The novel mechanism of bitter taste receptors attenuating rat ventricular contractility

Abstract

BackgroundBitter taste receptors (TAS2Rs) are a family of G‐protein coupled receptors, firstly identified in the tongue. Recent advances show the expression of TAS2Rs in extra‐oral organs, such as trachea, gastrointestinal tract, and heart. These findings raised up the interest of studying the physiological functions of TAS2Rs besides taste sensing. It has been demonstrated that the activation of TAS2Rs activates gustducin and release Gβγ, which leads to the inhibition of L‐type Ca2+ channels and the consequent airway smooth muscle relaxation.AimThis study investigates the expression of TAS2Rs in rat heart, and the mechanism of bitter compounds regulation of the contractility of cardiac muscle.MethodsRats were excised by thoracotomy and left ventricle strips were isolated. The strips were processed to study the expression levels of TAS2Rs mRNA by real time quantitative PCR (qPCR). Langendorff isolated heart models were used to record the left ventricle pressure and heart rate. Isometric tension recordings were used to measure electrical field stimulation (EFS,1 Hz – 5 V) and epinephrine‐induced contractions in combination with bitter compounds, denatonium and quinine. The conventional whole‐cell patch clamp techniques were used to record the voltage activated L‐type Ca2+ channel currents. The statistic data are expressed as mean ± SEM.ResultsWe detected the mRNA of 6 bitter receptors, TAS2R108, 120, 121, 126, 135, and 143 in the left ventricle tissues and isolated cardiomyocytes of rat, in which the mRNA level of TAS2R120 is the highest among the six followed by TAS2R143 and 121.In isolated perfused rat hearts denatonium (50 μM) reduced the heart rate from 235 ± 3 to 101 ± 12 (N=4). In isolated left ventricle strips, EFS and epinephrine induced phasic contractions which were inhibited completely by tetracaine (100 μM), a ryanodine channel blocker. Denatonium and quinine inhibited EFS‐induced ventricular contractions amplitude and frequency in a concentration dependent manner (N=6, n=6). Both of denatonium and quinine, at concentrations of 10 to 200 μM, caused a complete inhibition of epinephrine (10 μM)‐elicited phasic contractions (N=6, n=6).Nifedipine (10 μM), a selective L‐type Ca2+ channel blocker, partially inhibited EFS‐induced contractions, and the subsequent addition of denatonium (200 μM) and quinine (200 μM) cause a further and complete inhibition of the contractions (N=5, n=5). The non‐selective β‐adrenergic receptor antagonist, propranolol, did not have any effect on the EFS‐induced contractions. In isolated ventricular cardiomyocytes, denatonium (10 μM) reduced the L‐type Ca2+ channel currents density at 10 mV from 4.0 pA/pF to 1.6 pA/pF.ConclusionBitter taste receptor agonists, denatonium and quinine, induce negative ionotropic effects in rat hearts. Our data provide mechanistic evidence that TAS2Rs agonists can inhibit the cardiac contractions by attenuating the L‐type Ca2+ channels, and the consequent Ca2+ release by ryanodine receptors. TAS2Rs agonists can be useful pharmacological tools for the treatment of ventricular tachycardia.Support or Funding InformationSupported by Southwest University and the International Affair Agency of ChongqingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.