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Beneficial roles of adenosine in ischemic and reperfusion injury
J Mol
Cell
Cardiol
o-10 Beneficial Nasatsugu The First
24 (Supplement
II) (1992)
Roles of Adenosine Hori, Masafumi Department of
in Ischemic
Kitakaze, Medicine,
Akira Osaka
and Reperfusion Kitabatake University
Injury
and Takenobu Kamada School of Medicine, Osaka,
Japan
Adenosine has multipotent effects on hearts: It attenuates myocardial Ca overload and beta-mediated increases in contractility through its Al receptors, and increases coronary flow and attenuates the activities of leukocytes and platelets through its A receptors. Either of these actions may benefit the attenuation of myocardial ccl f ular injury. To test this idea, we used the two different models to cause ischemic reperfusion injury in dogs. One is myocardial stunning (15 min LAD occlusion followed by reperfusion) and the other is myocardial necrosis (40 ruin LAD occlusion followed by reperfusion). Exogenous adenosine attenuates myocardial stunning, through activation of Al and A2 receptors. Furthermore, enhancements of adenosine production due to administration of AICA riboside and alpha -stimulation also attenuates myocardial stunning. On the other hand, we elucidated t t at ischemic preconditioning, which significantly limits the infarct size, augments 5’nucleotidase activity and adenosine production. The increase in adenosine production may be attributed to ischemic preconditioning since adenosine is tightly related to its necrosis limiting effects. In summary, we conclude that adenosine plays important roles for the prevention and attenuation of ischemic reperfusion injury.
O-11 BENEFICIAL EFFECT OF ADENOSINE ON MYOCARDIALSTUNNING Robert M. Mentzer, Jr., Mohinder Randhawa, Rolf Bunget-*, Robert D. Lasley. Department of Surgery, Uy(iversity of Wisconsin, Madison, WI and *Deportment of Physiology, F. E. Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MI& USA. Since stunned myocardium may be associated with rofound hemodynamic abnormalities, treatment of the reversibly damaged Reart is a maater of considerable interest and debate. Adenosine (ADO), a purine nucleoslde catabolita of ATP metabolism, is a potentially attractive cardioprotective agent, Because ADO Is a rapidly metabolized endogenous compound the side effects associated with a therapeuttc regimen are likely to be minimal. To assess whether ADO enhances regional ventricular function in the stunned heart adult dogs wane instrumented with piezoelectric crystals to measure systolic wall thickening (SWT) in the left anterior descending artery (LAD) perfused region of the left ventricle. ADO (50 pg/kg/min) was infused into the LAD prior to and 30 mln after 15 min LAD Prior to LAD occlusion, ADO infusion bed no effect on SWT, i.e., 17i1.8% occlusion. vs. 15.8hl.81. Thirty min after LAD occlusion regional SWT was depressed, i,e., Subsequent ADO infusion increased SWT to ;:.;;i04i% of preischemic $WT (p < 0.05). . .* These data indicate ADO exerts a beneficial effect on myocardial This salutary effect has therapeutic implications with respect to stunning. improvtng cardiac survival and recovery after ischemia.
0-12POTENTIATION OF ENDOGENOUS ADENOSINE FORMATION. Jiirgen Schrader. Dept. Heinrich-Heine-Universitat, Diisseldorf, Germany. of Physiology, Intracellular turnover of adenosine (ado) is rapid and measurement not predict flux rates of steadv state substrate concentration does through ado forming pathways. This, however , is necessary to device strateqies for the potentiation of endogenous ado formation. Previous studies have reveiled that the conversion of SAH to ado occurs at a Since only 50 pmoles/min x g are rerate of 0.6 - 1.0 nmoles/min x g. leased this finding suggested an important role of ado-kinase in the We therefore have studied in the isolated intracellular salvage of ado. guinea pig heart the effect of ado-kinase inhibition (iodotubercidin, 5'-amino-5'--deoxy-adenosine) on the coronary efflux of ado using inhibitors of ado-deaminase (EHNA) and SAH-hydrolase (adenosine dialdehyde) Inhibition of adoto dissect the other adenosine forming pathways. kinase caused maximal coronary vasodilation in the normoxic heart and increased release of ado to 2.5 nmoles/min x g. Studies in the hypoxic heart reveiled that ado-kinase is not substrate saturated. Collectively our results demonstrate that ado-kinase is an important target to control adenosine formation in the normoxic and hypoxic heart. The implication of this new finding for myocardial protection will be discussed.
