title: Selective inhibition of the late sodium current has no adverse effect on electrophysiological or contractile function of the normal heart.
abstract: Inhibition of cardiac late Na(+) current (I(Na,L)) decreases sodium-dependent calcium overload in diseased hearts. Because INa,L is small in the absence of disease, its inhibition is not expected to significantly alter function of the normal heart. To test this hypothesis, we determined the effects of GS-458967 (GS967), a novel selective inhibitor of I(Na,L) (IC(50) = 0.13 μM), on cardiac function and hemodynamics. The bradycardic agent ivabradine and the Na(+) channel blocker flecainide were used for comparison. A single per os administration of GS967 (5 mg/kg) had no effect on blood pressure or heart rate (HR) in unanesthetized rats. In anesthetized rats, GS967 (0.6 ± 0.1 μM plasma concentration) had no significant effect on HR, PR or QRS electrocardiogram intervals, or contraction. Flecainide (8 mg/kg) slowed HR by 23% ± 3% (P < 0.001), prolonged the PR and QRS intervals by 42% ± 8% and 64% ± 12% (P < 0.001), and had a significant negative inotropic effect. Ivabradine (3 mg/kg) slowed HR by 36% ± 6% (P < 0.001). In rat and rabbit isolated perfused hearts, GS967 (0.1-3 μM) had no significant effects on HR, QRS interval, or contractile function. The results show that selective inhibition of cardiac I(Na,L) is not associated with chronotropic, dromotropic, inotropic, or hemodynamic changes.
authors.affiliation: Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fernandes
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoyer
authors.forename: Gongxin
authors.initials: G
authors.lastname: Liu
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Wang
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D011725:Pyridines; D026941:Sodium Channel Blockers; D014230:Triazoles