ABSTRACT
The effects of the K(+)-channel activator, cromakalim, on spontaneous tone and constrictor responses to vagal stimulation or acetylcholine were compared in trachea isolated from groups of guinea-pigs that were: untreated; sensitized and chronically exposed to inhaled albumin; or sham sensitized. Responses were assessed as changes in intraluminal pressure in the isolated, Krebs-filled trachea, increases and decreases in intraluminal pressure directly reflecting constriction and dilatation, respectively. Cromakalim reduced resting intraluminal pressure in normal trachea but in sensitized trachea mixed effects occurred, many preparations exhibiting increases in intraluminal pressure, particularly at lower concentrations of cromakalim. Cromakalim attenuated the frequency-dependent increases in intraluminal pressure evoked by stimulation of the vagus nerve in a concentration-dependent manner and to a similar degree in trachea from each of the three groups tested. The degree of attenuation was similar in the absence and presence of the cyclo-oxygenase inhibitor flurbiprofen. In untreated trachea, responses to a range of concentrations of applied acetylcholine were attenuated by cromakalim. In sensitized trachea the response to the lowest concentration of applied acetylcholine was attenuated by cromakalim but responses to higher concentrations of were unaffected. The results indicate that the direct relaxant effect of cromakalim is altered in sensitized trachea, which may indicate abnormal K(+)-channel behaviour in the smooth muscle cell membrane. Attenuation by cromakalim of vagal responses occurs in both normal and sensitized trachea, due chiefly to a pre-junctional effect on cholinergic neurotransmission which is independent of the generation of cyclo-oxygenase products.
Subject(s)
Albumins/immunology , Asthma/physiopathology , Benzopyrans/pharmacology , Bronchodilator Agents/pharmacology , Pyrroles/pharmacology , Trachea/drug effects , Acetylcholine/pharmacology , Animals , Cromakalim , Disease Models, Animal , Electric Stimulation , Flurbiprofen/pharmacology , Guinea Pigs , Immunization , In Vitro Techniques , Male , Potassium Channels/drug effectsABSTRACT
1. Cromakalim reduced intraluminal pressure in the guinea-pig isolated, innervated trachea. 2. Preganglionic stimulation of the cervical vagus nerve elicited a frequency-dependent increase in intraluminal pressure. Cromakalim attenuated responses to vagal stimulation in a concentration-dependent manner at all frequencies tested. 3. Field stimulation caused a frequency-dependent increase in intraluminal pressure mediated by muscarinic cholinoceptors. Cromakalim did not affect the amplitude of responses at any frequency of stimulation, even at high concentrations. 4. Acetylcholine, added to the Krebs solution bathing the adventitial surface of the trachea, evoked a concentration-dependent increase in intraluminal pressure. The concentration-effect curve for acetylcholine was unaltered in the presence of cromakalim. 5. It is concluded that cromakalim modulates cholinergic neuroeffector transmission in the trachea chiefly by a prejunctional mechanism. However, cromakalim probably does not interfere with acetylcholine release from postganglionic cholinergic neurones.
