The selective endothelin-A-receptor antagonist LU 135.252 inhibits the direct arrhythmogenic action of endothelin-1

Besides being a strong vasoconstrictor, endothelin-l (ET-1) also causes sev ere ventricular arrhythmias. The aim of our study was to differentiate betw een the vasoconstrictor and arrhythmogenic actions of ET-1 by using the sel ective endothelin-A(ETA) receptor antagonist LU 135.252 (LU). A bolus injec tion of 5 mg/kg LU was administered to 10 anesthetized mongrel dogs in grou p A. The 30 min intracoronary ET-1 infusion was started 20 min after the LU bolus at a rate of 60 pmol/min. In the control group (group B, n = 8) only ET-1 was administered (60 pmol/min). The left anterior descending coronary artery blood flow (CBF), cardiac output, electrocardiograph (ECG) and arte rial blood pressure were monitored. Two monophasic action potential duratio n (MAPD) catheters were placed onto the left ventricular epicardium (LVEP) and into the right ventricular endocardium (RVEND) to follow electrophysiol ogic changes. No significant changes were observed in blood pressure (0 min vs 30 min: group A, 99.0 +/- 3.5 vs 90.0 +/- 5.2 mmHg, p = NS; group B, 10 3 +/- 6 vs 103 +/- 3 mmHg, p = NS), cardiac output (0 min vs 30 min: group A, 3.5 +/- 0.7 VS 3.2 +/- 0.8 l/min, p = NS; group B, 3.6 +/- 0.4 vs 3.3 +/ - 0.3 l/min, p = NS), and MAPD(90) (0 min vs 30 min: group A, LVEP, 241 +/- 11 vs 260 +/- 14 ms; RVEND, 233 +/- 5 vs 239 +/- 8 ms, p = NS), whereas a significant decrease was observed in CBF (Delta CBF30min: group A, -28 +/- 2%, p < 0.05; group B, -32 +/- 3%, p < 0.05). In group A ventricular fibril lation (VF) occurred once. Ventricular premature contractions (VPCs) and sh ort, nonsustained ventricular tachycardias (nsVTs) were observed in seven c ases. Early afterdepolarizations and a MAPD, increase were observed in the control group B (0 min vs 30 min: LVEP, 244 +/- 10 vs 292 +/- 12 ms; RVEND, 255 +/- 9 vs 290 +/- 8 ms) accompanied by VPCs, incessant nsVTs. Sustained VT and VF were evident in seven cases. Our results indicate, that the appl ied single bolus injection of LU effectively prevents ET-1-induced major ve ntricular arrhythmias, whereas it has no effect on coronary vasoconstrictio n. These data support the notion that ET-1 possesses a direct arrhythmogeni c action.