© 1996 American Heart Association, Inc.
Articles |
Activation of ß-Adrenergic Receptor Kinase During Myocardial Ischemia
the 1. Medizinische Klinik der Technischen Universitat Munchen (M.U., K. Kessebohm,, K. Kronsbein, G.R.) and Pharmakologisches Institut der Universitat Wurzburg (M.J.L.) (Germany).
Correspondence to Dr Martin Ungerer, 1. Medizinische Klinik der Technischen Universitat Munchen, Klinikum rechts der Isar, Ismaningerstr 22, 81675 Munchen, Germany. E-mail ungerer@med1.med.tu-muenchen.de.
During myocardial ischemia, a local release of noradrenaline coincides with an increased density of ß-adrenergic receptors. The functional activity of these receptors, however, is mainly determined by their state of phosphorylation. The ß-adrenergic receptor kinase (ßARK) specifically phosphorylates and thereby inactivates ß-adrenergic receptors after stimulation by receptor agonists, facilitating the binding of the inhibitor protein ß-arrestin to the receptors. ßARK activation involves a translocation of the enzyme to the membrane. In the present study, we investigated the density and the functional activity of ß-adrenergic receptors, the enzymatic activity of ßARK in membranes and cytosol, the mRNA levels of ßARK-1, and the expression of ß-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart. After 60 minutes of stop-flow ischemia, ß-adrenergic receptor density was upregulated, but ß-agonist–mediated adenylate cyclase activity was blunted. Simultaneously, ßARK activity in the particulate fraction was significantly induced. The increase in ßARK activity was reversible after inhibition of ischemia-evoked noradrenaline release by desipramine. Also, exposure to externally given noradrenaline increased ßARK activity in the particulate fraction. Cytosolic ßARK activity remained largely unchanged during stop-flow or low-flow ischemia. The steady state concentration of ßARK-1 mRNA increased after 20 minutes of stop-flow ischemia and then returned to baseline values after another 20 minutes. Cardiac ischemia did not alter ß-arrestin levels. During myocardial ischemia, an increase in the number of ß-adrenergic receptors is paralleled by increased membrane activity of the receptor kinase ßARK. This increased membrane activity may contribute to enhanced receptor phosphorylation and inactivation.
Key Words: ischemia • ß-adrenergic receptor kinase • rat heart
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