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Titolo:
MOLECULAR-BASIS FOR THE LACK OF HERG K-RELATED CARDIOTOXICITY BY THE H-1 RECEPTOR BLOCKER CETIRIZINE COMPARED WITH OTHER 2ND-GENERATION ANTIHISTAMINES( CHANNEL BLOCK)
Autore:
TAGLIALATELA M; PANNACCIONE A; CASTALDO P; GIORGIO G; ZHOU ZF; JANUARY CT; GENOVESE A; MARONE G; ANNUNZIATO L;
Indirizzi:
UNIV NAPLES FEDERICO II,SCH MED,PHARMACOL SECT,DEPT NEUROSCI,VIA S PANSINI 5 I-80131 NAPLES ITALY UNIV NAPLES FEDERICO II,SCH MED,DEPT INTERNAL MED,CLIN IMMUNOL SECT I-80131 NAPLES ITALY UNIV WISCONSIN,CARDIOL SECT MADISON WI 53792
Titolo Testata:
Molecular pharmacology
fascicolo: 1, volume: 54, anno: 1998,
pagine: 113 - 121
SICI:
0026-895X(1998)54:1<113:MFTLOH>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
POTASSIUM CHANNEL; ASTEMIZOLE OVERDOSE; CARDIAC-ARRHYTHMIA; DE-POINTES; TERFENADINE; LORATADINE; RECTIFIER; FAMILY; CELLS; ECG;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
39
Recensione:
Indirizzi per estratti:
Citazione:
M. Taglialatela et al., "MOLECULAR-BASIS FOR THE LACK OF HERG K-RELATED CARDIOTOXICITY BY THE H-1 RECEPTOR BLOCKER CETIRIZINE COMPARED WITH OTHER 2ND-GENERATION ANTIHISTAMINES( CHANNEL BLOCK)", Molecular pharmacology, 54(1), 1998, pp. 113-121

Abstract

In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H-1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 mu M On the other hand, terfenadine and astemizole effectively blocked HERG KC channels with nanomolar affinities (the estimated lc,, values were 330 and 480 nM, respectively), whereas loratadine was similar to 300-fold less potent (IC50 approximate to 100 mu M). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried byHERG channels (I-HERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 muM cetirizine did not exert any inhibitory action on I-HERG. Astemizole (3 mu M), on the other hand, was highly effective. Terfenadine (3 muM) caused a marked (approximate to 80%) inhibition of I-HERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 mu M) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect I-HERG, whereas the same intracellularconcentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines displaymarked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituentgroups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/18 alle ore 08:35:57