Supersensitivity of the adenylyl cyclase system in acute myocardial ischemia: evaluation of three independent mechanisms.
Malignant arrhythmias and the spreading of the infarcted zone in acute myocardial ischemia may be influenced by the sympathetic system. It has been known for quite some time that acute ischemia leads to an increased release of endogenous catecholamines. Adaptive mechanisms at the postsynaptic level such as receptor desensitization, which are operative under normoxic conditions, are abolished in acute myocardial ischemia. On the contrary, three newly characterized, distinct mechanisms lead to a transiently increased activity of the beta-adrenergic system in the early phase of acute ischemia: 1) Functionally coupled beta-adrenergic receptors are rapidly and persistently increased at the cell surface due to the impairment of beta-agonist-promoted uncoupling and internalization. 2) Despite the reversible increase of inhibitory, muscarinic M2 receptors, the inhibitory pathway of the adenylyl cyclase systems becomes ineffective since the coupling protein, Gi, is rapidly impaired. Both the Gi-linked GTPase-activity and the binding of [gamma-35S]GTP are reduced by 25-30% without any loss of the total protein. Stimulatory effects prevail at the G-protein level since in the early period of ischemia the stimulatory G-protein, Gs, remains intact. 3) The adenylyl cyclase is transiently sensitized by about 30%. This increased activity is closely associated with the partially purified enzyme and may be due to a rapidly reversible covalent modification. Prolonged ischemia, in contrast, results in a general decrease of the cyclase activity notwithstanding any changes at the receptor or G-protein level. The individual mechanisms may play distinct and/or complimentary roles in the early sensitization of the adenylyl cyclase system in acute myocardial ischemia.
Strasser
R H
RH
Department of Cardiology, Medical Center, University of Heidelberg, FRG.
Marquetant
R
R
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003327:Coronary Disease / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases