Takahito Hirose

A possible role of a nonadrenergic inhibitory nervous system in airway hyperreactivity

To investigate a possible role of a nonadrenergic inhibitory nervous system in airway hyperreactivity, we measured changes in RL and CL caused by electrical stimulation of cervical vagus nerve during the infusion of 5-HT, after treatment with atropine and propranolol in 18 cats. RL decreased to 56 +/- 3% (mean +/- SE) and CL increased to 186 +/- 13% of the prestimulated values, respectively, after stimulation. Hexamethonium diminished these responses significantly. Airway reactivity to 5-HT was reduced by continuous electrical stimulation of cervical vagus nerve in cats pretreated with atropine and propranolol. Hexamethonium potentiated airway reactivity to 5-HT. These results suggest that a nonadrenergic inhibitory nervous system could play an important role in the control of the bronchomotor tone and contribute to airway hyperreactivity.

Neutrophil elastase inhibitor, ONO-5046 suppresses ozone-induced airway mucus hypersecretion in guinea pigs

To investigate the role of neutrophil elastase in ozone-induced airway hypersecretion, we measured goblet cell secretion by using a semiquantitative morphometric technique in guinea pigs. The magnitude of mucus discharge was estimated from the mucus score, which is inversely related to the degree of mucus discharge in histological sections of trachea stained for mucus glycoprotein with periodic acid Schiff/Alcian blue. Mucus hypersecretion of goblet cells was induced by ozone exposure and persisted for up to 5 h after exposure. Pretreatment with N-[2-¿4-(2,2-dimethyl-propionyloxy) phenyl-sulfonylamino¿ benzoyl] aminoacetic acid (ONO-5046), a specific neutrophil elastase inhibitor (200 mg/kg, intraperitoneally), significantly inhibited goblet cell hypersecretion both just after and 5 h after ozone-exposure, but the latter inhibition was not complete. In bronchoalveolar lavage fluid, ozone exposure significantly increased the number of neutrophils just after and 5 h after exposure, while ONO-5046 significantly inhibited the increase in neutrophils only 5 h after ozone-exposure. These results indicate that neutrophil elastase may play an important role in the ozone-induced tracheal goblet cell hypersecretion and influx of neutrophils.

Protective effect of a thromboxane synthetase inhibitor, OKY-1581, on increased lung vascular permeability in pulmonary microembolization in dogs

To evaluate the potential beneficial effect of a thromboxane synthetase inhibitor, OKY-1581, on increased pulmonary vascular permeability in pulmonary microembolization, we have measured the filtration coefficient in the nonembolized lung after unilateral microembolization in dogs. The unilateral microembolization caused marked elevations in pulmonary artery pressure and blood flow to the nonembolized lung, while pulmonary venous pressure in nonembolized lung did not change. The pulmonary vascular resistance in nonembolized lung did not increase significantly. The filtration coefficient (Kf) in nonembolized lung increased to 0.14 +/- 0.02 from the baseline value of 0.07 +/- 0.01 ml/min/mmHg/100g at 30 min after microembolization when the initial hemodynamic changes reduced toward the baseline value. In OKY-1581 treated dogs, similar hemodynamic changes did not result in the increase in the filtration coefficient in nonembolized lung. Platelet aggregation was also inhibited after microembolization in OKY-1581 treated dogs. Based on these results, we could conclude that OKY-1581 could prevent the increase in pulmonary vascular permeability following pulmonary microembolization by inhibiting platelet aggregation and possibly by preventing the release of thromboxane A2.

