Effect of thiazide diuretics against neurally mediated contraction of guinea pig airways. Contribution of carbonic anhydrase.
The effect of thiazide diuretics on neurally and agonist-induced contractile responses of guinea pig airways in vitro were investigated. Tracheal or bronchial strips were suspended in organ baths and isometric tension recorded. Chlorothiazide (CTZ, 10(-4) to 3 x 10(-3) M), hydrochlorothiazide (HCTZ, 10(-3) M), and dichlorphenamide (DCPM, 10(-3) M) significantly potentiated contraction of tracheal strips induced by electrical field stimulation (EFS). They also increased acetylcholine (ACh)- but not carbachol-induced tracheal contraction. In the presence of atropine and propranolol, on the other hand, CTZ and DCPM but not HCTZ significantly inhibited EFS-induced contraction in bronchial strips. We determined whether carbonic anhydrase inhibition could mimic the effects of CTZ and DCPM. Acetazolamide (ATZ), an inhibitor of carbonic anhydrase, had no effect on either EFS- or ACh-induced contraction in tracheal strips but significantly inhibited nonadrenergic, noncholinergic (NANC) contractile responses induced by EFS in bronchial strips. CTZ, DCPM, and ATZ did not affect substance P-induced contractile responses in the bronchi. We conclude that CTZ, DCPM, and ATZ attenuate NANC neurally mediated bronchial contraction by preventing the release of contractile neuropeptides from sensory nerve endings. This effect may occur through inhibition of carbonic anhydrase activity. In addition, thiazide diuretics potentiate contractile responses to ACh in the trachea, probably through inhibition of acetylcholinesterase activity.
Sun
J
J
Department of Thoracic Medicine, National Heart and Lung Institute, London, England.
Elwood
W
W
Barnes
P J
PJ
Chung
K F
KF
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001581:Benzothiadiazines; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000502:physiology; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001581:Benzothiadiazines; D002257:Carbonic Anhydrase Inhibitors; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D013373:Substance P; D002217:Carbachol; D002256:Carbonic Anhydrases; D000109:Acetylcholine