Adrenergic activation of electrogenic [K.sup.+] secretion in guinea pig distal colonic epithelium: involvement of [beta]1- and [beta]2-adrenergic receptors

Adrenergic stimulation of electrogenic [K.sup.+] secretion in isolated mucosa from guinea pig distal colon required activation of two [beta]-adrenergic receptor subtypes (13-AdrR). Addition of epinephrine (epi) or norepinephrine (norepi) to the bathing solution of mucosae in Ussing chambers increased short-circuit current ([I.sub.sc]) and transepithelial conductance ([G.sub.t]), consistent with this cation secretion. A [beta]-adrenergic classification was supported by propranolol antagonism of this secretory response and the lack of effect by the [alpha]-AdrR antagonists BE2254 ([alpha]l-AdrR) and yohimbine ([alpha]2-AdrR). Subtype-selective antagonists CGP20712A ([beta]1-AdrR), ICI-118551 ([beta]2-AdrR), and SR59320A ([beta]3-AdrR) were relatively ineffective at inhibiting the epi-stimulated [I.sub.sc] response. In combination, CGP20712A and ICI-118551 inhibited the response, which supported a synergistic action by [beta]1-AdrR and [beta]2-AdrR. Expression of mRNA for both [beta]l-AdrR and [beta]2-AdrR was indicated by RT-PCR of RNA from colonic epithelial cells. Protein expression was indicated by immunoblot showing bands at molecular weights consistent with monomers and oligomers. Immunoreactivity (ir) for [beta]1-AdrR and [beta]2-AdrR was prominent in basolateral membranes of columnar epithelial cells in the crypts of Lieberkahn as well as intercrypt surface epithelium. Cells in the pericryptal sheath also had [beta]1-Adr[R.sup.ir] but did not have discernable [beta]2-Adr[R.sup.ir]. The adrenergic sensitivity of [K.sup.+] secretion measured by [I.sub.sc] and [G.sub.t] was relatively low as indicated by [EC.sub.50]s of 41 [+ or -] 7 nM for epi and 50 [+ or -] 14 nM for norepi. Adrenergic activation of electrogenic [K.sup.+] secretion required the involvement of both [beta]1-AdrR and [beta]2-AdrR, occurring with an agonist sensitivity reduced compared with reported values for either receptor subtype. epinephrine; norepinephrine; isoproteranol; CGP20712A; ICI-118551