Long-term exposure to norepinephrine results in down-regulation and reduced mRNA expression of pulmonary beta-adrenergic receptors in guinea pigs.
We studied the down-regulation of beta 2-adrenoceptors in guinea pig lung after chronic exposure to a beta-agonist. Guinea pigs were exposed to either norepinephrine (NE) or vehicle for 7 days. The density and affinity of beta-adrenoceptors were determined by Scatchard analysis of [125I]cyanopindolol binding in a lung membrane preparation and beta 1- and beta 2-adrenoceptor subtypes were studied in the presence of 0.1 microM ICI 118,551, a selective beta 2-adrenoceptor antagonist, or 0.1 microM CGP 20712 A, a selective beta 1-adrenoceptor antagonist, respectively. beta 2-Adrenoceptor mRNA was examined by Northern blot analysis. The tissue distribution of beta 2-adrenoceptors and of beta 2-adrenoceptor mRNA in lung after NE infusion were determined using receptor autoradiography and in situ hybridization, respectively. The functional significance of the decrease in beta 2-adrenoceptor was tested by measuring the relaxation response to a beta 2-agonist in isolated parenchymal strips. NE treatment resulted in decreases of 75 +/- 9%, 84 +/- 4%, and 66 +/- 9% of total beta-, beta 1-, and beta 2-adrenoceptors in the lung, compared with control animals. The administration of NE had only minimal effects on the dissociation constant (Kd) of the receptor for the radioligand. beta 2-Adrenoceptors mRNA was decreased by 46 +/- 13% after NE treatment. There was a correspondence between the distribution of beta 2-adrenoceptors and beta 2-adrenoceptor mRNA localization in both control and NE-treated guinea pigs. NE treatment reduced alveolar beta 2-adrenoceptors by 70 +/- 3% and its mRNA expression by 78 +/- 5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishikawa
M
M
Department of Thoracic Medicine, Royal Bromptom National Heart and Lung Institute, London, United Kingdom.
Mak
J C
JC
Shirasaki
H
H
Harding
S E
SE
Barnes
P J
PJ
D000818:Animals; D015152:Blotting, Northern; D015536:Down-Regulation; D006168:Guinea Pigs; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D009638:Norepinephrine