A pathophysiological role of endogenous prostacyclin in endotoxin induced increase in lung vascular permeability in dogs

Escherichia coli endotoxin (1 mg/kg) infusion over 30 min into anesthetized artificially ventilated dogs caused a biphasic response: an early phase of pulmonary hypertension and a late phase of increased lung vascular permeability. During an early phase, PG F2 alpha, Tx A2 (as Tx B2) and prostacyclin (as 6-keto-PG F1 alpha) concentrations increased in plasma or right duct lymph of dogs. During a late phase, the concentrations of PG F2 alpha and Tx A2 decreased to near the base-line values, while the concentration of prostacyclin remained elevated. Administrations of PG synthetase inhibitors 45 min prior to endotoxin inhibited the increase in concentration of prostacyclin following the infusion of endotoxin and potentiated the increase in lung vascular permeability at the beginning of the late phase. Continuous infusion of prostacyclin (20 ng/kg/min) starting one hour before endotoxin for 5 hour periods prevented the increase in lung vascular permeability induced by endotoxin. Based on these results, we could conclude that endogenous prostacyclin might play an important role in preserving cell integrity of lungs and counteract the deleterious effects of endotoxin.

The effect of prostacyclin on increased hydraulic conductivity of pulmonary exchange vessels following microembolization in dogs

Prostacyclin (PG I2) generated by vascular endothelium is a strong antiaggregating substance. As platelet aggregation and release of humoral factor(s) have been reported to be crucial in the pathogenesis of acute lung injury following pulmonary microembolization, PG I2 could have a protective effect against microembolic lung vascular injury. Following unilateral microembolization, we have observed a large increase in the filtration coefficient in the nonembolized lung with a significant increase in 6-keto PG F1 alpha, the stable metabolite of PG I2, in arterial blood. The pretreatment with indomethacin (10 mg/kg) prevented the increase in 6-keto PG F1 alpha and potentiated the lung injury after microembolization. Exogenously administered PG I2 (20 ng/kg/min) prevented completely the increase in the filtration coefficient without any effects on hemodynamics, although these effects of indomethacin and PG I2 did not relate to their effects on platelet aggregation. Based on these results, we could conclude that prostacyclin could play an important role in preserving cell integrity of the lung and in prevention of increased lung vascular permeability following pulmonary microembolization.

Effects of epinastine hydrochloride on cholinergic neuro-effector transmission in canine tracheal smooth muscle

We determined the effects of epinastine hydrochloride, an anti-asthmatic drug, on cholinergic neuro-effector transmission in canine trachea. Isometric tension of tracheal strips was measured in the presence of indomethacin and propranolol. Epinastine (10(-6) M) significantly suppressed the contraction evoked by electrical field stimulation, but had no effect on the acetylcholine-evoked contraction. An L-type Ca2+ channel blocker, nicardipine, did not suppress the electrical field stimulation-induced smooth muscle contraction and did not alter the inhibitory effect of epinastine. An N-type Ca2+ channel blocker, omega-conotoxin, suppressed the electrical field stimulation-induced contraction in a dose-dependent manner, and in a subthreshold/intermediate concentration abolished the inhibitory effect of epinastine. These findings indicate that epinastine exerts prejunctional inhibitory effects on airway smooth muscle of dogs, presumably by inhibiting acetylcholine release from vagal nerve terminals, and suggest that this effect is mediated by N-type Ca2+ channels.

The effect of prostacyclin infusion on increased pulmonary vascular permeability following microembolization in dogs

Prostacyclin (PG I2) generated by vascular endothelium is a strong antiaggregating substance. As platelet aggregation and release of humoral factor(s) have been reported to be crucial in the pathogenesis of acute lung injury following pulmonary microembolization, prostacyclin could have a protective effect against microembolic lung vascular injury. Following unilateral microembolization, the filtration coefficient in the nonembolized lung increased significantly to 0.14 +/- 0.02 from the base line value of 0.07 +/- 0.01 ml/min/mmHg/100g. Prostacyclin as measured as 6-keto PG F1 alpha in arterial blood increased significantly to 4.15 +/- 1.76 at 30 min from the base line value of 1.90 +/- 0.45 ng/ml and increased further to 5.67 +/- 1.49 ng/ml at 60 min following microembolization. Exogenously administered PG I2 methylester (20 ng/kg/min) prevented completely the increase in the filtration coefficient without any effects on hemodynamics, although the effects of PG I2 methylester did not depend on its action on platelet aggregation. Based on these results, we conclude that prostacyclin could play an important role in preserving cell integrity of the lung and prevention of increased lung vascular permeability following pulmonary microembolization.