Mechanism of respiratory effects of methylxanthines.
Neural respiratory responses to theophylline, aminophylline and ethylenediamine were determined in paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 and brain temperature were kept constant. Intravenous theophylline and aminophylline similarly stimulated respiration, but ethylenediamine had no effect. The following did not cause the response: muscular and mechanical factors, carotid body and vagal reflexes, spinally mediated mechanisms arising below C7, changes of arterial PCO2 or medullary ECF pH, changes of whole body metabolic rate or release of substances from the adrenal glands. Absence of suprapontine brain did not prevent the response. Pretreatment with a serotonin antagonist did not affect the response but two different dopamine antagonists caused its attenuation. When administered into the third ventricle, theophylline did not stimulate respiration, but both aminophylline and ethylenediamine, due to the latter's ability to mimic the inhibitory effects on neurons of gamma-aminobutyric acid (GABA), caused significant depression of respiration. We conclude that the neural respiratory response to systemically administered theophylline is mediated at the level of the brainstem, and somehow involves the action of the neurochemical dopamine. The failure of cerebroventricularly administered theophylline to stimulate respiration must be related to its inability to reach the appropriate neurons from the cerebrospinal fluid.
D000628:Aminophylline / Q000494:pharmacology*; D000818:Animals; D002415:Cats; D002818:Cordotomy; D003655:Decerebrate State / Q000503:physiopathology; D003964:Diaphragm / Q000294:innervation; D004357:Drug Synergism; D005029:Ethylenediamines / Q000494:pharmacology*; D010243:Paralysis / Q000503:physiopathology; D010791:Phrenic Nerve / Q000502:physiology; D012119:Respiration / Q000187:drug effects*; D013268:Stimulation, Chemical; D013806:Theophylline / Q000494:pharmacology*; D014628:Vagotomy
D005029:Ethylenediamines; D000628:Aminophylline; D013806:Theophylline