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(Circulation. 2000;102:2535.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Ischemic Inactivation of G Protein–Coupled Receptor Kinase and Altered Desensitization of Canine Cardiac ß-Adrenergic Receptors

Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-274).

Xichun Yu, MD; Min Zhang, MD; Kimberly Kyker, MS; Eugene Patterson, PhD; Jeffrey L. Benovic, PhD; David C. Kem, MD

From the Departments of Medicine (X.Y., M.Z., K.K., E.P., D.K.) and Cell Biology (E.P.) and the Cardiac Arrhythmia Research Institute (E.P., D.C.K.), University of Oklahoma Health Sciences Center and VA Medical Center, Oklahoma City; and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pa (J.L.B.).

Correspondence to David C. Kem, MD, Endocrinology, Metabolism, and Hypertension, 3E107, 913 N E 13th, Oklahoma City, OK 73104. E-mail david-kem{at}ouhsc.edu

Background—G protein–coupled receptor kinases (GRKs) modulate myocardial ß-adrenergic receptor (ßAR) signaling. We examined whether GRK activity was altered 6, 24, and 96 hours after left anterior descending coronary artery ligation (LAD CAL) in the dog.

Methods and Results—GRK activity was measured in arrhythmogenic subepicardial border zone (EBZ) tissue overlying the infarct and from nonischemic remote-site (RS) subepicardial tissue from the same animal. GRK activity in the ischemic EBZ was 15% of RS (P=0.03, n=6) 24 hours after CAL and appeared to start as early as 6 hours through 96 hours. GRK activity and immunoblot data demonstrated a marked decrease of GRK2 but not GRK5 at 24 hours. EBZ tissue exhibited high-affinity binding for (-)-isoproterenol (K_i of 0.076±0.026 nmol/L [SEM]) at 24 hours, which was not significantly different from control tissue from nonoperated animals (1.2±0.8 nmol/L, P>0.05, n=6). A significantly lower K_i of 13.8±2.8 nmol/L (P<0.001, n=6) was observed for RS taken from the ischemic animals. This was reflected by a 4-fold increase in the EC₅₀ of isoproterenol-stimulated adenylyl cyclase activity from 18 nmol/L in EBZ tissue to 73 nmol/L in RS (P<0.05, n=4).

Conclusions—There is a selective decrease in GRK2 activity and a loss of the ability of the arrhythmia-prone EBZ tissue to desensitize to ß-adrenergic stimulation 24 hours after CAL. This correlates temporally with a second (late) peak in sudden cardiac death previously observed between 6 and 24 hours in dog and rat models of myocardial infarction.

Key Words: proteins • kinases • receptors, adrenergic, beta • death, sudden • myocardial infarction

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