Investigating the dual nature of endothelin-1: Ischemia or direct arrhythmogenic effect?

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which may also eli cit severe ventricular arrhythmias. The aims of our study were to compare t he effects of total left anterior descending coronary artery (LAD) occlusio n to intracoronary (ic.) ET-1 administration and to investigate the pathome chanism of ET-1 induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group (A) under bar (n=10) a total LAD occlusion was carr ied out for 30 min, followed by a 60 min reperfusion period. In groups (B) under bar and (C) under bar ET-1 was administered into LAD for 30 min at a rate of 30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monop hasic action potential (MAP) recordings were performed to detect electrophy siologic changes and ischemia. Blood samples for lactate measurements were collected from the coronary sinus (CS) and from the femoral artery. Infrare d imaging was applied to follow epimyocardial heat emission changes. At the end of the ET-1 infusion period coronary blood flow (CBF) was reduced sign ificantly in groups (B) under bar and (C) under bar (Delta CBF30MIN (B) und er bar: 21+/-2%, p<0.05; (C) under bar: 35+/-2%, p<0.05), paralleled by a s ignificant epimyocardial temperature decrease in group (C) under bar (Delta T-30MIN: -0.65+/-0.29 degrees C, p<0.05). Two dogs died of ventricular fib rillation (VF) in the reperfusion period in group (A) under bar. Ventricula r premature contractions and nonsustained ventricular tachycardic episodes appeared in group (B) under bar, whereas six dogs died of VF in group (C) u nder bar. Significant CS lactate level elevation indicating ischemia was ob served only in group (A) under bar from the 30(th) min occlusion throughout the reperfusion period (control vs. 30 min:1.3+/-0.29 vs. 2.2+/-0.37 mmol/ l, p<0.05). Epi- and endocardial MAP durations (MAPD(90)) and left ventricu lar epicardial (LVEPI) upstroke velocity decreased significantly in group ( A) under bar in the occlusion period. ET-1 infusion significantly increased LVEPI MAPD(90) in group (B) under bar and both MAPD(90)-s in group (C) und er bar. In conclusion, ischemic MAP and CS lactate changes were observed on ly in group (A) under bar. Although ET-1 reduced CBF significantly in group s (B) under bar and (C) under bar, neither MAP nor lactate indicated ischem ic alterations. ET-1 induced major ventricular arrhythmias appeared before signs of myocardial ischemia developed, though reduced CBF presumably contr ibuted to sustaining the arrhythmias.