Bitter tastants induce relaxation of rat thoracic aorta precontracted with high K⁺

Abstract

It has been reported that bitter tastants decrease blood pressure and relax precontracted vascular smooth muscle. However, the underlying mechanisms remain unclear. The aim of the present study was to determine the mechanism underlying the vasorelaxant effect of the bitter tastants. Thoracic aortic rings were isolated from Wistar rats and contractions were measured using an isometric myograph. Intracellular Ca(2+) ([Ca(2+)]i) in single rat thoracic aortic smooth muscle cells was recorded by calcium imaging. Calcium currents in single cells were recorded using patch-clamp techniques. High K(+) (140 mmol/L) induced contractions in rat thoracic aortic rings that were inhibited by 3 mmol/L chloroquine, 3 mmol/L denatonium and 10 μmol/L nifedipine. In single rat thoracic aortic smooth muscle cells, high K(+) increased [Ca(2+)]i and this effect was also blocked by 3 mmol/L chloroquine and 10 μmol/L nifedipine. Under Ca(2+) -free conditions, high K(+) failed to induce contractions in rat thoracic aortic rings. On its own, chloroquine had no effect on the muscle tension of rat aortic rings and [Ca(2+) ]i. The vasorelaxant effects of chloroquine on precontracted rat thoracic aortic rings were not altered by either 1 μg/mL pertussis toxin (PTX), an inhibitor of Gαo/i-protein, or 1 mmol/L gallein, an inhibitor of Gβγ-protein. The results of patch-clamp analysis in single cells indicate that 1 mmol/L chloroquine blocks voltage-dependent L-type Ca(2+) channel (VDLCC) currents from both extracellular and intracellular sides. Together, the results indicate that chloroquine can block VDLCC, independent of PTX- and gallein-sensitive G-proteins, resulting in relaxation of high K(+)-precontracted thoracic aortic smooth muscle.

Chloroquine inhibits Ca2+ permeable ion channels-mediated Ca2+ signaling in primary B lymphocytes

“…These data indicate that TG-induced intracellular Ca 2+ elevations were mediated by above described ion channels, and which will be inhibited by chloroquine and then resulting in decreases. These results are consistent with previous findings that chloroquine blocks TRPC3 and/or STIM/Orai channels resulting in decreases in Ca 2+ levels in smooth muscle cells [1, 3] and in murine CD4 + thymocytes [4]. In addition, BCR engagement frequently occurs in vivo, which then results in immunological responses.…”

“…Chloroquine is a bitter tastant [1–4], which was used to treat malaria [5] and immune-related diseases such as rheumatic disease, systemic lupus erythematosus [6], early-stage AIDS [7] and chronic graft-versus-host disease [8]. Moreover, it inhibits Ia molecule biosynthesis [9] and CpG DNA-induced protection [10] in B cells.…”

Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

“…Intracellular Ca 2+ levels are modulated by several types of Ca 2+ channels in the ER and plasma membranes. We and others have demonstrated that chloroquine can block these Ca 2+ channels in smooth muscle [25,26], skeletal muscle [29] and macrophages [30]. Interestingly, several studies have indicated that chloroquine can inhibit tetanus toxin- and mitogen-induced proliferative responses and cytokine secretion by inhibiting Ca 2+ signaling [9].…”

“…In a previous study, we found that bitter-tasting chloroquine can inhibit cytosolic Ca 2+ elevations by blocking TRPC3 channels [25] and VDCCs in mouse airway smooth muscle cells [25,26]. In the present study, we explored whether chloroquine could inhibit Ca 2+ increases in T cells.…”

Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia‐induced pulmonary hypertension

“…In thoracic aortas precontracted by noradrenaline or high K + , treatment with chloroquine resulted in a concentration‐dependent relaxation (Aziba and Okpako, ). Furthermore, vasodilatation following chloroquine was associated with blockade of L‐type voltage‐dependent Ca 2+ channels (VDCCs) (Manson et al ., ; Sai et al ., ). A recent study found that chloroquine induced relaxation in human PAs precontracted by the thromboxane A 2 analogue U46619 and phenylephrine (Manson et al ., ).…”