Background Endothelin (ET), one of the most potent vasoconstrictors, is known to influence ventricular tachycardia (VT). The mechanism thought to be involved includes triggered activity (TA). We investigated effects of ET-1 and the ET-1A receptor blocker BQ123 in a canine model of focal and reentrant VT in a combined in vivo and in vitro study to test the hypothesis that focal VT and TA were selectively affected.
Methods Thirty-eight alpha-chloralose-anesthetized dogs with 1 to 3 hours of coronary artery occlusion were studied. Three-dimensional activation mapping identified the mechanism of VT. If VT was not inducible at baseline, incremental doses of ET-1 were given until the VT was induced. If VT was reproducibly induced at baseline, BQ123 was given (2.5 μg/kg, IV), and then induction was repeated. The effect of these agents on action potentials (APs), delayed and early afterdepolarizations (DADs and EADs), and TA measured from ischemic endocardium were studied in vitro by standard microelectrode techniques.
Results Of 15 dogs with no VT inducible, ET-1 (0.2 μg/kg, IV) produced sustained VT of mixed reentrant and focal origin in five dogs (p < .05 [*] vs saline alone). ET-1 did not change effective refractory period (ERP), pacing threshold, mean arterial pressure (MAP), or infarct size (37 ± 3% [SEM] to 39 ± 4%). Of 12 dogs with reproducible reentrant VT in control, only 1 had no VT inducible after saline. Of 11 dogs given BQ123, reentrant VT was prevented in 4 of 6*; surface ECG and intracardiac T-wave alternans was blocked in all experiments. Zero of five dogs with focal origin of VT was prevented. BQ123 did not change ERP, threshold, MAP, or infarct size. In vitro APs were not substantially changed by ET-1 until rapid pacing produced AP alternans facilitated by ET-1 in 8 of 15 tissues; however, ET-1 (10-10-10-8 M) did not facilitate EADs, DADs, or TA.
Conclusion ET-1 promotes focal and reentrant VT under conditions of myocardial ischemia; however, in vitro tissues do not show TA as we expected. The specific ET-1A receptor blocker BQ123 significantly blocked only reentrant VT. Endothelin plays a major role in reentrant VTs in the dog model of myocardial ischemia probably by promoting AP alternans.
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