Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi.
We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.
Ten Berge
R E
RE
Groningen/Utrecht Institute for Drug Exploration, Department of Medicinal Chemistry and Molecular Pharmacology, University of Groningen, Netherlands.
Weening
E C
EC
Roffel
A F
AF
Zaagsma
J
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D005280:Fenoterol / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015288:Neurokinin A / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D005280:Fenoterol; C026777:ICI 118551; C057368:BRL 37344; D015288:Neurokinin A; D000420:Albuterol