Cell
Cardiol
o-10 Beneficial Nasatsugu The First
24 (Supplement
II) (1992)
Roles of Adenosine Hori, Masafumi Department of
in Ischemic
Kitakaze, Medicine,
Akira Osaka
and Reperfusion Kitabatake University
Injury
and Takenobu Kamada School of Medicine, Osaka,
Japan
Adenosine has multipotent effects on hearts: It attenuates myocardial Ca overload and beta-mediated increases in contractility through its Al receptors, and increases coronary flow and attenuates the activities of leukocytes and platelets through its A receptors. Either of these actions may benefit the attenuation of myocardial ccl f ular injury. To test this idea, we used the two different models to cause ischemic reperfusion injury in dogs. One is myocardial stunning (15 min LAD occlusion followed by reperfusion) and the other is myocardial necrosis (40 ruin LAD occlusion followed by reperfusion). Exogenous adenosine attenuates myocardial stunning, through activation of Al and A2 receptors. Furthermore, enhancements of adenosine production due to administration of AICA riboside and alpha -stimulation also attenuates myocardial stunning. On the other hand, we elucidated t t at ischemic preconditioning, which significantly limits the infarct size, augments 5’nucleotidase activity and adenosine production. The increase in adenosine production may be attributed to ischemic preconditioning since adenosine is tightly related to its necrosis limiting effects. In summary, we conclude that adenosine plays important roles for the prevention and attenuation of ischemic reperfusion injury.
O-11 BENEFICIAL EFFECT OF ADENOSINE ON MYOCARDIALSTUNNING Robert M. Mentzer, Jr., Mohinder Randhawa, Rolf Bunget-*, Robert D. Lasley. Department of Surgery, Uy(iversity of Wisconsin, Madison, WI and *Deportment of Physiology, F. E. Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MI& USA. Since stunned myocardium may be associated with rofound hemodynamic abnormalities, treatment of the reversibly damaged Reart is a maater of considerable interest and debate. Adenosine (ADO), a purine nucleoslde catabolita of ATP metabolism, is a potentially attractive cardioprotective agent, Because ADO Is a rapidly metabolized endogenous compound the side effects associated with a therapeuttc regimen are likely to be minimal. To assess whether ADO enhances regional ventricular function in the stunned heart adult dogs wane instrumented with piezoelectric crystals to measure systolic wall thickening (SWT) in the left anterior descending artery (LAD) perfused region of the left ventricle. ADO (50 pg/kg/min) was infused into the LAD prior to and 30 mln after 15 min LAD Prior to LAD occlusion, ADO infusion bed no effect on SWT, i.e., 17i1.8% occlusion. vs. 15.8hl.81. Thirty min after LAD occlusion regional SWT was depressed, i,e., Subsequent ADO infusion increased SWT to ;:.;;i04i% of preischemic $WT (p < 0.05). . .* These data indicate ADO exerts a beneficial effect on myocardial This salutary effect has therapeutic implications with respect to stunning. improvtng cardiac survival and recovery after ischemia.
0-12POTENTIATION OF ENDOGENOUS ADENOSINE FORMATION. Jiirgen Schrader. Dept. Heinrich-Heine-Universitat, Diisseldorf, Germany. of Physiology, Intracellular turnover of adenosine (ado) is rapid and measurement not predict flux rates of steadv state substrate concentration does through ado forming pathways. This, however , is necessary to device strateqies for the potentiation of endogenous ado formation. Previous studies have reveiled that the conversion of SAH to ado occurs at a Since only 50 pmoles/min x g are rerate of 0.6 - 1.0 nmoles/min x g. leased this finding suggested an important role of ado-kinase in the We therefore have studied in the isolated intracellular salvage of ado. guinea pig heart the effect of ado-kinase inhibition (iodotubercidin, 5'-amino-5'--deoxy-adenosine) on the coronary efflux of ado using inhibitors of ado-deaminase (EHNA) and SAH-hydrolase (adenosine dialdehyde) Inhibition of adoto dissect the other adenosine forming pathways. kinase caused maximal coronary vasodilation in the normoxic heart and increased release of ado to 2.5 nmoles/min x g. Studies in the hypoxic heart reveiled that ado-kinase is not substrate saturated. Collectively our results demonstrate that ado-kinase is an important target to control adenosine formation in the normoxic and hypoxic heart. The implication of this new finding for myocardial protection will be discussed.