Asuka Baba1, Masahiro Tachi2, Yoshio Maruyama3, Itsuro Kazama4. 1. Department of Physiology I, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. 2. Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. 3. Department of Physiology I, Tohoku University Graduate School of Medicine, Sendai, Japan. 4. Department of Physiology I, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: kazaitsu@med.tohoku.ac.jp.
Abstract
BACKGROUND: Lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and these channels play crucial roles in the lymphocyte activation and proliferation. Since diltiazem and verapamil, which are highly lipophilic Ca(2+) channel blockers (CCBs), exert relatively stronger immunomodulatory effects than the other types of CCBs, they would affect the Kv1.3-channel currents in lymphocytes. METHODS: Employing the standard patch-clamp whole-cell recording technique in murine thymocytes, we examined the effects of these drugs on the channel currents and the membrane capacitance. RESULTS: Both diltiazem and verapamil significantly suppressed the peak and the pulse-end currents of the channels, although the effects of verapamil were more marked than those of diltiazem. Both drugs significantly lowered the membrane capacitance, indicating the interactions between the drugs and the plasma membranes. CONCLUSIONS: This study demonstrated for the first time that CCBs, such as diltiazem and verapamil, exert inhibitory effects on Kv1.3-channels expressed in lymphocytes. The effects of these drugs may be associated with the mechanisms of immunomodulation by which they decrease the production of inflammatory cytokines.
BACKGROUND: Lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and these channels play crucial roles in the lymphocyte activation and proliferation. Since diltiazem and verapamil, which are highly lipophilic Ca(2+) channel blockers (CCBs), exert relatively stronger immunomodulatory effects than the other types of CCBs, they would affect the Kv1.3-channel currents in lymphocytes. METHODS: Employing the standard patch-clamp whole-cell recording technique in murine thymocytes, we examined the effects of these drugs on the channel currents and the membrane capacitance. RESULTS: Both diltiazem and verapamil significantly suppressed the peak and the pulse-end currents of the channels, although the effects of verapamil were more marked than those of diltiazem. Both drugs significantly lowered the membrane capacitance, indicating the interactions between the drugs and the plasma membranes. CONCLUSIONS: This study demonstrated for the first time that CCBs, such as diltiazem and verapamil, exert inhibitory effects on Kv1.3-channels expressed in lymphocytes. The effects of these drugs may be associated with the mechanisms of immunomodulation by which they decrease the production of inflammatory cytokines.
Authors: S Herrera-Pérez; L Rueda-Ruzafa; A Campos-Ríos; D Fernández-Fernández; J A Lamas Journal: Front Pharmacol Date: 2022-09-15 Impact factor: 5.988