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Effects of Ca2+ channel antagonists on sinus node: prolongation of late phase 4 depolarization by efonidipine
H Masumiya1, H Tanaka, K Shigenobu
1Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Abstract:
Effects of various Ca2+ channel antagonists on the action potential configuration of rabbit sino-atrial node tissue were examined with standard microelectrode techniques. All Ca2+ channel antagonists decreased the maximum rate of phase 0 depolarization (Vmax) and increased the cycle length. The potency order to increase the cycle length was nisoldipine = verapamil > nifedipine = clentiazem > efonidipine > diltiazem. The potency order to decrease Vmax and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca2+ current. All Ca2+ channel antagonists except efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca2+ current. A characteristic feature of efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 microM Ni2+, which is reported to inhibit the T-type, but not L-type, Ca2+ current. Thus, efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.
Insights
Calcium channel antagonists affect heart rhythm by slowing depolarization and increasing cycle length. Efonidipine uniquely targets both L- and T-type calcium currents, impacting pacemaker depolarization.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Sino-atrial node (SAN) function is crucial for heart rate regulation.
- Calcium (Ca2+) channels play a vital role in cardiac action potential generation.
Purpose of the Study:
- To investigate the effects of various Ca2+ channel antagonists on rabbit SAN action potential.
- To elucidate the specific mechanisms underlying the chronotropic effects of these antagonists.
Main Methods:
- Standard microelectrode techniques were employed to record action potentials from rabbit SAN tissue.
- Comparative analysis of different Ca2+ channel antagonists, including efonidipine, verapamil, nifedipine, diltiazem, nisoldipine, and clentiazem.
Main Results:
- All tested Ca2+ channel antagonists reduced the maximum rate of phase 0 depolarization (Vmax) and increased action potential cycle length.
- Potency order for increasing cycle length and decreasing Vmax was consistent, implicating L-type Ca2+ current inhibition.
- Efonidipine uniquely suppressed the later phase of pacemaker depolarization, suggesting T-type Ca2+ current involvement, unlike other antagonists.
Conclusions:
- The primary mechanism for negative chronotropism induced by most Ca2+ channel antagonists is L-type Ca2+ current inhibition.
- Efonidipine's selective suppression of pacemaker depolarization, potentially via L- and T-type Ca2+ current inhibition, explains its potent negative chronotropic and weak inotropic effects.