Characterization of catecholamine‐mediated relaxations in rat isolated gastric fundus: evidence for an atypical β‐adrenoceptor

Abstract

1 Experiments were carried out in order to characterize the receptors mediating relaxant responses to catecholamines in the rat gastric fundus. The effects of noradrenaline, isoprenaline and the 'atypical' or 13-adrenoceptor agonist, BRL 37344, on methacholine-induced tone were measured. Prazosin, propranolol and cyanopindolol were used as antagonists. 2 Relaxant responses to noradrenaline, in the presence of propranolol (1 M) were antagonized in a concentration-dependent manner by prazosin (0.01 to 1,pM), although this antagonism was weak and non-competitive in nature. Relaxant responses to isoprenaline, in the presence of prazosin (0.1 ,UM), were antagonized only by the highest concentration of propranolol (1 pM) giving a pKB of 6.3. BRL 37344 also relaxed the rat gastric fundus in the presence of prazosin (0.1 pM), and the responses to BRL 37344 were unaffected by propranolol (1 pM). 3 Tachyphylaxis to BRL 37344 was observed, a second concentration-response curve being significantly shifted to the right. Exposure of tissues to BRL 37344 (1 pM) between concentration-response curves also caused an 11 fold rightward shift in the response to isoprenaline. 4 In the presence of prazosin (0.1 uM) and propranolol (1,UM), the rank order of potency of the agonists was: (-)-isoprenaline (1.0) > (-)-noradrenaline (0.39) > BRL 37344 (0.10). 5 Responses to BRL 37344 in the presence of prazosin (0.1 pM) and propranolol (1 pM) were antagonized by (±)-cyanopindolol (1pM), with a pKB of 6.56. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (±)-cyanopindolol (0.1-1 uM), with the slope of a Schild plot close to unity and a pA2 value of 7.44. 6 The resistance to blockade by prazosin and propranolol and the antagonism by cyanopindolol of the responses mediated by isoprenaline and BRL 37344 suggest that atypical f-adrenoceptors similar to 'atypical',f-adrenoceptors in rat adipocytes and other tissues are present in the rat gastric fundus.

Characterization of propranolol‐resistant (−)‐[125I]‐cyanopindolol binding sites in rat soleus muscle

“…The affinity of ( ± )-CYP (pKD 7.63) in this study is lower than its affinity at typical ,B-adrenoceptors (pKD 9.4, Meunier & Labrie, 1982) but compares with the pA2 values for (± )-CYP antagonism of isoprenaline responses in guinea-pig ileum in the presence of propranolol with a pA2 value of 7.63 (Blue et al, 1989) and more recently in rat oesophagus pA2 7.3 (Ford et al, 1992). These values are also similar to those found for the ( ± )-CYP antagonism of BRL 37344 mediated responses in rat gastric fundus (McLaughlin & MacDonald, 1991) and distal colon (McLaughlin & MacDonald, 1990) (Table 2).…”

“…The action of BRL 37344 tends to be variable in different tissues. In rat gastric fundus (McLaughlin & MacDonald, 1991) and rat distal colon (McLaughlin & MacDonald, 1990) it produced tachyphylaxis to itself and to isoprenaline and was only weakly antagonized by propranolol (1 IAM). ICI D7114 shows selectivity for effects on brown fat and in stimulating whole body oxygen consumption at doses which show no chronotropic effects in the heart (Holloway et al, 1991).…”

Expression of β3‐adrenoceptor mRNA in rat tissues

“…In intact animals and in vitro studies, atypical fl-ARs respond to novel lipolytic fi-AR agonists such as BRL37344 and ICID7114, are resistant to blockade by conventional fl-AR antagonists such as (-)-propranolol, and often display resistance to desensitization upon prolonged exposure to agonists (Arch & Kaumann,1993). Receptors with these functional characteristics have been described in brown and white adipose tissue (Harms et al, 1977;Arch et al, 1984, Hollenga & Zaagsma, 1989; skeletal muscle (Abe et al, 1993;Liu & Stock, 1995), and multiple regions from the gastrointestinal tract (Coleman et al, 1987;Bond & Clarke, 1988;Croci et al,1988;Blue et al, 1990;McLaughlin & MacDonald, 1990;Bianchetti & Manara, 1990;McLaughlin & MacDonald, 1991;Canfield & Paraskeva, 1992 ;Canfield & Abdul-Ghaffar, 1992;Roberts et al, 1995;Cohen et al, 1995).…”

Involvement of β3-Adrenoceptor in the Relaxation Response in Guinea Pig Taenia Caecum

“…In addition to adipose tissue, atypical f3-adrenoceptors have been shown to exist in a number of gastrointestinal smooth muscle preparations: for example, guinea pig ile um (5), rat proximal colon (6), rat distal colon (7), rat jeju num (8), rat gastric fundus (9), and rat oesophageal mus cularis mucosae (10). Also, the presence of atypical (3 adrenoceptors has been indicated in other non-gastrointes tinal tissues: for example, in skeletal muscle (11,12) and in tracheal epithelium (13).…”