Capsaicin pre- and post-treatment on rat monocrotaline pneumotoxicity.

Monocrotaline (MCT) produces respiratory dysfunction, pulmonary hypertension (PH), and right ventricular hypertrophy (RVH) in rats. Tachykinins, such as substance P (SP) and neurokinin A (NKA), may mediate these effects. The purpose of this study was to investigate the length of tachykinin depletion (via capsaicin treatment) is needed to prevent (or attenuate) PH and/or RVH. Six groups of rats were injected subcutaneously with saline (3 ml/kg); capsaicin followed by saline or MCT (60 mg/kg); or MCT followed 7, 11, or 14 days later by capsaicin. Capsaicin (cumulative dose, 500 mg/kg) was given over a period of 4-5 days. Respiratory function, pulmonary vascular parameters, lung tachykinin levels, and tracheal neutral endopeptidase (NEP) activity were measured 21 days after MCT or saline injection. Capsaicin significantly decreased lung levels of SP but not NKA. Both capsaicin pretreatment and posttreatment blocked the following MCT-induced alterations: increases in lung SP and airway constriction; decreases in tracheal NEP activity and dynamic respiratory compliance. Administration of capsaicin before or 7 days after MCT blocked MCT-induced PH and RVH. The above data suggest that the early tachykinin-mediated airway dysfunction requires only transient elevated tachykinins, while progression of late tachykinin-mediated effects (PH and RVH) requires elevated tachykinins for more than one week.

Effect of blood flow on capillary transit time and oxygenation in excised rabbit lung.

We used an isolated perfused lung preparation of the rabbit to study the effect of increasing blood flow on pulmonary capillary transit time by two methods. In one method, capillary transit time was measured from fluorescent dye dilution curves from arterioles and venules of the subpleural microcirculation. Values of transit time were similar to those for the whole lung determined by dividing capillary blood volume by blood flow. Capillary transit times averaged 0.50-0.62 sec at a control blood flow of 80 ml min-1 kg-1 and decreased to 0.14-0.18 sec as blood flow increased to 6 times control. To determine whether the reduced transit time would limit O2 transport, we studied the effect of blood flow on oxygenation. Two isolated rabbit lungs were perfused in series. Blood from one lung deoxygenated by ventilation with a N2-CO2 mixture was oxygenated by the test lung ventilated with air. Ventilation was matched to blood flow. PO2 and PCO2 were measured in blood flowing into and out of the test lung. At all flows, no significant alveolar gas-to-end-capillary blood PO2 gradient (A-aDO2) was measured. The isolated perfused rabbit lung showed no transit time limitation to oxygenation for blood flows that are consistent with heavy exercise in vivo.

CGS 8216: agonist and diazepam-antagonist effects in rodents.

CGS 8216, a pyrazoloquinolinone benzodiazepine receptor ligand, was administered alone and concomitantly with diazepam in order to assess its agonist and diazepam-antagonist properties on several behaviors in rodents. In mice, CGS 8216 (i.p.) potentiated the convulsant effects of pentylenetetrazole. Moreover, doses of 1.0 to 10 mg/kg of CGS 8216 produced dose-related antagonism of the anticonvulsant effects of diazepam. In rats, CGS 8216 (0.3-3.0 mg/kg) was without effect on the Rotarod, but produced dose-related, nonparallel shifts to the right in the diazepam dose-effect curve. Also in rats, behavior was maintained under a multiple schedule where in one component every 20th response resulted in water presentation (unpunished component) and in a second component every 20th response resulted in both footshock and water presentation (punished component). CGS 8216 produced dose-related decreases in response rates in both components, but was approximately 10-fold more potent in decreasing rates of punished responding. These effects were blocked by the benzodiazepine antagonist Ro 15-1788 (30 mg/kg i.p.). Increasing doses of diazepam (0.1-10 mg/kg p.o.) first increased and then decreased rates of punished responding but only decreased rates of unpunished responding. CGS 8216 produced a dose-related antagonism of the rate-increasing, but had little effect on the rate-decreasing, effects of diazepam. In another group of rats, behavior was maintained under a multiple fixed interval 5-min fixed ratio 20-response schedule of water presentation. CGS 8216 produced a dose-related decrease in response rates in both components, but these effects were not blocked by Ro 15-1788 (30 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential diazepam-antagonist effects of the benzodiazepine receptor ligand CGS 9895 in rodents.

CGS 9895, a pyrazoloquinolone benzodiazepine receptor ligand, was administered alone and concomitantly with diazepam in order to assess its agonist and diazepam-antagonist properties on various behaviors in rodents. In mice, CGS 9895 neither potentiated nor blocked the convulsant effects of pentylenetetrazole. However, doses of 3.0 and 10 mg/kg of CGS 9895 i.p. produced dose-related antagonism of the anticonvulsant effects of diazepam against pentylenetetrazole (80 mg/kg i.p.). In rats, diazepam produced dose-related increases in ataxia as measured on the rotarod. CGS 9895 (0.3-10 mg/kg i.p.) was without effect on performance on the rotarod, but produced dose-related parallel shifts to the right in the diazepam dose-effect curve. Also in rats, behavior was maintained under a multiple schedule where in one component every 20th response resulted in water presentation (unpunished behavior) and in a second component every 20th response resulted in both shock and water presentation (punished behavior). CGS 9895 (0.3-30 mg/kg i.p.) was without significant effect on either punished or unpunished responding. Increasing doses of diazepam (0.1-10 mg/kg p.o.) first increased and then decreased rates of punished responding but only decreased rates of unpunished responding. CGS 9895 (3.0 mg/kg i.p.) neither potentiated nor antagonized diazepam. In another group of rats, behavior was maintained under a multiple fixed-interval 5 min fixed-ratio 20 response schedule of water presentation. CGS 9895 (0.3-30 mg/kg i.p.) did not affect performance under this schedule. Diazepam (0.3-30 mg/kg p.o.) primarily decreased rates under the fixed-ratio schedule, but increasing doses first increased and then decreased rates under the fixed-interval schedule.(ABSTRACT TRUNCATED AT 250 WORDS)