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beta(1) and beta(2)-adrenergic receptor subtype effects in German shepherd dogs with inherited lethal ventricular
E A Sosunov1, R Z Gainullin, N S Moise
1Department of Pharmacology, Columbia University, College of Physicians and Surgeons, 630 West 168 Street, PH7W-321, 10032, New York, NY, USA.
Objective:
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.