title: Cicletanine prevents the excitation-conduction blocks induced by terfenadine in ischemic myocardium.
abstract: 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 microM terfenadine, 10 microM 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 microM 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 (1) 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.
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Department of Cardiac Surgery and the Second Section of Cardiology, University "La Sapienza", Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Criniti
authors.forename: S
authors.initials: S
authors.lastname: Picard
authors.forename: F
authors.initials: F
authors.lastname: Monti
authors.forename: A A
authors.initials: AA
authors.lastname: Dawodu
authors.forename: G
authors.initials: G
authors.lastname: Ruvolo
authors.forename: P E
authors.initials: PE
authors.lastname: Puddu
authors.forename: P P
authors.initials: PP
authors.lastname: Campa
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004347:Drug Interactions; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006634:Histamine H1 Antagonists / Q000633:toxicity; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D015999:Multivariate Analysis; D017202:Myocardial Ischemia / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000503:physiopathology*; D016593:Terfenadine / Q000633:toxicity; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D006634:Histamine H1 Antagonists; D011725:Pyridines; D016593:Terfenadine; C038068:cicletanine; D011464:Epoprostenol; D007213:Indomethacin; D004121:Dimethyl Sulfoxide