes of LAD occlusion followed by 10 minutes of reperfusion was elicited before the 60-minute occlusion period. In two other groups, bimakalim 1 µg/kg bolus followed by a 0.05 µg · kg-1 · min-1 infusion or an equivalent volume of saline was administered intravenously 15 minutes before occlusion and continued until the time of reperfusion. In a final group, bimakalim was administered 10 minutes before reperfusion and continued until the end of the experiment. To measure the release of adenosine from the ischemic region, coronary venous blood samples were collected at various times during ischemia and after reperfusion, and the concentration of adenosine was measured. Myocardial infarct size was determined by triphenyl tetrazolium chloride; transmural myocardial blood flow, by radioactive microspheres. Transmural myeloperoxidase (MPO) activity, an index of neutrophil infiltration in the area at risk, was also measured. Preconditioning produced a marked reduction in infarct size (9.8±3.0% versus 28.6±5.2% in the control group, mean±SEM); adenosine release at 5, 10, 15, and 30 minutes of the 3-hour reperfusion period; and transmural MPO activity in the risk area. Similarly, pretreatment with bimakalim resulted in reductions in infarct size, adenosine release, and transmural MPO activity to an extent almost identical to that of preconditioning. When bimakalim was administered 10 minutes before reperfusion, the drug also produced a significant reduction in infarct size and transmural MPO activity; however, no significant reduction in coronary venous adenosine concentrations was observed. There were no significant differences in collateral blood flow between groups.
Conclusions These results indicate that myocardial preconditioning in the canine heart produced by a short period of ischemia or a KATP channel opener is not mediated by an increase in adenosine release, as measured by coronary venous adenosine concentrations, during 60 minutes of occlusion or the initial 30 minutes of reperfusion. A significant reduction in transmural MPO activity in the ischemic area also appears to result from KATP channel activation and may play a role, at least in part, in the reduction in infarct size observed, particularly when a KATP channel opener is administered just before reperfusion.
Key Words: infarction • adenosine • reperfusion • occlusions • ischemia
This article has been cited by other articles:
 |
|
 |
|
  K. Takarabe, Y. Okazaki, S. Higuchi, J. Murayama, M. Natsuaki, and T. Itoh Nicorandil Attenuates Reperfusion Injury after Long Cardioplegic Arrest Asian Cardiovasc Thorac Ann, June 1, 2007; 15(3): 204 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Moses, P. D. Addison, P. C. Neligan, H. Ashrafpour, N. Huang, S. E. McAllister, J. E. Lipa, C. R. Forrest, and C. Y. Pang Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: efficacy and mechanism Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1609 - R1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Matsuo, S. Watanabe, T. Segawa, S. Yasuda, T. Hirose, M. Iwama, S. Tanaka, T. Yamaki, Y. Matsuno, M. Tomita, et al. Evidence of pharmacologic preconditioning during PTCA by intravenous pretreatment with ATP-sensitive K+ channel opener nicorandil Eur. Heart J., July 2, 2003; 24(14): 1296 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M Bell, H. L Maddock, and D. M Yellon The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart Cardiovasc Res, February 1, 2003; 57(2): 405 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Grover, A. J. D'Alonzo, R. B. Darbenzio, C. S. Parham, T. A. Hess, and M. S. Bathala In Vivo Characterization of the Mitochondrial Selective KATP Opener (3R)-trans-4-((4-Chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril Monohydrochloride (BMS-191095): Cardioprotective, Hemodynamic, and Electrophysiological Effects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 132 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dos Santos, A. J. Kowaltowski, M. N. Laclau, S. Seetharaman, P. Paucek, S. Boudina, J.-B. Thambo, L. Tariosse, and K. D. Garlid Mechanisms by which opening the mitochondrial ATP- sensitive K+ channel protects the ischemic heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H284 - H295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Stevens, M. S. Jahania, J. E. Stivers, R. M. Mentzer Jr, and R. D. Lasley Effects of in vivo myocardial ischemia and reperfusion on interstitial nitric oxide metabolites Ann. Thorac. Surg., April 1, 2002; 73(4): 1261 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hu, J. Vinten-Johansen, M. R. Salem, Z.-Q. Zhao, and G. J. Crystal Isoflurane Inhibits Neutrophil-Endothelium Interactions in the Coronary Circulation: Lack of a Role for Adenosine Triphosphate-Sensitive Potassium Channels Anesth. Analg., April 1, 2002; 94(4): 849 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Grover, A. J. D'Alonzo, K. D. Garlid, R. Bajgar, N. J. Lodge, P. G. Sleph, R. B. Darbenzio, T. A. Hess, M. A. Smith, P. Paucek, et al. Pharmacologic Characterization of BMS-191095, a Mitochondrial KATP Opener with No Peripheral Vasodilator or Cardiac Action Potential Shortening Activity J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 1184 - 1192. [Abstract] [Full Text]
