Dextromethorphan Mediated Bitter Taste Receptor Activation in the Pulmonary Circuit Causes Vasoconstriction

Abstract

Activation of bitter taste receptors (T2Rs) in human airway smooth muscle cells leads to muscle relaxation and bronchodilation. This finding led to our hypothesis that T2Rs are expressed in human pulmonary artery smooth muscle cells and might be involved in regulating the vascular tone. RT-PCR was performed to reveal the expression of T2Rs in human pulmonary artery smooth muscle cells. Of the 25 T2Rs, 21 were expressed in these cells. Functional characterization was done by calcium imaging after stimulating the cells with different bitter agonists. Increased calcium responses were observed with most of the agonists, the largest increase seen for dextromethorphan. Previously in site-directed mutational studies, we have characterized the response of T2R1 to dextromethorphan, therefore, T2R1 was selected for further analysis in this study. Knockdown with T2R1 specific shRNA decreased mRNA levels, protein levels and dextromethorphan-induced calcium responses in pulmonary artery smooth muscle cells by up to 50%. To analyze if T2Rs are involved in regulating the pulmonary vascular tone, ex vivo studies using pulmonary arterial and airway rings were pursued. Myographic studies using porcine pulmonary arterial and airway rings showed that stimulation with dextromethorphan led to contraction of the pulmonary arterial and relaxation of the airway rings. This study shows that dextromethorphan, acting through T2R1, causes vasoconstrictor responses in the pulmonary circuit and relaxation in the airways.

Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle

“…On the other hand, pooled siRNAs against TAS2R14 reduced TAS2R14 mRNA expression in HASM cells by 50% (Paper 3, Figure 6). The efficacy of this TAS2R14-mediated knockdown in HASM cells was comparable to recent siRNA attempts at reducing TAS2R1 [157], and higher than the 35% reduction for TAS2R10 reported by Deshpande et al, when the function of TAS2Rs in HASM cells was first described [67].…”

Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation

“…Rises in [Ca 2+ ] i in response to bitter tastants have been described in airway smooth muscle, but are being claimed to be part of the relaxation mechanism 14 on the one hand, or have been considered too low to induce a contraction on the other hand 22 . A recent paper however described Ca 2+ mobilization in the pulmonary artery in response to various bitter tastants, including DB, and a TAS2R-mediated vasoconstriction 23 . We are the first to describe a small contraction in response to bitter tastant-induced Ca 2+ -rises in mouse gut smooth muscle, enhanced by incubation with a promiscuous K + -channel blocker, charybdotoxin.…”

Bitter taste receptors as targets for tocolytics in preterm labor therapy

“…TAS2Rs have been increasingly detected in the cells and tissues outside the oral cavity, and they mediate diverse biologic functions dependent their location. Bitter tastants relax airway, vascular, bladder, and gastrointestinal smooth muscle, and they also contract pulmonary arteries and gastrointestinal smooth muscle (11,12,(52)(53)(54)(55). The wide expression of TAS2Rs on the one hand reveals their important biologic roles, and on the other hand poses a challenge to find bitter tastants that act on a specific cell.…”