A. Criniti et al., Cicletanine prevents the excitation-conduction blocks induced by terfenadine in ischemic myocardium, EUR J PHARM, 382(3), 1999, pp. 197-205
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.