INTRAPERICARDIAL INFUSION OF ENDOTHELIN-1 INDUCES VENTRICULAR ARRHYTHMIAS IN DOGS

Objectives: Recently, extremely high levels of endothelin-l (ET-I) wer e detected in the pericardial fluid of patients with heart disease; ho wever, the pathophysiological importance of this finding is not known. The present study was designed to characterize ET-I levels in canine pericardial fluid and to investigate the effects of local high concent rations of exogenous ET-I in vivo. Methods: In anesthetized, open-ches t dogs ET-I (Groups 1 and 2,: 11 and 33 pmol kg(-1) min(-1); n = 6 and 6, respectively) or physiological saline (Group 3, n = 5) were infuse d into the closed pericardial sac for 40 min. In serial pericardial fl uid and aortic blood plasma samples, ET-I levels were measured by radi oimmunoassay, and analysed by high-performance liquid chromatographp ! HPLC), Systemic arterial blood pressure, heart rate, cardiac output (C O), standard ECG and right ventricular endocardial monophasic action p otentials (MAPs) were recorded. Results: Basal pericardial fluid ET-I levels were significantly higher than I respective plasma levels (342 +/- 210 vs. 8.0 +/- 5.2 pmol l(-1). n = 14, P < 0.001. In HPLC analysi s pericardial fluid ET-I was indistinguishable from ET-1(1-21), Infusi on of exogenous ET-I into the pericardial space induced ventricular ar rhythmias in all instances, which were associated with 9.7-fold increa se in pericardial fluid ET-I levels. Ventricular tachycardias develope d in 9 of 12 animals, The arrhythmogenic affect of ET-I was more appar ent in dogs with the larger dose. Before the onset of arrhythmias, int rapericardial infusion of ET-I increased QT time (Group 1: 207 +/- 18 to 230 +/- 23 ms, P < 0.01; Group 2: 220 +/- 12 to 277 +/- 17 ms, P < 0.01) and MAP duration at 90% repolarization (at 300 ms cycle length) (Group I: 192 +/- 9 to 216 +/- 9 ms, P < 0.01; Group 2: 205 +/- 9 to 2 55 +/- 9 ms, P < 0,001), Hemodynamic variables did not change signific antly prior to the onset of ventricular tachyarrhythmias. In Group 3, arrhythmias were not observed and all electrophysiological and hemodyn amic parameters remained unchanged. Conclusions: Administration of exo genous ET-I into the pericardial space induces ventricular arrhythmias associated with prolongation of QT time and MAP duration. Whether per icardial fluid ET-I under pathophysiological conditions can ever reach sufficiently high levels to induce ventricular arrhythmias remains to be elucidated. (C) 1998 Elsevier Science B.V. All rights reserved.