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Titolo:
Effects of anorexinogen agents on cloned voltage-gated K+ channel hKv1.5
Autore:
Perchenet, L; Hilfiger, L; Mizrahi, J; Clement-Chomienne, O;
Indirizzi:
F Hoffmann La Roche & Co Ltd, Preclin Res, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd Basel Switzerland CH-4070 asel, Switzerland
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 298, anno: 2001,
pagine: 1108 - 1119
SICI:
0022-3565(200109)298:3<1108:EOAAOC>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
PRIMARY PULMONARY-HYPERTENSION; SMOOTH-MUSCLE CELLS; HEART DELAYED RECTIFIER; POTASSIUM CHANNELS; PLASMA SEROTONIN; ARTERY MYOCYTES; DEXFENFLURAMINE; KV1.5; BLOCK; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Clement-Chomienne, O F Hoffmann La Roche & Co Ltd, Preclin Res, PRBM-M Bau70-423, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd PRBM-M Bau70-423 Basel Switzerland CH-4070
Citazione:
L. Perchenet et al., "Effects of anorexinogen agents on cloned voltage-gated K+ channel hKv1.5", J PHARM EXP, 298(3), 2001, pp. 1108-1119

Abstract

Appetite suppressants have been associated with primary pulmonary hypertension (PPH), inhibition of voltage-gated potassium channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells. In cells taken from pulmonary arteries of primary pulmonary hypertensive patients, voltage-gated potassium channels appear to be dysfunctional and in particular, reduced hKv1.5 gene transcription and hKv1.5 mRNA instability have been shown. We have compared the effects of anorexinogen agents on hKv1.5 channels stably expressed in mammalian cell line. We found that aminorex, phentermine, dexfenfluramine, sibutramine, and fluoxetine cause a dose-dependent inhibition of hKv1.5 current. Aminorex, phentermine, and dexfenfluramine had a K-D of inhibition greater than to 300 muM and are not potent inhibitors of hKv1.5. Sibutramine and fluoxetine inhibited hKv1.5 current with lower K-D values of 41 and 21 muM, respectively. Block by both drugs increased rapidly between -20 and +10 mV, coincident with channel opening and suggested an open channel block mechanism. This was confirmed by a slower deactivation time course resulting in a "crossover" phenomenon when tail currents recorded under control conditions and in the presence of either drug were superimposed. Single channel experiments demonstrated that open probability and open duration of hKv1.5 were decreased by fluoxetine and sibutramine. These results indicate that among the anorexinogen agents tested, sibutramineand fluoxetine are the most potent toward hKv1.5 channel, which they preferentially block in the open state. Nevertheless, their inhibitory effects do not correlate with their ability to produce PPH neither with their previously reported therapeutic plasma concentrations.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/04/20 alle ore 23:13:05