Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits

Summary

The sensitivity of the myocardium to ischemia and the level of protection achieved by ischemic preconditioning is shaped by the joint influence of several mechanisms in diabetes mellitus.

In vivo studies were made in alloxan diabetic and non-diabetic control rabbits to assess if the effects of preconditioning and sulfonylurea pretreatment with either glibenclamide or glimepiride (0.05-0.2-0.6 μmol kg^-1) influence the extent of the infarcted area caused by one hour ligature of the left coronary artery. For our study, we defined preconditioning as 2 minutes of ischemia followed by 2 minutes of reperfusion, which was repeated 3 times. The interrelationship of the diabetic pathophysiological state, and sulfonylurea treatment during ischemic preconditioning were studied by comparing the infarcted areas and the rate of infarction to risk areas in left ventricular slices using computer planimetry. In healthy control rabbits preconditioning reduced infarcted area (29.6 ± 3.0% vs. 48.8 ± 2.8% p < 0.0005), while in diabetic rabbits this protection did not occur (53.3 ± 7.3% vs. 56.6 ± 4.4% NS). Glibenclamide in all of applied doses prevented the protective effect in control animals (infarction/ risk area: HP: 0.47 ± 0.04 vs. HP_Glib-0.05: 0.69±0.06 p< 0.004 vs. HP_Glib-0.2: 0.72±0.09 p< 0.002 vs. HP _Glib-0.6: 0.75 ± 0.04 p< 0.001). In contrast, in diabetic rabbits low dose of glibenclamide contributed to the same development of preconditioning. However the highest dose of glibenclamide (infarction/risk area: DP_Glib-0.6: 0.77 ± 0.17 vs. DP_Glib-0.05: 0.55 < 0.03 p < 0.047) and the consequences of the diabetic state blocked the salutary effect. Glimepiride had no considerable influence on the protective effect, either in control nor in diabetic animals.

Glibenclamide and glimepiride, presumably due to their different sulfonylurea receptor affinity in the heart, resulted in different influence on preconditioning in healthy control animals. Glibenclamide treatment seemed to be more harmful when less K⁺ _ATP channels were activated. The accomplishment of myocardial preconditioning in diabetes mellitus is claimed to be determined by the interaction of both metabolically influenced K⁺ _ATP channel activity and the dose of sulfonylurea.

Key words:

