دورية أكاديمية
A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents.
| العنوان: | A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. |
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| المؤلفون: | Salata JJ; Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. joseph_salata@merck.com, Jurkiewicz NK, Wang J, Evans BE, Orme HT, Sanguinetti MC |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 1998 Jul; Vol. 54 (1), pp. 220-30. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print Cited Medium: Print ISSN: 0026-895X (Print) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Potassium Channels, Voltage-Gated*, Benzodiazepines/*pharmacology , Heart/*drug effects , Potassium Channels/*drug effects, Action Potentials/drug effects ; Animals ; Delayed Rectifier Potassium Channels ; Guinea Pigs ; Heart/physiology ; Heart Ventricles/drug effects ; Humans ; Ion Channels/drug effects ; KCNQ Potassium Channels ; KCNQ1 Potassium Channel ; Potassium Channels/metabolism ; Receptors, Adrenergic, beta/drug effects ; Receptors, Adrenergic, beta/metabolism ; Ventricular Function ; Xenopus laevis/genetics |
| مستخلص: | The slowly activating delayed rectifier K+ current, IKs, is an important modulator of cardiac action potential repolarization. Here, we describe a novel benzodiazepine, [L-364,373 [(3-R)-1, 3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H- 1,4-benzodiazepin-2-one] (R-L3), that activates IKs and shortens action potentials in guinea pig cardiac myocytes. These effects were additive to isoproterenol, indicating that channel activation by R-L3 was independent of beta-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; the S-enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKs activation. R-L3 slowed the rate of IKs deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for IKs by -16 mV at 0.1 microM and -24 mV at 1 microM. R-L3 had similar effects on cloned KvLQT1 channels expressed in Xenopus laevis oocytes but did not affect channels formed by coassembly of KvLQT1 and hminK subunits. These findings indicate that the association of minK with KvLQT1 interferes with the binding of R-L3 or prevents its action once bound to KvLQT1 subunits. |
| معلومات مُعتمدة: | R01-HL55236 United States HL NHLBI NIH HHS |
| المشرفين على المادة: | 0 (Delayed Rectifier Potassium Channels) 0 (Ion Channels) 0 (KCNQ Potassium Channels) 0 (KCNQ1 Potassium Channel) 0 (KCNQ1 protein, human) 0 (L 364373) 0 (Potassium Channels) 0 (Potassium Channels, Voltage-Gated) 0 (Receptors, Adrenergic, beta) 12794-10-4 (Benzodiazepines) |
| تواريخ الأحداث: | Date Created: 19980711 Date Completed: 19980806 Latest Revision: 20190607 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/mol.54.1.220 |
| PMID: | 9658209 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 0026-895X |
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| DOI: | 10.1124/mol.54.1.220 |