β1 and β2-adrenergic receptor subtype effects in German shepherd dogs with inherited lethal ventricular arrhythmias

Delayed afterdepolarization-induced triggered activity originating in ventricular myocardium is a mechanism for some age-dependent, inherited ventricular tachycardias in a colony of German shepherd dogs. Methods: We used standard microelectrode techniques to study beta -adrenergic receptor subtype modulation of the triggered activity in anteroseptal left ventricular myocardium from eleven of these dogs and seven unafflicted, age-matched German shepherd controls. Results: During sustained stimulation at cycle lengths of 300-4000 ms, 10(-9)-10(-7) M isoproterenol concentration-dependently shortened action potential duration (APD) to 90% repolarization more in myocardium from afflicted than from unafflicted dogs. This shortening was prevented by a beta (1)-blocker CGP20712A (10(-7) M) while a beta (2)-blocker ICI118551 (10(-7) M) did not modify the effect of isoproterenol in either group. The beta (2)-agonist zinterol 10(-8)-10(-6) M had no effect on APD. Stimulation at a cycle length of 250 ms in the presence of 10(-7) M isoproterenol induced more triggered AP in myocardium from afflicted than unafflicted dogs. beta (1)-Blockade completely eliminated, while beta (2)-blockade facilitated, and the beta (2)-agonist zinterol did not induce triggered activity in the two groups. Conclusion: Isoproterenol effects on APD and triggered activity in the myocardium of dogs with inherited arrhythmias are due primarily to an abnormality of beta (1)-adrenoceptor mediated signaling that is subject to beta (2)-adrenergic modulation. (C) 2000 Elsevier Science B.V. All rights reserved.