Cholinergic control of human airways in vitro following extrinsic denervation of the human respiratory tract by heart-lung transplantation.
In heart-lung transplantation (HLT), the airways have been assumed to be denervated since cholinergic, adrenergic, and sensory nerves are severed. Challenge studies of such patients suggest that there is an increase in airway responsiveness to inhaled cholinergic agonists, which may be explained by denervation hypersensitivity of muscarinic receptors on airway smooth muscle. We have studied the cholinergic control of airways from lungs removed from five patients (8 to 31 yr of age) undergoing retransplantation because of rejection-related bronchiolitis, with time since transplantation ranging from 12 to 32 months. These airways were compared with airways obtained from eight heart donors (24 to 42 yr of age) and from five patients undergoing surgical lobectomy for bronchial carcinoma (54 to 72 yr of age). Bronchial rings (distal lobar and subsegmental) were mounted in organ baths and isometric contractile responses measured. Contractile responses to acetylcholine (ACh, 10 nM to 10 mM) and to electrical field stimulation (EFS) (40 V, 0.5 ms, 1 to 64 Hz for 15 s) were determined. Transplant and control airways showed the same response to ACh, with mean EC50 values of 61.0 +/- 0.32 microM for HLT patients, 57.6 +/- 0.24 microM for donor patients, and 48.7 +/- 1.2 microM for lobectomy patients, suggesting no denervation hypersensitivity of muscarinic receptors. EFS, which activates postganglionic cholinergic nerves, caused similar frequency responses in both transplant and control airways, suggesting that postganglionic nerves are intact. [3H]quinuclidinyl benzilate binding to membranes prepared from lung was performed to determine muscarinic binding characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)
Stretton
C D
CD
Department of Thoracic Medicine, National Heart and Lung Institute, London, England, United Kingdom.
Mak
J C
JC
Belvisi
M G
MG
Yacoub
M H
MH
Barnes
P J
PJ
D000109:Acetylcholine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001980:Bronchi / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D002648:Child; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D016040:Lung Transplantation; D008297:Male; D011950:Receptors, Cholinergic / Q000378:metabolism / Q000502:physiology*
D011950:Receptors, Cholinergic; D007545:Isoproterenol; D000109:Acetylcholine