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  • Title: Comparison of duration of agonist action at beta 1- and beta 2- adrenoceptors in C6 glioma cells: evidence that the long duration of action of salmeterol is specific to the beta 2-adrenoceptor.
    Author: McCrea KE, Hill SJ.
    Journal: Mol Pharmacol; 1996 May; 49(5):927-37. PubMed ID: 8622643.
    Abstract:
    The C6 glioma cell line, which expresses beta 1- and beta 2-adrenoceptors at a ratio of 80:20, was used to investigate the durations of action of formoterol at beta 1-adrenoceptors and of salmeterol at both beta 1- and beta 2-adrenoceptors in an attempt to determine whether the sustained duration of action of salmeterol was unique to beta 2-adrenoceptors or, as with formoterol, resulted from its lipophilic nature and partitioning into the bulk lipid of the plasma membrane. In this cell line, formoterol, like the nonselective beta-adrenoceptor agonist isoprenaline, behaved as a potent, full agonist at beta 1-adrenoceptors and did not seem to exhibit a high degree of selectivity for beta 2-adrenoceptors. Salmeterol seemed to stimulate cAMP accumulation in C6 cells predominantly via activation of the subpopulation of beta 2-adrenoceptors. However, at high (micromolar) agonist concentrations, salmeterol also activated beta 1-adrenoceptors, albeit with low potency and efficacy. At high concentrations (30 microM), salmeterol attenuated cAMP responses mediated by activation of beta 1-adrenoceptors by isoprenaline (Kp = 1.6 microM), indicating that salmeterol exhibited a low affinity for beta 1-adrenoceptors in C6 cells. In multiple washout experiments, cAMP responses to isoprenaline and formoterol waned with increasing numbers of washing processes. Therefore, it seemed that formoterol relied on its moderately lipophilic nature to partition into bulk lipid of the plasma membrane to produce sustained activity, particularly at high agonist concentrations. Salmeterol was found to persist at beta 2-adrenoceptors in C6 cells despite washing cell monolayers up to four times. To determine the duration of action of salmeterol at beta 1-adrenoceptors expressed on the same cells, use was made of full/partial agonist interactions. In cells exposed to a single washout of agonist-containing medium, salmeterol (30 microM) lost its ability to attenuate responses to the more efficacious agonist, isoprenaline. This observation provided convincing evidence to support the hypothesis that salmeterol exhibits sustained agonist activity at beta 2-adrenoceptors, but not beta 1-adrenoceptors, expressed on the same cells. Therefore, the sustained activity of salmeterol at beta 2-adrenoceptors seems to be unique and does not result solely from its partitioning into bulk lipid of the plasma membrane.
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