beta(1) and beta(2)-adrenergic receptor subtype effects in German shepherddogs with inherited lethal ventricular arrhythmias

Delayed afterdepolarization-induced triggered activity originating in ventr icular myocardium is a mechanism for some age-dependent, inherited ventricu lar tachycardias in a colony of German shepherd dogs. Methods: We used stan dard microelectrode techniques to study beta -adrenergic receptor subtype m odulation of the triggered activity in anteroseptal left ventricular myocar dium from eleven of these dogs and seven unafflicted, age-matched German sh epherd controls. Results: During sustained stimulation at cycle lengths of 300-4000 ms, 10(-9)-10(-7) M isoproterenol concentration-dependently shorte ned action potential duration (APD) to 90% repolarization more in myocardiu m from afflicted than from unafflicted dogs. This shortening was prevented by a beta (1)-blocker CGP20712A (10(-7) M) while a beta (2)-blocker ICI1185 51 (10(-7) M) did not modify the effect of isoproterenol in either group. T he beta (2)-agonist zinterol 10(-8)-10(-6) M had no effect on APD. Stimulat ion at a cycle length of 250 ms in the presence of 10(-7) M isoproterenol i nduced more triggered AP in myocardium from afflicted than unafflicted dogs . beta (1)-Blockade completely eliminated, while beta (2)-blockade facilita ted, and the beta (2)-agonist zinterol did not induce triggered activity in the two groups. Conclusion: Isoproterenol effects on APD and triggered act ivity in the myocardium of dogs with inherited arrhythmias are due primaril y to an abnormality of beta (1)-adrenoceptor mediated signaling that is sub ject to beta (2)-adrenergic modulation. (C) 2000 Elsevier Science B.V. All rights reserved.