Resistance of beta 2-adrenoceptor-mediated responses of lung strips to desensitization by long-term agonist exposure--comparison with atrial beta 1-adrenoceptor-mediated responses.
In vitro desensitization of beta 2-adrenoceptor-mediated relaxation of guinea-pig isolated parenchymal strips was examined. Concentration-response curves for isoprenaline were obtained and after long-term incubation with isoprenaline, followed by washout, a second curve was obtained. Correction for time-dependent loss of sensitivity was made from time-matched controls. After incubation with 10(-5) M isoprenaline for 0.5, 1, 2, 4 and 8 h, loss of responsiveness of carbachol-contracted lung strips was observed after 4h as a reduced post-incubation maximum response. When the concentration was reduced to 10(-6) M, a 4 h incubation with 1 h washout no longer induced a shift of the post-incubation curve in carbachol-contracted lung strips. In contrast, lung strips with intrinsic tone displayed reduced responsiveness to isoprenaline after 4 h incubation with 10(-6) M isoprenaline. Incubation of the tissue for 4 h with lanthanum (1.4 x 10(-6) M), a relaxant not operating through beta 2-adrenoceptors or their effector coupling, had the same effect upon isoprenaline concentration-response curves as incubation with isoprenaline. This was irrespective of whether intrinsic tone (10(-6) M isoprenaline) or carbachol-contracted (10(-5) M isoprenaline) lung strips were used. It was concluded that the loss of beta 2-adrenoceptor responsiveness after incubation with 10(-6) M isoprenaline was due to the prolonged maximal relaxation of the tissue for 4 h rather than desensitization of the beta 2-adrenoceptor. Indeed, after correction for maximal relaxation and for time, no significant change in beta 2-adrenoceptor sensitivity of the lung occurred after incubation with 10(-6) M isoprenaline for 4 h. This contrasts with significant rightwards shifts of the concentration-response curves for the beta 1-adrenoceptor-mediated increases in rate and tension of guinea-pig right and left atria after identical incubation conditions. Thus whereas beta 1-adrenoceptor-mediated responses displayed desensitization after long-term in vitro agonist exposure, the beta 2-adrenoceptor-mediated responses were resistant.
Department of Pharmacology, Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
M L
ML
Herepath
K J
KJ
Broadley
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007811:Lanthanum / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009928:Organ Specificity; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D007811:Lanthanum; D002217:Carbachol; D007545:Isoproterenol