|
|
|
|
|
|
S. Sanada, M. Kitakaze, H. Asanuma, K. Harada, H. Ogita, K. Node, S. Takashima, Y. Sakata, M. Asakura, Y. Shinozaki, et al. Role of mitochondrial and sarcolemmal KATP channels in ischemic preconditioning of the canine heart Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H256 - H263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Pagel, W. G. Toller, E. R. Gross, M. Gare, J. R. Kersten, and D. C. Warltier KATP channels mediate the beneficial effects of chronic ethanol ingestion Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2574 - H2579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Hopper, C. R. Forrest, H. Xu, A. Zhong, W. He, J. Rutka, P. Neligan, and C. Y. Pang Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R666 - R676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sato, N. Sasaki, J. Seharaseyon, B. O'Rourke, and E. Marban Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal KATP Channels in Ischemic Cardioprotection Circulation, May 23, 2000; 101(20): 2418 - 2423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. V. Hoek, L. B. Becker, Z.-H. Shao, C.-Q. Li, and P. T. Schumacker Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion Circ. Res., March 17, 2000; 86(5): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ito, Y. Taniyama, K. Iwakura, N. Nishikawa, T. Masuyama, T. Kuzuya, M. Hori, Y. Higashino, K. Fujii, and T. Minamino Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction J. Am. Coll. Cardiol., March 1, 1999; 33(3): 654 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.R. Tracey, W. Magee, H. Masamune, J. J. Oleynek, and R. J. Hill Selective activation of adenosine A3 receptors with N6-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation Cardiovasc Res, October 1, 1998; 40(1): 138 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sato, B. O'Rourke, and E. Marban Modulation of Mitochondrial ATP-Dependent K+ Channels by Protein Kinase C Circ. Res., July 13, 1998; 83(1): 110 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yokoshiki, M. Sunagawa, T. Seki, and N. Sperelakis ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C25 - C37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M Yellon, G. F Baxter, D. Garcia-Dorado, G. Heusch, and M. S Sumeray Ischaemic preconditioning: present position and future directions Cardiovasc Res, January 1, 1998; 37(1): 21 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Zhao, J. C. Todd, H. Sato, X.-L. Ma, and J. Vinten-Johansen Adenosine inhibition of neutrophil damage during reperfusion does not involve KATP-channel activation Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1677 - H1687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Giannella, H.-C. Mochmann, and R. Levi Ischemic Preconditioning Prevents the Impairment of Hypoxic Coronary Vasodilatation Caused by Ischemia/Reperfusion : Role of Adenosine A1/A3 and Bradykinin B2 Receptor Activation Circ. Res., September 19, 1997; 81(3): 415 - 422. [Abstract] [Full Text]
|
|
|
|
|
|
A. Tosaki and D. K. Das Extracellular Mg++ Manipulation Prevents the Proarrhythmic Activity of Cromakalim in Ischemic/Reperfused Diabetic Hearts J. Pharmacol. Exp. Ther., July 1, 1997; 282(1): 309 - 317. [Abstract] [Full Text]
|
|
|
|
|
|
A. W. Gomoll, R. A. Roth, R. E. Swillo, A. J. Baird, C. S. Sargent, R. W. Behling, H. J. Malone, and G. J. Grover Effect of Timing of Treatment of the Glyburide-Reversible Cardioprotective Activity of BMS-180448 J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 24 - 33. [Abstract] [Full Text]
|
|
|
|
|
|
G. J. Gross, D. A. Mei, P. G. Sleph, and G. J. Grover Adenosine A1 Receptor Blockade Does Not Abolish the Cardioprotective Effects of the Adenosine Triphosphate-sensitive Potassium Channel Opener Bimakalim J. Pharmacol. Exp. Ther., February 1, 1997; 280(2): 533 - 540. [Abstract] [Full Text]
|
|
|
|
|
|
T. Mizumura, J. A. Auchampach, J. Linden, R. F. Bruns, and G. J. Gross PD 81,723, an Allosteric Enhancer of the A1 Adenosine Receptor, Lowers the Threshold for Ischemic Preconditioning in Dogs Circ. Res., September 1, 1996; 79(3): 415 - 423. [Abstract] [Full Text]
|
|
|
|
|
|
M. Murata, M. Akao, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca2+ Overload During Simulated Ischemia and Reperfusion: Possible Mechanism of Cardioprotection Circ. Res., November 9, 2001; 89(10): 891 - 898. [Abstract] [Full Text] [PDF]
|
|