ARRHYTHMOGENIC EFFECTS INDUCED BY CORONARY CONVERSION OF PULMONARY BIG ENDOTHELIN TO ENDOTHELIN - AGGRAVATION OF THIS PHENOMENON IN HERITABLE HYPERLIPIDEMIA

Objectives. We investigated whether endogenous pulmonary big endotheli n has arrhythmogenic properties under normal conditions and in heritab le hyperlipidemia. Background. Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is u nclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis. Methods. In a lung-heart mo del in which a Langendorff heart is serially perfused with the effluen t from the isolated lung of the same animal, me evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits.Res ults. In both controls (n = 12) and WHHL (n = 8), serial perfusion evo ked a decrease in coronary flow (controls, -11 +/- 3%; WHHL, -25 +/- 6 %) and a fourfold increase of ventricular extrasystoles (VES) (control s, 40.7 +/- 8; WHHL, 40.2 +/- 5 VES/40 min, p < 0.05). However, WHHL d eveloped more and longer nonsustained ventricular tachycardias (VT) co mpared with controls (incidence, 1.38 +/- 1.1 vs. 0.33 +/- 0.5 VT/40 m in, p < 0.05; length, 14.36 +/- 3.1 vs. 7.25 +/- 1.5 beats/VT, p < 0.0 5). Arrhythmias were not ischemia-induced because corresponding mechan ical flow reduction had no arrhythmogenic effect (n = 6 in controls an d WHHL). Although vasoconstriction disappeared entirely, arrhythmias w ere only partly suppressed by ETA antagonists (BQ-123, 2 mu mol/liter; A-127722, 20 mu mol/liter). The ET-converting enzyme inhibitor phosph oramidon (50 mu mol/liter) completely suppressed arrhythmias and vasoc onstriction. The ETB antagonists (IRL-1038, 4 mu mol/liter; IRL-1025, 5 mu mol/liter) had no effect (n = 6). Conclusions. Endogenous pulmona ry big ET produces arrhythmogenic effects that are aggravated in herit able hyperlipidemia. These effects, requiring coronary conversion of b ig ET into ET, are partly ETA-mediated and ETB-independent. (J Am Coil Cardiol 1998;32:1773-8) (C) 1998 by the American College of Cardiolog y.