Sensitization of the beta-adrenergic system in acute myocardial ischaemia by a protein kinase C-dependent mechanism.
In acute myocardial infarction the occurrence of malignant arrhythmias and the spreading of the infarcted zone followed by the development of heart failure determine the clinical outcome of the disease. The activity of the adrenergic system plays an important role in both. At various levels acute myocardial ischaemia induces an inadequate activation of the adrenergic system. The increased presynaptic release of endogenous catecholamines does not promote the expected desensitization at the postsynaptic level. In contrast, acute ischaemia leads to a rapid and persistent increase of functionally coupled beta-adrenergic receptors, which in the early phase of acute ischaemia, induce an increased responsiveness of the adenylyl cyclase system to beta-adrenergic stimulation. This sensitization at the receptor level is superimposed by a receptor-independent sensitization of the adenylyl cyclase and a loss of tonic inhibition due to the functional impairment of the inhibitory G protein. At the enzyme level a transient sensitization of adenylyl cyclase in acute myocardial ischaemia is due to a modification of the enzyme, which is tightly associated with the purified enzyme. Only inhibition of protein kinase C is able to block completely the ischaemia-induced sensitization of adenylyl cyclase. Based on these data, it could be demonstrated that acute myocardial ischaemia leads to a rapid activation of protein kinase C by an as yet undefined mechanism. Beyond the sensitization of adenylyl cyclase, activation of protein kinase C may directly activate ion channels or the N+/H+ echanger, and it may induce the increased expression of oncogenes and thus crucially influence the clinical outcome of an acute myocardial infarction.
Strasser
R H
RH
University of Heidelberg, Department of Cardiology, Germany.
Marquetant
R
R
D000262:Adenylyl Cyclases / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D009203:Myocardial Infarction / Q000201:enzymology*; D011493:Protein Kinase C / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases