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 cicletanine, a prostacyclin generation stimulator. We aimed at determining in vitro if cicletanine can protect the ischemic myocardium from excitation-conduction blocks and specifically those induced by terfenadine. In a double-chamber bath, isolated guinea pig ventricular strips were partly exposed to normoxia and partly to ischemic, then reperfused, conditions, in the presence of 10 mu M terfenadine, 10 mu M indomethacin (prostacyclin generation blocker) 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 cicletanine during the total protocol duration. The multivariate Cox's model was used to predict the excitation-conduction block events and to assess the estimated survival of preparations (excitation-conduction block-free rate). Cicletanine protected the preparations (relative risk = 0.08, t = -3.28) from the ischemia-induced excitation-conduction blocks (estimated survival = 0.83 versus 0.30 in control), and this effect was abolished by indomethacin (estimated survival = 0.35). Terfenadine enhanced 3.58-fold the risk of 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 vitro 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) efficacy of cicletanine to prevent excitation-conduction blocks induced by terfenadine in ischemic cardiac tissue. (C) 1999 Elsevier Science B.V. All rights reserved.