Correlation of cyclic AMP accumulation and relaxant actions of salmeterol and salbutamol in bovine tracheal smooth muscle

Abstract

1 The ability of salmeterol to stimulate cyclic AMP accumulation and relaxation has been compared with that of salbutamol in bovine tracheal smooth muscle. In addition, the anti-spasmogenic effects of these agents and their abilities to modulate histamine-stimulated [3H]-inositol phosphate accumulation have also been investigated.2 In tissue strips, a close temporal correlation was found to exist between salmeterol (0.1 puM)-induced relaxation of methacholine (500 nM)-induced tone and cyclic AMP accumulation, both maximal reversal of induced tone (26.2+ 6.0%) and maximal levels of cyclic AMP accumulation being achieved after 30-40 min. In contrast to salmeterol, salbutamol exerted greater and more rapid effects on both parameters. Maximal reversal of methacholine-induced tone (79.3 + 14.0%) and maximal levels of cyclic AMP accumulation were produced within 5 min. 4 Anti-spasmogenic effects were examined by fl-adrenoceptor agonist application to tissue strips prior to construction of spasmogen concentration-effect curves. Both salmeterol and salbutamol exerted more marked inhibition of the contractile response induced by histamine than that induced by methacholine, salmeterol being the more potent agent, while salbutamol produced a greater maximal inhibitory effect. 5 The results demonstrate that salmeterol is a more potent agent than salbutamol and have highlighted a close temporal correlation between promotion of cyclic AMP accumulation and tissue relaxation stimulated by each agent when both parameters are measured under identical conditions.

Multiplex GPCR Assay in Reverse Transfection Cell Microarrays

“…Salbutamol, normally considered a β 2 adrenergic agonist, has been shown to inhibit stimulation by histamine if used as a pretreatment. 17 This is consistent with salbutamol stimulation of histamine H 1 receptor followed by desensitization, which makes it subsequently unresponsive to histamine. Although 9 well-characterized receptor:agonist pairs, including melanocortin MC 1 :NDP-MSH, melanocortin MC 3 :NDP-MSH, APJ:apelin-13, bradykinin B 1 :des-arg 10 -kallidin, CCR1: RANTES, CCR5:RANTES, CXCR5:BCA-1, GPR43:propionate, and GPR68:SPC, did not elicit a calcium flux response, we did not observe any false positives.…”

Effects of a range of β2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP driven gene expression in cultured human airway smooth muscle cells

“…It is also interesting to note that salmeterol demonstrated an equivalent rapid increase in cyclic AMP accumulation in cultured HASM cells compared to the other agonists used in this study, which is distinct from its slow onset of action in airway smooth muscle (Naline et al ., 1994; Anderson et al ., 1996). This finding is in agreement with similar studies performed in rat B50 neuroblastoma cells (McCrea & Hill, 1993), bovine tracheal smooth muscle (Ellis et al ., 1995), CHO‐K1 cells transfected with the human β 2 adrenoceptor (McDonnell et al ., 1998), and for activation of adenylyl cyclase activity in mouse L‐cells transfected with the hamster β 2 adrenoceptor (Clark et al ., 1996) and the human epithelial cell line BEAS‐2B (January et al ., 1998). This is presumably related to cell monolayers being used instead of tissue which significantly reduces the diffusion barrier to the drug.…”

Salmeterol‐induced desensitization, internalization and phosphorylation of the human β2‐adrenoceptor

“…There is no evidence from studies of bronchodilatation that chronic salmeterol treatment induces tolerance (desensitization) to its bronchodilating effects, although there is evidence that tolerance develops to its protective effects against a bronchoconstrictor stimulus (Cheung et al , 1992; Ramage et al , 1994; Bhagat et al , 1995). One of the primary actions of β 2 ‐adrenoceptor agonists in the relaxation of smooth muscle is the activation of adenylyl cyclase (Johnson et al , 1993), and the relaxant effects of salmeterol on airway smooth muscle are directly correlated with the activation of adenylyl cyclase and subsequent intracellular accumulation of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) (Ellis et al , 1995). However, there have been few insights into the cellular mechanisms of salmeterol activation and desensitization of β 2 ‐adrenoceptor stimulation of adenylyl cyclase.…”