Life Sciences, Vol. 66, No. 26, pp. 2527-2541,200O Copyright 0 Zoo0 Ekvicr Science Inc. printed in the USA. All rights merved 0024-3205/00/s-see front matter zyxwvutsr PIISOO243205(00)00587-7 INVESTIGATING THE DUAL NATURE OF ENDOTHELIN-1: ISCHEMIA OR DIRECT ARRHYTHMOGENIC EFFECT? Tamas Szabo, LLzl6 Gel& Bela Merkely, L&l6 Selmeci, Alexander Juhasz-Nagy, Francis Solti Department of Cardiovascular Surgery, Semmelweis University of Medicine Vkosmajor u. 68., Budapest H-l 122, Hungary (Received in final form January 25,200O) Summary Endothelin-1 (ET-l) is a potent vasoconstrictor peptide, which may also elicit severe ventrkuhr arrhythmias. The aims of our study were to compare the effects of total left anterior descending coronary artery (LAD) occlusion to intracoronary (ic.) ET-l administration and to investigate the pathomechanism of ET-l induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group A (n=lO) a total LAD occlusion was carried out for 30 min, followed by a 60 min reperf&ion period. In groups B and C ET-l wasadministeredintoLADfor30minatarateof30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monophasic action potential (MAP) recordings were performed to detect electrophysiologic changes and ischemia. Blood samples for lactate measurements were collected from the coronary sinus (CS) and I?om the femoral artery. Infrared imaging was applied to follow epimyocardial heat emission changes. At the end of the ET- 1 infusion period coronary blood flow (CBF) was reduced significantly in groups B and C (ACBF,,,, B: 21ti%, fl.05; C: 35ti%, p<O.O5), paralleled by a significant epimyocardial tempemture decrease in group C (ATWm: -0.65ti.29 %, ~0.05). Two dogs died of ventricular fibrillation (VF) in the repermsion period in group A. Ventricular premature contractions and non- sustained ventricular tachycardic episodes appeared in group B, whereas six dogs died of VF in group C. Significant CS lactate level elevation indicating &hernia was observed only in group B from the 30”’ min occlusion throughout the mperfusion period (control vs. 30 min1.3M.29 vs. 2.2ti.37 mmol/l, ~0.05). Epi- and endocardial MAP durations (MAPD,) and let? ventricular epicardial (LV& upstroke velocity decreased significantly in group _A in the occlusion period. ET- 1 infusion significantly increased LV,, MAPDW in group B and both MAPD,-s in group C. In conclusion, ischemic MAP and CS lactate changes were observed only in group A. Although ET- 1 reduced CBF significantly in groups B and C, neither MAP nor lactate indicated ischemic alterations. ET-l induced major ventricular arrhythmias appeared before signs of myocatdial ischemia developed, though reduced CBF presumably contributed to sustaining the arrhythmias. Key Words: endothelin- 1, monophasic action potential, cardiothermography, ventricular tachycardia, ischemia Corresponding author: Tamas Szabo, M.D. Department of Cardiovascular Surgery, Semmelweis University of Medicine, Varosmajor u. 68., H-l 122 Budapest, Hungary. Phone/Fax: +36-l-355-46-84 E-mail: tamas.szabo@excite.com