Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells

Abstract

1 The effect of the bradycardic agent S 16257 on the main ionic mechanisms of diastolic depolarization in sinoatrial node cells isolated from rabbit heart, was investigated by the patch-clamp technique in whole-cell and macro-patch recordings. 4 A high concentration of S 16257 (10 yM) had no detectable effect on T-type calcium current and slightly decreased L-type calcium current (-18.12+0.66%), without significant use-dependent blockade. 5 S 16257 had no effect on the delayed outward potassium current IK at 3 pM and slightly decreased it only at high concentrations, -16.3+ 1.2% at 10 gM. In contrast, zatebradine, another bradycardic agent, reduced IK by 20.3+2.5% at 3 gM. 6 In conclusion, S 16257 may lower heart rate without significant negative inotropic action. In comparison with zatebradine, S 16257 had less effect on IK suggesting less prolongation of repolarization time.

Abstracts of Papers at the Fifty-Sixth Annual Meeting of the Society of General Physiologists

“…Fitting the dose-response curve with the Hill equation yielded a half-block concentration of 1.5 M and a slope coefficient of 0.8. The concentration dependence of I f block was similar to that reported previously by Bois et al (1996).…”

“…A previous study has shown that ivabradine acts with a high degree of specificity on f-channels from the intracellular side of the membrane (Bois et al, 1996). We find that ivabradine blocks f-channels when they are open, and its block is strongly use-dependent.…”

“…Several f-channel blocker molecules have been developed, such as UL-FS49 (Goethals et al, 1993;DiFrancesco, 1994), ZD7288 (BoSmith et al, 1993;Gasparini and DiFrancesco, 1997;Shin et al, 2001), and ivabradine (Thollon et al, 1994;Bois et al, 1996). These molecules have been shown to induce heart rate slowing with limited inotropic side effects, and have therefore a potential for therapeutic application in those cases where it is useful to slow heart rate without altering other cardiovascular functions.…”

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

“…It is interesting to observe that in the mice treated orally with ivabradine for 1 week, reduction in HR was detectable with ivabradine plasma level in the range of 0.01-0.04 mM. In vitro patch-clamp studies showed that the IC 50 for the I f blockade by ivabradine is 1.5-2.2 mM (Bois et al, 1996;Thollon et al, 1997;Bucchi et al, 2002).…”

“…It has been shown that I f current of sinoatrial node pacemaker cells is affected by adrenergic stimulation (DiFrancesco & Tortora, 1991) and that ivabradine is a usedependent I f current blocker (Bois et al, 1996;Bucchi et al, 2002). Therefore, it is expected that the efficacy of ivabradine on HR would be modulated by alterations in the sympathetic activity.…”