Pulmonary responses of conscious strain 13 guinea pigs to Pichinde viral infection.

A laboratory animal model for studying pulmonary responses to arenaviral infection was established with advanced technologies. Tidal volume (TV), respiratory rate (RR), minute volume (MV), expiratory time (TE), inspiratory time (TI), peak expiratory flow (PEF), and specific pulmonary airway resistance (RES) were measured with a double plethysmograph and a computer data-acquisition system in six conscious, strain 13 guinea pigs. Using the same animal, experiments were conducted before and after subcutaneous inoculation with 10(4) plaque-forming units of Pichinde virus. Pulmonary functions were determined for 1 minute every 10 minutes for 2 hours before and at postinoculation days (PID) 3, 6, 8, and daily thereafter until shortly before death. The mean time to death was 18 +/- 0.7 days. Tidal volume, RR, MV, PEF, RES, and rectal temperature increased slightly on PID 3 and reached peak values at the midpoint of disease. At 95% of the mean time to death (16.5 +/- 0.5 days), RR, MV, and rectal temperatures suddenly decreased to lower than baseline values; while TV, RES, and PEF values remained high. When TE decreased with the increase in RR, TI did not change. When RR decreased at the terminal stage, both TE and TI increased. Hyperventilation, increased specific pulmonary airway resistance, terminal hypoventilation, and respiratory arrest were noted in strain 13 guinea pigs infected with Pichinde virus.     

Airway hyperresponsiveness and remodeling in antigen-challenged guinea pigs

Airway hyperresponsiveness (AHR) is the main feature of allergic subjects/animals, and its underlying mechanism is not clear. We explored whether antigen-induced AHR is associated with cytokine generation, inflammatory cell infiltration, and/or remodeling of airway smooth muscle. Guinea pigs were divided into three groups: control-1, control-2, and ovalbumin (OA). Animals in the control-1 group were not sensitized, while those in the control-2 and the OA group were sensitized with OA. Forty to forty-two days after the initial sensitization or equivalent time, animals in the control-2 group inhaled saline aerosol and those in the OA group inhaled OA aerosol for 30 min. Twenty-four h after OA challenge or equivalent time, animals in each group were further divided into two subgroups: methacholine and hyperventilation. Functional tests were carried out before and after the methacholine or hyperventilation treatment. Immediately after the functional study, bronchoalveolar lavage fluid was collected for determination of inflammatory cells and tumor necrosis factor-alpha (TNF-alpha. The trachea was then removed to determine smooth muscle mass. In both the methacholine and hyperventilation subgroups, significantly more severe airway constriction was found in the OA group, indicating OA-induced AHR. Eosinophil accumulation increased in the control-2 group and this increase was further augmented in the OA group. In addition, TNF-alpha level and smooth muscle mass significantly increased in the OA group. These results suggest that OA challenge-induced AHR is associated with increases in TNF-alpha level, cellular infiltration, and airway smooth muscle mass.     

Bronchial reactivities in guinea pigs to acetylcholine or histamine exposure

The bronchial reactivities in Hartley guinea pigs to acetylcholine (ACh) or histamine (Hist) were investigated, and the following results obtained; 1. Eight-week-old animals were exposed to ACh and Hist. A significant relationship was observed between the concentrations of the chemicals and the time needed to produce falling down (TNPFD) due to the asthmatic reaction to ACh and Hist. 2. Eight-week-old animals were exposed to 0.1% ACh and 0.05% Hist, for which the mean TNPFD +/- standard error were 377 +/- 33 sec and 122 +/- 5 sec respectivity. However, no difference in reactivity between male and female animals was noted. 3. Eight- and 9-week-old animals were exposed to 0.01% ACh and 0.025% Hist. A positive correlation was observed (r = 0.736, p less than 0.01) between the TNPFD for ACh and that for Hist. 4. Growing animals from 2 weeks to 20 weeks old were exposed to 0.08% ACh and 0.025% Hist. After inhalation of both chemicals, 6-week-old animals showed the greatest prolongation of mean TNPFD (lowest sensitivity). 5. Eight-week-old animals were exposed to 0.08% ACh and 0.025% Hist. With both of these chemicals, a positive correlation was observed between TNPFD and dose threshold (ACh r = 0.886, p less than 0.001; Hist r = 0.891, p less than 0.001).     

Airway responsiveness and prostaglandin generation in scorbutic guinea pigs

Airway responsiveness to histamine aerosol and lung prostaglandin generation were investigated in normal, partially vitamin C deficient and scorbutic guinea pigs. The ascorbic acid content of the lung expressed as microgram/100 mg wet weight lung parenchyma decreased from 22.1 +/- 1.8 (mean +/- SE) in the control group to 9.0 +/- 1.4 and 1.8 +/- 0.4 in tissues from partially ascorbic acid deficient and scorbutic animals, respectively. Guinea pigs on low and ascorbic acid deficient diets developed significant airway hyperresponsiveness to histamine aerosol after 3 and 4 weeks. Indomethacin (30 mg/Kg, i.p.) further increased the airway hyperresponsiveness in scorbutic animals but was without effect in control animals. Prostaglandin generation from different parts of the lung was significantly changed by the diets. However, airway hyperresponsiveness was not directly attributable to altered prostanoid generation. Scorbutic conditions did not alter the electrophysiological characteristics of airway smooth muscle namely, resting membrane potential and electrogenic sodium pump activity. In summary, ascorbic acid deficiency causes airway hyperresponsiveness to histamine in guinea pigs. This alteration seems not to be related to an altered prostaglandin generation by the lung or to the electrophysiological properties of airway smooth muscle.     

