Mechanisms of Activation of Cardiac Glycogen Phosphorylase in Ischemia and Anoxia

Abstract

The effects of ischemia and anoxia on cardiac adenosine 3',5'-monophosphate (cyclic AMP) concentration, glycogen phosphorylase activity ratio (-5'-AMP: + 5'-AMP), phosphorylase kinase activity ratio (pH 6.8:8.2), and myocardial contractility (left ventricular dP/dt) were studied in an open-chest rat heart preparation. Ischemia produced by termination of coronary blood flow increased cyclic AMP from 0.55 to 0.77 yu.moles/kg in 5 seconds and phosphorylase from 0.14 to 0.57 in 20 seconds. Anoxia induced by breathing N., increased cyclic AMP from 0.50 to 0.62 ju.moles/kg in 10 seconds and phosphorylase from 0.14 to 0.65 in 30 seconds. Phosphorylase kinase increased with ischemia but did not change with anoxia. Beta-receptor blockade with practolol prevented the rise in cyclic AMP and phosphorylase kinase but blocked the increase in phosphorylase only in ischemia. Myocardial contractility declined precipitously during the first 20 seconds of anoxia. Epinephrine (0.1 |ixg/kg) caused an increase in cyclic AMP comparable to that elicited by anoxia, and it produced an increase in dP/dt during N a breathing. These results suggest that in the intact working heart ischemia induces phosphorylase a formation through a cyclic AMP-dependent transformation of phosphorylase kinase; however, in anoxia phosphorylase a formation depends only on the regulation of the catalytic activity of phosphorylase kinase without conversion of this enzyme to its activated form. An increase in cyclic AMP during anoxia is not associated with a positive inotropic response even though such a response is obtained with epinephrine. Factors other than the elevation of myocardial cyclic AMP may be limiting in the control of both cardiac glycogenolysis and inotropic state. KEY WORDS adenosine 3',5'-monophosphate phosphorylase kinase practolol glycogenolysis contractility epinephrine rat heart• The activation of glycogenolysis that occurs with ischemia and anoxia in the myocardium results from an increase in glycogen phosphorylase activity (1-4). The increase in enzyme activity occurs very rapidly, within approximately 10 seconds, and appears to be largely due to the conversion of the enzyme from the b to the a form (4-6). Epinephrine elicits activation of cardiac phosphorylase by a sequence of reactions beginning with the production of adenosine 3',5'-monophosphate (cyclic AMP) through the activation of adenylate cyclase (7-9). The mechanism of action of cyclic AMP appears to be the activation of protein kinase (10). This enzyme catalyzes the adenosine triphosphate-dependent transformation of phosphory-

Increased uptake of 18F-fluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina.

“…This was responsible for a consistently higher 4 This seems to be largely caused by the conversion of phosphorylase from the b to the a form, which could be mediated by epinephrine through an increased production of cyclic AMP. 16 Increased glycogen synthesis in the myocardium has been reported in experimental animals after exercise. 17 FIGURE 5.…”

Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts.

“…The role of coronary blood flow in maintaining a suitable intracellular environment in addition to providing the oxygen supply has been emphasized recently in studies comparing the effects of anoxia with those of ischemia (15)(16)(17). Ischemia has been shown to be more detrimental to cellular function and metabolism than is anoxia in which coronary blood flow is maintained at normal rates.…”

Increase in Content of Glycogen Phosphorylase during Ischemia in Isolated Rabbit Heart.

“…Although the present model most closely resembles hypoxic ischemia, GP kinase may have been activated if 1 h of ischemia induced anoxia. Though the present study did not determine whether GP in the microsomel fraction was GP-a or -b, but it is likely that the majority of GP in the present study was GP-b, since hypoxic ischemia increases GP-a [23,34] that could be liberated from SR [17]. In addition, reperfusion increased GP-b for long periods after ischemia [9].…”

“…On the other hand, Morgan and Parmeggiani concluded that phosphofructokinase activated GP-b in the anaerobically reperfused isolated heart [3] . In contrast, no change in GP activity was reported in the anoxic heart [28,34] , and GP kinase was reported to be activated by Mg2+ and Ca2+ [34] . Although the present model most closely resembles hypoxic ischemia, GP kinase may have been activated if 1 h of ischemia induced anoxia.…”

“…The activity of GP is regulated in two ways, by covalent modification and by allosteric effectors [33] . Ischemia-induced activation of GP is thought to be the result of an increase in GP-a due to elevated cAMP [23,34], activation of GP-b by cAMP and/or Pi [1, 32,35] or by glucose 6-phosphate and Pi [31]. On the other hand, Morgan and Parmeggiani concluded that phosphofructokinase activated GP-b in the anaerobically reperfused isolated heart [3] .…”