The neuromodulatory action of adenosine and ATP was investigated in isolated guinea pig bronchial strip chain preparations contracted with electrical field stimulation. The tissues were placed in organ baths containing physiological salt solution and stimulated at 8-Hz frequency, 0.5-ms pulse duration, and 30 V (approximately 100 mA) for 5 s. Electrical field stimulation evoked a biphasic contraction of bronchial muscle, consisting of an initial contraction followed by a sustained contraction, which was mediated by intramural cholinergic and noncholinergic nerve stimulations, respectively. Adenosine, at concentrations greater than M, caused a concentration-dependent inhibition in the height of the noncholinergically mediated contraction, accompanied by a very weak inhibition on the cholinergically mediated response. ATP (10(-5) to 3 x 10(-3) M) also produced a similar inhibitory effect on the noncholinergically mediated contraction, but the inhibitory potency was less than that of adenosine. The inhibitory response to adenosine was enhanced by the pretreatment with dipyridamole (2 x 10(-6) M) but antagonized with aminophylline (10(-5) M). Contractions of bronchial muscle evoked by exogenous acetylcholine (2 x 10(-6) M) or substance P (2 x 10(-7) M) were significantly inhibited by the adenosine (3 x 10(-4) M) pretreatment. These data suggest that in isolated guinea pig bronchi adenosine selectively inhibits noncholinergic neurotransmission through prejunctional P1-purinoceptors.
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ATP, at a dose higher than 0-1 mug m1(-1), showed a biphasic action consisting of an initial increase followed by a gradual decrease of muscle tension in the isolated tracheal strip-chains of guinea-pigs. The pattern of this biphasic response to ATP varied with the level of basal tone of the preparation at the moment of application of ATP. A smiliar biphasic action was obtained by prostaglandin (PG) E2 among the various active substances studied including acetylcholine, histamine, catecholamines and various types of PG. Indomethacin (0-1 mug m1(-1) and aspirin (30 mug m1(-1)) completely abolished the ATP-induced inhibitory response observed in the presence of histamine (10 muM). Polyphloretin phosphate (100 mug m1(-1)) also significantly depressed the inhibitory response to ATP or PGE2. It is concluded that the response to ATP of the preparation is mediated by PGE2 released via the stimulation of its biosynthesis.
Isolated tracheal and bronchial strip-chain preparations of the rat were used to study the effect of temperature on electrically or acetylcholine-induced contraction. The preparations were suspended in the organ bath containing Krebs bicarbonate solution for isometric tension recording. A decrease of bath temperature from 37 degrees C to 20 degrees C (cooling) had no effect on basal tone but augmented the contractile responses of the trachea and bronchus caused by stimulation of intramural cholinergic nerves (0.5-5 Hz) or acetylcholine (3 mumol/l-0.3 mmol/l). Cooling-induced augmentation of the contractile response to acetylcholine was not affected by pretreatment of the tissue with physostigmine (0.1 mumol/l) or tetrodotoxin (0.3 mumol/l). The affinity of acetylcholine for the tracheal muscarinic receptors at 20 degrees C, determined from its dissociation constant (KA), was not significantly different from that at 37 degrees C. On the other hand, acetylcholine-induced contraction of trachea which was incubated with isosmotic K+- rich Krebs solution and with Ca-free, EGTA (0.1 mmol/l) containing Krebs solution were both augmented at 20 degrees C. Caffeine or vanadate, each at a lower concentration than the threshold for causing contraction by itself, augmented the contractile responses of the trachea to acetylcholine (1 mumol/l-0.3 mmol/l). These potentiating effects of caffeine and vanadate were greater at 20 degrees C then 37 degrees C. From these observations, it is concluded that increased responsiveness of the rat airway smooth muscle to acetylcholine with lowered temperature may involve the acceleration of Ca release from intracellular storage sites, inhibition of Ca extrusion from the cell and or the inhibition of Ca reuptake by intracellular storage sites.
The actions of catecholamines on the responses evoked by electrical field stimulation or by acetylcholine and substance P in guinea-pig bronchial strip chain have been examined. Electrical field stimulation evoked a biphasic contraction, consisting of a cholinergically-mediated fast contraction followed by a non-cholinergically-mediated slow contraction. All catecholamines tested caused a concentration-dependent reduction in the height of the biphasic contraction, where non-cholinergic contractions were more potently inhibited. The inhibitory effect of isoprenaline was largely prevented by propranolol (2 microM) alone, whereas those of noradrenaline and adrenaline were prevented by treatment with both propranolol (2 microM) and yohimbine (2 microM). The inhibitory effect of dopamine was unaffected either by propranolol (2 microM), yohimbine (2 microM) or haloperidol (10 microM). Submaximal contractions of bronchial muscle evoked by exogenous acetylcholine (2 microM) or substance P (0.2 microM) were also inhibited by catecholamines, except dopamine, but the effects were antagonized by propranolol (2 microM) alone. The results suggest that in guinea-pig isolated bronchial muscle, catecholamines can inhibit both cholinergic and non-cholinergic excitatory neurotransmissions not only by postjunctional beta-adrenoceptors but also by prejunctional alpha 2-adrenoceptors.
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