Cicletanine prevents the excitation-conduction blocks induced by terfenadine in ischemic myocardium

Terfenadine, a histamine H-1 receptor antagonist, has been associated with clinical ventricular arrhythmias and in vitro excitation-conduction blocks, whereas anti-ischemic and antiarrhythmic effects have been shown with cicl etanine, a prostacyclin generation stimulator. We aimed at determining in v itro if cicletanine can protect the ischemic myocardium from excitation-con duction blocks and specifically those induced by terfenadine. In a double-c hamber bath, isolated guinea pig ventricular strips were partly exposed to normoxia and partly to ischemic, then reperfused, conditions, in the presen ce of 10 mu M terfenadine, 10 mu M indomethacin (prostacyclin generation bl ocker) or the solvent (dimethylsulfoxide 1:100, control) randomly allocated , and thus either in the absence (n = 20) or presence (n = 21) of 10 mu M c icletanine during the total protocol duration. The multivariate Cox's model was used to predict the excitation-conduction block events and to assess t he estimated survival of preparations (excitation-conduction block-free rat e). Cicletanine protected the preparations (relative risk = 0.08, t = -3.28 ) from the ischemia-induced excitation-conduction blocks (estimated surviva l = 0.83 versus 0.30 in control), and this effect was abolished by indometh acin (estimated survival = 0.35). Terfenadine enhanced 3.58-fold the risk o f occurrence of excitation-conduction blocks during ischemia (t = 2.10) and this effect was inhibited by cicletanine pretreatment (estimated survival = 0.40 versus 0.10 in untreated preparations). In conclusion, these in vitr o findings have provided evidence for (I) protective effects of cicletanine against ischemia-induced excitation-conduction blocks, possibly related to its stimulating activity on local prostacyclin generation, and (2) efficac y of cicletanine to prevent excitation-conduction blocks induced by terfena dine in ischemic cardiac tissue. (C) 1999 Elsevier Science B.V. All rights reserved.