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EXPERIMENTAL STUDIES

Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin

Aggravation of this phenomenon in heritable hyperlipidemia

^a Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität zu Berlin, D-10098 Berlin, Germany

Manuscript received March 9, 1998; revised manuscript received June 26, 1998, accepted July 24, 1998.

Address for correspondence: Dr. Karl Stangl, Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität zu Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany
kstangl{at}rz.charite.de

Objectives. We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia.

Background. Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis.

Methods. In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits.

Results. In both controls (n = 12) and WHHL (n = 8), serial perfusion evoked a decrease in coronary flow (controls, –11 ± 3%; WHHL, –25 ± 6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7 ± 8; WHHL, 40.2 ± 5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38 ± 1.1 vs. 0.33 ± 0.5 VT/40 min, p < 0.05; length, 14.36 ± 3.1 vs. 7.25 ± 1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n = 6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET_A antagonists (BQ-123, 2 µmol/liter; A-127722, 20 µmol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 µmol/liter) completely suppressed arrhythmias and vasoconstriction. The ET_B antagonists (IRL-1038, 4 µmol/liter; IRL-1025, 5 µmol/liter) had no effect (n = 6).

Conclusions. Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET_A-mediated and ET_B-independent.

Abbreviations and Acronyms   ECE = endothelin-converting enzyme   ET = endothelin   NZW = New Zealand White rabbits   VES = ventricular extrasystole   VT = ventricular tachycardia   WHHL = Watanabe heritable hyperlipidemic rabbits

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