Beta2-adrenergic receptor antagonists protect against ventricular fibrillation: in vivo and in vitro evidence for enhanced sensitivity to beta2-adrenergic stimulation in animals susceptible to sudden death.
BACKGROUND
The ventricular myocardium contains functional beta2-adrenergic receptors that when activated increase intracellular Ca2+ transients. Because elevated Ca2+ has been implicated in the induction of ventricular fibrillation (VF), it is possible that the activation of these receptors may also provoke malignant arrhythmias.


RESULTS
To test this hypothesis, a 2-minute occlusion of the left circumflex coronary artery was made during the last minute of exercise in 28 dogs with healed anterior myocardial infarctions: 17 had VF (susceptible) and 11 did not (resistant). On a subsequent day, this test was repeated after administration of the beta2-adrenergic receptor antagonist ICI 118,551 (0.2 mg/kg). This drug did not alter the hemodynamic response to the coronary occlusion, yet it prevented VF in 10 of 11 animals tested (P<.001). However, heart rate was reduced in 6 animals. Therefore, the ICI 118,551 exercise-plus-ischemia test was repeated with heart rate held constant by ventricular pacing (n=3). ICI 118,551 still prevented VF when heart rate was maintained. Next, the effects of increasing doses of the beta2-adrenergic receptor agonist zinterol on Ca2+ transient amplitudes were examined in ventricular myocytes. Zinterol elicited significantly greater increases in Ca2+ transient amplitudes at all doses tested (10(-9) to 10(-6) mol/L) in myocytes prepared from susceptible versus resistant animals. The cardiomyocyte response to isoproterenol (10(-7) mol/L) in the presence or absence of the selective beta1- (CGP-20712A, 300 nmol/L) or beta2- (ICI 118,551, 100 nmol/L) adrenergic receptor antagonist was also examined. Isoproterenol elicited larger Ca2+ transient increases in the susceptible myocytes, which were eliminated by ICI but not by CGP.


CONCLUSIONS
When considered together, these data demonstrate that canine myocytes contain functional beta2-adrenergic receptors that are activated to a greater extent in the susceptible animals. The resulting cytosolic Ca2+ transient increases may lead to afterpotentials that ultimately trigger VF in these animals.
Billman
G E
GE
Department of Physiology, Ohio State University, Columbus 43210-1218, USA. billman.1@postbox.acs.ohio-state.edu
Castillo
L C
LC
Hensley
J
J
Hohl
C M
CM
Altschuld
R A
RA
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D003645:Death, Sudden / Q000209:etiology; D004285:Dogs; D004983:Ethanolamines / Q000494:pharmacology; D005080:Exercise Test; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications / Q000401:mortality; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D012680:Sensitivity and Specificity; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control*
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D007093:Imidazoles; D011412:Propanolamines; C026777:ICI 118551; C002904:zinterol; C049763:CGP 20712A; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium