Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors.

Abstract

Background. Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified.

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

“…In n ϭ 6 cells, the mean time constants of current activation at Ϫ100 mV in control, in the early fraction of Ͼ25-s long steps to -100 mV during drug perfusion (3 M), and on return from the long-step protocol were: 215 Ϯ 15, 237 Ϯ 28, and 213 Ϯ 14 ms, respectively, whereas the slow increase at Ϫ100 mV had a time constant of 7.0 Ϯ 0.5 s. These data indicate that ivabradine, as has been proposed for UL-FS49 and ZD7288 (Goethals et al, 1993;DiFrancesco, 1994;Shin et al, 2001), binds to the channel blocking site less favorably at hyperpolarized than at depolarized voltages.…”

“…Other drugs have been synthesized on the basis of their ability to slow heart rate, such as UL-FS49 and ZD7288, and are known to exert their action by blocking the cardiac I f current or the related neuronal I h current (BoSmith et al, 1993;Goethals et al, 1993;DiFrancesco, 1994;Pape, 1994;Gasparini and DiFrancesco, 1997). The correlation between the inhibitory action on I f and the bradycardic effect is a direct consequence of the relevance of I f to the generation and control of pacemaker activity in mammalian heart (DiFrancesco, 1993).…”

“…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.…”

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

“…These changes were partially reversible after 15 min of washout in 5 out of 8 cells. The right panels of Figure 4a and b show the current-density of Modulation of the delayed potassium current by S 16257 and zatebradine Time ( action on If resembles that of zatebradine (Goethals et al, 1993) but differs from the effect of ZD7288 (BoSmith et al, 1993) A similar molecular mode of action has also been proposed for zatebradine in the SA node cells (Goethals et al, 1993) and in sheep cardiac Purkinje fibres (van Bogaert & Goethals, 1992).…”

“…During recent years, drugs with a new pharmacological profile have been described as 'specific bradycardic agents': zatebradine (Goethals et al, 1993) and ZD7288 (BoSmith et al, 1993). These agents decrease the heart rate by direct interaction with the pacemaking cells of the SA node.…”