Blockade by mefloquine of intercellular electrical coupling between vascular endothelial cells in the guinea-pig mesenteric arteries

Abstract

Mefloquine, an antimalarial drug, has been reported to block exogenously transfected gap junctions composed of either C x 36 or C x 50 more potently than those composed of other connexins. Using the conventional whole-cell clamp technique, we investigated the effects of mefloquine on intercellular electrical coupling in vascular endothelial cells of guinea-pig mesenteric arteries, where expressions of C x 40 and C x 43 have been identified. Mefloquine (50 microM) almost abolished the current required to impose a 10 mV command step, leaving only rapid capacitive currents and some sustained currents after about 3 min. The relaxation of the capacitive current could be well fitted with a single exponential function. The effect of mefloquine was reversible and the time course of the current induced by the voltage step gradually changed back after mefloquine was removed. The mean input resistance and capacitance in the presence of mefloquine were 323 MOmega and 10.1 pF, respectively. While intercellular electrical coupling was well blocked by mefloquine (50 microM), the membrane hyperpolarized from -24.0 to -32.5 mV. The results indicate that mefloquine effectively blocks gap junctions without producing major side effects in vascular endothelial cells and that this compound is a useful tool in the investigation of gap junctions.

Analysis of acetylcholine-induced membrane responses in vascular endothelial cells of the guinea-pig mesenteric artery using mefloquine as a gap junction blocker

“…In the presence of mefloquine, only rapid capacitive currents and some sustained currents were observed. The membrane potential was also measured in the current clamp mode and it was found that mefloquine hyperpolarized the membrane as reported previously (Yamamoto and Suzuki, 2008). The effect of mefloquine was reversible and the current comparable to the control was obtained 11 min after the removal of mefloquine.…”

“…Small numbers of gap junctions seemed to be still open in the presence of mefloquine. In the previous paper we fitted the relaxation of capacitive current induced by a step depolarization with a single exponential function (Yamamoto and Suzuki, 2008). But it was found in the present analysis that the sum of two exponential functions fitted the relaxation better than a single exponential function (Fig.…”

“…We have previously measured the input resistance to be around 2-3 MΩ when a patch electrode was applied to one of the endothelial cells within such a preparation (Yamamoto and Suzuki, 2007). To control the membrane potential of the patched cell accurately, mefloquine, an antimalarial drug, was used as a gap junction blocker (Yamamoto and Suzuki, 2008). In the present experiments, mefloquine was evaluated more extensively as a gap junction blocker and then the ACh-induced membrane responses in vascular endothelial cells were analyzed while the gap junctions were effectively blocked by mefloquine.…”

“…Although higher concentrations are required, mefloquine blocks gap junctions in endothelial cells of guinea-pig mesenteric artery where Cx40 is mainly expressed (Yamamoto and Suzuki, 2008). In the present experiments, we again employed mefloquine as a gap junction blocker, enabling both the membrane potential and the intracellular ionic condition of the chemically-isolated endothelial cells to be properly controlled.…”

Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro

“…We therefore tested the effects of a 20 minute application of mefloquine (25 µM), which blocks a number of connexins (Cruikshank et al, 2004;Yamamoto and Suzuki, 2008) found in neuronal gap junctions. In the presence of mefloquine there was an increase in burst-like activity in CA3 neurons that for short segments (maximum about 0.6 seconds) was quite rhythmic in 2 of 4 neurons (ACF 0.304 ± 0.063, period 90.1 ± 15.6 ms, n = 4).…”