Our results nevertheless suggest that the TAS2R5, 10 and 14 subtypes may have a prime role in the in non-small-cell lung carcinoma vitro Inhibitors,Modulators,Libraries relaxation of human bronchi, which would be in agreement with the known ability of the TAS2R10 and 14 subtypes to recognise the widest range of bitter compounds and the high transcript expression level of TAS2R14. With respect to drug potency, all the active bitter taste receptor agonists were essentially as potent as theophylline but were much less potent than the B2 adrenoreceptors agonists isoproterenol and formoterol. These values are in agreement with observations of chloroquine and iso proterenol in human bronchi. However, the agonists were highly effective, with Emax values greater than 90%. this demonstrates that even though higher concentrations are needed, a similar degree of bronchial relaxation can be achieved.

Given that the exact mechan ism of action of theophylline Inhibitors,Modulators,Libraries is still debated and that this compound is known to taste bitter, it cannot be ruled out that TAS2R signalling may also participate in its relaxing activity. The different pharmacological inhibitors used in the mechanistic part of the study might have impacted pre contraction to histamine, and therefore the subsequent relaxation to TAS2R agonists. To Inhibitors,Modulators,Libraries analyse the potential relationship between the level of precontraction and the relaxation, we have studied the relaxations to chloro quine as a function of the precontractions induced by 10 uM histamine. On 59 bronchial segments, the relax ation was found independent of the precontraction level.

Hence, the effect of the pharmacological in hibitors on the relaxation to TAS2R agonists is not related to an indirect effect in link with a potential alter ation of the precontraction induced by histamine. Desphande et al. have suggested that relaxation was due to membrane hyperpolarization following the open ing of calcium dependent potassium channels of large conductance Inhibitors,Modulators,Libraries and a localized increase in intracellular cal cium. The inhibitors of BKCa channels, sarcoplasmic reticulum Ca2 Inhibitors,Modulators,Libraries ATPases and PLCB used in the present work did not affect chloroquine or phenanthroline induced relaxation. Contrasting with findings in smooth muscle cells, these observations suggest that BKCa signal ling is not involved in the TAS2R relaxant response in isolated human bronchi and agree with recent data from experiments on murine airways. However, others modulators of calcium signalling such as ouabain or BAY K8644 revealed differential modulation of TAS2R agonists induced relaxation, with a clear reduction of chloroquine potency, a more modest reduction of phe nanthroline potency, small molecule while response to dapsone and flu fenamic acid was unaffected.