Beta 3-adrenoceptor agonists, BRL 37344 and SR 58611A, do not induce relaxation of human, sheep and guinea-pig airway smooth muscle in vitro

Abstract

The existence of atypical-or β 3 -adrenoceptors has now been generally accepted. These receptors have been shown to be abundant in adipose tissue and in a number of gastrointestinal smooth muscle preparations. A recent study reported that β 3 -adrenoceptor stimulation mediated relaxation of isolated canine bronchial smooth muscle. The aim of the present study was to extend this observation to other species.We investigated the in vitro responses of guinea-pig, human and sheep bronchial smooth muscle to isoprenaline, salbutamol (a selective β 2 -adrenoceptor agonist), and BRL 37344 and SR 58611A (two presumably selective β 3 -adrenoceptor agonists). The preparations were precontracted to 60-70% of maximal tension with histamine 10 -6 M for guinea-pig and human bronchi, or acetylcholine 10 -6 M for sheep bronchi.In each species, SR 58611A produced a slight fall in tension of about 10% of the effects of theophylline (3 mM), but this decrease in tension was not significantly different from the spontaneous and weak relaxation observed with saline addition during the same duration of the experiment. These relaxations were not modified by either the nonselective β-adrenoceptor antagonist propranolol or the selective β 2 -adrenoceptor antagonist ICI 118,551. In contrast, BRL 37344 induced a significant concentration-dependent fall in tension induced by both spasmogens. Its relaxant effects were inhibited both by propranolol and ICI 118,551 in human and guinea-pig airways, whereas on the isolated sheep bronchus BRL 37344-induced relaxations were only slightly, albeit significantly, reduced with either of the β-adrenoceptor antagonists tested. Salbutamol and isoprenaline induced potent relaxations of guinea-pig, human and sheep airway smooth muscle in vitro, which were antagonized both by propranolol and ICI 118,551.Our findings show that β 3 -adrenoceptor stimulation does not induce relaxation in guinea-pig, human and sheep bronchial smooth muscle, and that a β 2 -adrenoceptor agonistic component might be implicated in the relaxant effects of BRL 37344. Eur Respir J., 1994Respir J., , 7, 1610Respir J., -1615 The existence of atypical or β 3 -adrenoceptors has now been generally accepted. The gene encoding for human β 3 -adrenoceptor has been identified and sequenced [1]. These receptors have been shown to be abundant in adipose tissue and in a number of gastrointestinal smooth muscle preparations, for example guinea-pig ileum [2], rat proximal colon [3,4], rat distal colon [5], rat jejunum [6] and rat gastric fundus [7]. They have also been identified in rat skeletal muscle [8], ferret tracheal epithelium [9], and canine airways [10].Furthermore, stimulation of β 3 -adrenoceptors has been shown to induce relaxation of the rat oesophageal muscularis mucosae [11], lipolysis in omental and subcutaneous human fat cells [12], and inotropic effects in human [13] and canine heart [14].In the lung, β 3 -adrenoceptor stimulation increases epithelial fluid movements in ferret trachea [9], and reduces the release of the ...

Relaxant effect ofThymus vulgaris on guinea-pig tracheal chains and its possible mechanism(s)

“…The relaxant effect of different extracts from Thymus vulgaris on tracheal chains of guinea pigs might be due to several different mechanisms including stimulation of β-adrenergic receptors, inhibition of histamine H 1 receptors or an anticholinergic property of this plant, because the relaxant effect of β 2 -stimulatory (Martin et al, 1994;Linden et al, 1993), histamine H 1 receptor inhibitory (Popa et al, 1984) and anticholinergic drugs (Loenders et al, 1992) have been shown in previous studies. To evaluate the contribution of β-adrenergic stimulatory and/or the H 1 histamine blocking effect of macerated and aqueous extracts from this plant on their bronchodilatory effects, the effects of these extracts on tracheal chains with inhibited β-adrenergic and histamine H 1 receptors by propranolol and chlorphenamine respectively, were re-examined in group 3 experiments.…”

“…A decrease in tone was considered as a relaxant (bronchodilatory) effect and expressed as a positive percentage change in proportion to the maximum contraction and an increase in tone was considered as a contractile (bronchoconstrictory) effect, which was expressed as a negative percentage change (Martin et al, 1994).…”

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

“…This finding may have significance for epithelial cell function, where functional b 3 -adrenoceptor has been described, but not for ASM, which seemingly lacks expression of this subtype [32][33][34]. In addition to being widely expressed on ASM [31], b 2 -adrenoceptors are also expressed on The free a subunit then augments the basal activity of one or more isoforms of adenylyl cyclase (AC), resulting in an increase in the formation of cAMP from adenosine triphosphate (ATP).…”

In vitro evaluation of antiasthmatic activity of ethanol leaf extract of Guiera senegalensis j. F. GMEL (Combretaceae)

“…Similar result was observed with atropine. These indicate that ELEGS has a nonspecific spasmolytic activity on smooth muscles that may probably be due to β-adrenergic stimulatory (Martin et al, 1994), histamine H1 (Popa et al, 1984) and/or muscarinic inhibition (Linden et al, 1993). However, result obtained from rabbit jejunum after addition of ELEGS up to 6.4 mg/ml to baths pretreated with propranolol was not significantly different from the control.…”