Multiple cellular electrophysiological effects of azimilide in canine cardiac preparations

Takács, János and Iost, Norbert and Lengyel, Csaba Attila and Virág, László and Nesic, Momir and Varró, András and Papp, Julius Gyula (2003) Multiple cellular electrophysiological effects of azimilide in canine cardiac preparations. European Journal of Pharmacology, 470 (3). pp. 163-170. ISSN 0014-2999

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The cellular electrophysiological effect of azimilide (0.1-30 muM) was analyzed in canine ventricular preparations by applying the standard microelectrode and patch-clamp techniques at 37 degreesC. In papillary muscle, the drug prolonged the action potential duration (APD) in a concentration-dependent manner at a cycle length (CL) of 1000 ms. In Purkinje fibers, at the same CL, the concentration-dependent lengthening of the APD was observed in the presence of up to 3 muM azimilide (at 3.0 muM: 24.1 +/- 4.2%, n = 9); at higher drug concentration, no further APD prolongation was observed. Azimilide lengthened APD in a reverse frequency-dependent manner in papillary muscle and Purkinje fibers alike. Azimilide (10 muM) caused a rate-dependent depression in the maximal upstroke velocity of the action potential (V-max) in papillary muscle. The time and rate constants of the offset and onset kinetics of this V-max block were 1754 +/- 267 ms (n = 6) and 5.1 +/- 0.4 beats (n = 6), respectively. Azimilide did not prevent the APD shortening effect of 10 muM pinacidil in papillary muscle, suggesting that the drug does not influence the ATP-sensitive K+ current. Azimilide inhibited the rapid (I-Kr) and slow component (I-Ks) of the delayed rectifier K+ current and the L-type Ca2+ current (I-Ca). The estimated EC50 value of the drug was 0.59 muM for I-Ks, 0.39 muM for I-Kr and 7.5 muM for I-Ca. The transient outward (I-to) and the inward rectifier (I-kl) K+ currents were not influenced by the drug. It is concluded that the site of action of azimilide is multiple, it inhibits not only K+ (I-Kr, I-Ks) currents but, in higher concentrations, it also exerts calcium- and use-dependent sodium channel block.

Item Type: Article
Subjects: R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan
R Medicine / orvostudomány > RS Pharmacy and materia medica / gyógyszerészet, gyógyászati eszközök
Depositing User: Erika Bilicsi
Date Deposited: 13 Mar 2013 07:21
Last Modified: 13 Mar 2013 07:21

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