Effects Of Dextromethorphan Mediated Bitter Taste Receptor Activation In Pulmonary Artery Smooth Muscle Cells

Abstract

Activation of bitter taste receptors (T2Rs) in human airway smooth muscle cells lead to muscle relaxation and bronchodilation. However, the presence of T2Rs in human pulmonary artery smooth muscle cells (hPASMCs) has not been established. The previous finding in airway smooth muscle led to our hypothesis that T2Rs, if present in hPASMCs, might be involved in regulating the vascular tone. RT‐PCR analysis revealed the expression of multiple T2R transcripts in hPASMCs. Functional analysis showed that these cells responded to many bitter‐tasting compounds, by increasing intracellular calcium concentration, indicating that T2Rs in hPASMCs are functional. Since the response of T2R1 to dextromethorphan (DXM) has been characterized in our previous studies, T2R1 was selected for further analysis in this study. Knockdown with T2R1‐specific shRNA decreased mRNA levels and DXM‐induced calcium responses by up to 40%. ELISA data obtained from in vitro studies using hPASMC showed that DXM‐treatment led to increased levels of endothelin‐1, biomarker of systemic hypertension. To analyze if T2R1 is involved in regulating the pulmonary vascular tone, ex vivo studies using pulmonary arterial rings are being pursued. Furthermore, it remains to be analyzed if this effect of DXM in hPASMCs is T2R1 specific or due to the blockade of NMDA receptors.Supported by MHRC, NSERC and a New Investigator Award from HSFC.