Carbohydrate metabolism - Sulfonylurea - Preconditioning

References

• 1 Ashcroft F M. Mechanism of the glycaemic effects of sulfonylureas.  Horm Metab Res. 1996;  28 456-463
• 2 Bahr M M, Holtey V, Müller G, Eckel J. Direct stimulation of myocardial glucose transport and transporterGLUT₁ and GLUT₄ protein expression by the sulphonylurea glimepiride.  Endocrinology. 1995;  136 2547-2553
• 3 Baker J E, Curry B D, Olinger G N, Gross G J. Increased tolerance of the chronically hypoxic immature heart to ischaemia. Contribution of the K_-ATP channel.  Circulation. 1997;  95 1278-1285
• 4 Brady P A, Terzic A. The sulfonylurea controversery: more questions from the heart.  J Am Coll Cardiol. 1998;  31 950-956
• 5 Buffington C K, Kitabchi A E. Activation of pyruvate dehydrogenase complex (PDC) of rat heart mito chondria by glyburide.  Biochem Biophys Res Comm. 1984;  123 202-209
• 6 Cameron J S, Baghdady R. Role of ATP sensitive potassium channels in long term adaptation to metabolic stress.  Cardiovasc Res. 1994;  28 788-796
• 7 Engler R L, Yellown D M. Sulfonylurea KATP blockade in type II diabetes and preconditioning in cardiovascular disease: Time for reconsideration.  Circulation. 1996;  94 2297-2301
• 8 Feuvray D. The regulation of intracellular pH in the diabetic myocardium.  Cardiovasc Res. 1997;  34 48-54
• 9 Feuvray D, Lupaschuk G D. Controversies on the sensitivity of the diabetic heart to ischemic injury: the sensitivity of the diabetic heart to ischemic injury is decreased.  Cardiovasc Res. 1997;  34 113-120
• 10 Findlay I, Faivre J F. Spare channels.  FEBS-Lett. 1991;  279 95-7
• 11 Fosset M, DeWeille J R, Green R D, Schmid-Antomarchi H, Lazdunski M. Antidiabetic sulfonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K⁺ channels.  J Biol Chem. 1988;  17 7933-7936
• 12 Garrath K N, Brady P A, Hassinger N L, Gril D E, Terzic A, Holme. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acut myocardial infarction.  J Am Coll Cardiol. 1999;  33 119-124
• 13 Gopalakrishnan M, Triggle D J. Regulation of ATP-sensitive K⁺ channels by chronic glyburide and pinacidil administration.  Biochem Pharmacol. 1992;  44 1843-1847
• 14 Gribble F M, Tucker S J, Seino S, Aschroft F M. Tissue specificity of sulfonylureas: Studies on cloned cardiac and beta -cell K⁺ _ATP channels.  Diabetes. 1998;  47 1412-1418
• 15 Gwilt D J, Petri M, Lewis P W, Nattrass M, Pentecost B L. Myocardial infarct size and mortality in diabetic patients.  Br Heart J. 1985;  54 466-472
• 16 Hadour G, Ferrera R, Sebbag L, Forrat R, Delaye J, de Lorgeril M. Improved myocardial tolerance to ischaemia in the diabetic heart.  J Mol Cell Cardiol. 1998;  9 1869-1875
• 17 Haffner S M, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.  Engl J Med. 1998;  339 229-234
• 18 Janovich A, Zhang S, Alekseev A E, Terzic A. Diadenosine phosphate induced inhibition of cardiac ATP-K⁺ channels: Operative state dependent regulation by a nucleoside diphosphate.  Pfleugers Archiv Eur J Physiol. 1996;  431 800-802
• 19 Kramer W, Müller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride at beta cells.  Horm Metab Res. 1996;  28 464-469
• 20 Lederer W J, Nichols C G. Nucleotid modulation of activity of rat heart ATP-sensitive K⁺ channels in isolated membrane patches.  J Physiol(Lond). 1989;  419 193-211
• 21 Lopaschuk G D, Saddik M. The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischaemia.  Mol Cel Biochem. 1992;  116 111-116
• 22 Noma A. ATP-regulated K⁺ channels in cardiac muscle.  Nature. 1983;  305 147-148
• 23 Parratt J R, Kane K A. K _ATP channels in ischaemic preconditioning.  Cardiovasc Res. 1994;  28 783-787
• 24 Pulido N, Casla A, Suarez A, Casanova B, Arrieta F J, Rovira A. Sulfonylurea stimulates glucose uptake in rats through an ATP-sensitive K+ channel dependent mechanism.  Diabetologia. 1996;  39 22-27
• 25 Reimer K A, Murry C E, Yamasawa I, Hill M L, Jennings R B. Four brief periods of ischemia cause no cumulative ATP loss or necrosis.  Am J Physiol. 1986;  251 H1306-H1315
• 26 Shigematsu S, Arit M. Anoxia induced activation of ATP-sensitive K⁺ channels in guinea pig ventricular cells and its modulation by glycolysis.  Cardiovasc Res. 1997;  35 273-282
• 27 Stanley W C, Lopaschuk G D, McGormack J G. Regulation of energy substrate metabolism in the diabetic heart.  Cardiovasc Res. 1997;  34 25-33
• 28 Stanley W C, Hall J L, Smith K R. Myocardial glucose transporters and glycolytic metabolism during ischaemia in hyperglycemic diabetic swine.  Metabolism. 1994;  43 61-69
• 29 Terrand J, Rosenblatt-Velin N, Papageorgiou I, Lerch R. Calcium-mediated activation of pyruvate dehidrogenase enhances glucose oxidation during reperfusion in isolated rat hearts.  J Mol Cell Cardiol. 1999;  31 A 47
• 30 Toombs C F, Moore T L, Shebuski R J. Limitation of infarct size in the rabbit ischemic preconditioning is reversible with glibenclamide.  Cardiovasc Res. 1993;  27 617-622
• 31 Ventakesh N, Lamp S T, Weiss J N. Sulphonylureas, ATP-sensitive K⁺ channels and cellular K⁺ loss during hypoxia, ischaemia and metabolic inhibition in mamallian ventricle.  Circ Res. 1991;  69 623-637
• 32 Weiss J N, Ventakesh N. Metabolic regulation of cardiac ATP sensitive K⁺ channels.  Cardiovasc Drug Ther. 1993;  7 499-505
• 33 Wilde A AM. ATP and the role of I_K-ATP during acut myocardial ischaemia: controversies review.  Cardiovasc Res. 1997;  35 181-183
• 34 Ytrehus K, Liu Y, Donway J. Preconditioning protects ischaemic rabbit heart by protein C activation.  Am J Physiol. 1994;  266 H1145-H1152