We have developed an experimental system to measure the permeability of the cultured endothelial monolayer. The luminal-to-abluminal flux of 125I-albumin across cultured pulmonary endothelium was expressed as a clearance rate equal to the permeability-surface area product. After clearance rate measurement for a 30-min base-line period, a test agent was added to the luminal side, and the clearance rate was remeasured during a 30-min experimental period. In control studies the base-line clearance rate was 0.343 +/- 0.017 microliter/min. After correction for the diffusional resistances of the filter and unstirred layers, the calculated permeability of the endothelial monolayer was 1.2 X 10(-5) cm/s. When culture medium was the test agent, the experimental clearance rate was unchanged from the base-line value. After addition of 4 mM oleic acid to the luminal chamber, the clearance rate was 0.528 +/- 0.017 microliter/min compared with a base-line value of 0.330 +/- 0.008 microliter/min (P less than 0.005). This method allows the calculation of endothelial permeability with correction for unstirred layers and the use of each monolayer as its own control.

1 Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. ). 4 These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated o0.3 mg kg À1) suggest that there may be a peripheral component to the antitussive effect.

No abstract

5-, 15-, and 12-HETE (monohydroxyeicosatetraenoic acids) are products of the lipoxygenation of arachidonic acid. We investigated their role as possible mediators of pulmonary vasoactivity and pulmonary edema. Pulmonary artery pressure (?"), capillary pressure (P ap ), the change in lung wet weight (Awt) from baseline, and capillary filtration coefficient (K,) (as a measure of vascular permeability) were determined following an intravenous injection of each mono-HETE in lungs perfused at constant flow with either a phosphate-buffered Ringer's-albumin solution (PBR) or diluted blood. Injection of 2 (xg of each compound into the pulmonary artery of lungs perfused with either PBR or diluted blood did not produce any effect. However, in PBR-perfused lungs, 4 (ig 15-HETE induced increases in Pp., P^., and lung wet weight (p<0.05), which were greater than the increases observed after 4 jig 5-HETE. K r increased following both 5-and 15-HETE. The pulmonary vasoconstrictor and edemagenic responses were attenuated by increasing perfusate albumin concentration from 0.5 to 1.5 g%. In contrast, 12-HETE (4 |i.g) had no effect on these parameters. In blood-perfused lungs, the pulmonary vascular responses to all HETE compounds (4 |xg) were attenuated. In both RingerValbumin-perfused and blood-perfused lungs, the relative magnitude of the hemodynamic and fluid filtration responses to each mono-HETE were as follows: 15-HETE > 5-HETE > 12-HETE. In conclusion, the pulmonary vasoconstrictor and edemagenic effects of 5-and 15-HETE occur independently of blood-formed elements. 15-HETE causes greater pulmonary vasoconstriction and edema than 5-HETE. The role of mono-HETEs in mediating changes in pulmonary hemodynamics and vascular permeability is not clear. The purpose of the present study was: 1) to compare the pulmonary microvascular responses to injection of 5-, 15-, and 12-HETE in the isolated Ringer's-albumin-perfused guinea pig lung; 2) to compare the responses of the mono-HETEs in bloodperfused lungs to examine the role of blood-formed elements in the response; and 3) to evaluate the role of mono-HETEs as possible mediators of pulmonary edema. Materials and Methods Isolated, Perfused Guinea Pig LungGuinea pigs (400-500 g) were anesthetized with sodium pentobarbital (50 mg/kg i.v.; Abbott, Chicago, Illinois) and tracheotomized. Following a thoracotomy, intracardiac heparin (700 U/kg, Invenex, Chagrin Falls, Ohio) was administered, and the animals were exsanguinated. The lungs and heart were removed together and suspended from one end of a counterweighted beam balance to monitor lung weight. The pulmonary artery and left atrium were cannulated. Perfusion was begun at a low flow rate within 5 minutes of pneumothorax using a peristaltic roller pump (model 1215, Harvard Apparatus, Millis, Massachusetts). Airway pressure was maintained at 1 cm H 2 O with 95% O 2 -5% CO 2 , and venous outflow pressure was set at 3 cm H 2 O so all lungs remained in the Zone III condition to minimize changes in vascular surface area. Lungs were covered w...