Airway hyperresponsiveness to bronchoconstrictor challenge after wood smoke exposure in guinea pigs.

Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.     

Differential responses of the airways and pulmonary tissues to inhaled histamine in young dogs

Airway and pulmonary tissue responses to aerosolized histamine were studied in five mongrel puppies (8-10 wk old). Alveolar pressure was measured by use of alveolar capsules and respiratory mechanics calculated during tidal ventilation and flow interruptions. Aerosolized histamine caused an increase in the tissue viscoelastic properties, which was measured as an increase in pulmonary resistance during tidal ventilation. An increase in stress recovery of the pulmonary tissues was measured with the interrupter technique after aerosolized histamine. These data demonstrate that aerosolized histamine caused an increase in the tissue viscoelastic properties. The most reasonable explanation for the mechanism of this increase would seem to be via reflex pathways stimulated by centrally located receptors.     

Fasting stress exacerbates classical conditioned histamine release in guinea pigs

To clarify the contribution of stress to classical conditioning-associated asthmatic responses, the effect of fasting stress on conditioned histamine release was investigated in a guinea pig model of asthma. The animals were randomly divided into 2 groups for Experiment 1 and 2, and received a conditioning procedure in which ovalbumin (OA) as an unconditioned stimulus (US) and dimethylsulfide (DMS, sulfur smelling) as a conditioned stimulus (CS) were simultaneously inhaled after fasting for 16 h. Then, one group was given food as a reward for respiratory distress, and the other group was denied it for more than 3 h, while being placed in front of the feeding group. After this procedure was repeated 5 times, the plasma histamine levels in response to the CS were measured in half of each group in Experiment 1, and the respiratory resistance (Rrs) was assessed similarly in the other half of each group in Experiment 2. The same experiments were again performed after exchanging assignments of feeding group or fasting group in both experiments. The control groups in both experiments received the CS and the US 10 times separately in a random order under 16 h fasting conditions and were provided food after the exposures. After these pseudo-conditioning presentations, the plasma histamine levels or the Rrs in response to the CS were measured. In Experiment 1, the plasma histamine levels in the fasting stress group after the first conditioning sessions were significantly higher than those of the other groups. This difference was not observed when the groups were exchanged. In Experiment 2, the fasting stress group showed higher values in the Rrs compared to the other groups, irrespective of the first or second conditionings; however, they were not significant. The present study indicates that fasting stress after the conditioning procedures exacerbates the following conditioned histamine release, although the stress effect on bronchoconstriction was not confirmed.     

Phosphoramidon potentiates the bronchoconstriction induced by inhaled bombesin in guinea pigs

The effect of the neutral endopeptidase inhibitor, phosphoramidon, on the bronchoconstriction induced by aerosolized bombesin in the guinea pig was investigated. Administered by aerosol for 1 min, bombesin (0.01 or 0.1 mg/ml) induced a dose-dependent increase in pulmonary inflation pressure. Pretreatment of the guinea-pigs with phosphoramidon (0.1 mM), administered by aerosol for 15 min, 15 min prior to challenge, markedly potentiated the increase in pulmonary inflation pressure induced by bombesin (0.01 mg/ml) and substance P (0.1 mg/ml). This result suggests a local hydrolysis of bombesin by airway neutral endopeptidase reducing the activity of this peptide on smooth muscle.     

Effect of B-HT 920 on cardiotoxic effects of ouabain in guinea pigs.

Effect of B-HT 920, a selective alpha 2 adrenoceptor agonist, was studied on ouabain induced cardiac arrhythmias and cardiac arrest in guinea pigs. Ventricular premature beats, ventricular tachyarrhythmias and cardiac arrest were induced in anaesthetized guinea pigs by slow infusion of ouabain. B-HT 920 accorded significant protection to guinea pigs against ouabain induced arrhythmias. Yohimbine inhibited the antiarrhythmic effect of B-HT 920 significantly. It is concluded that the protective effect of B-HT 920 against ouabain induced cardiac arrhythmias and cardiac arrest is mediated through the stimulation of alpha 2 adrenoceptors.     

Nitric oxide derived from sympathetic nerves regulates airway responsiveness to histamine in guinea pigs

Matsumoto, Koichiro, Hisamichi Aizawa, Shohei Takata,Hiromasa Inoue, Naotsugu Takahashi, and Nobuyuki Hara.Nitric oxide derived from sympathetic nerves regulates airwayresponsiveness to histamine in guinea pigs. J. Appl.Physiol. 83(5): 1432-1437, 1997.Nitric oxide(NO), which can be derived from the nervous system or the epithelium ofthe airway, may modulate airway responsiveness. We investigated how NOderived from the airway nervous system would affect the airwayresponsiveness to histamine and acetylcholine in mechanicallyventilated guinea pigs. An NO synthase inhibitor N^G-nitro-L-argininemethyl ester (L-NAME) (1 mmol/kgip) significantly enhanced airway responsiveness to histamine but notto acetylcholine. Its enantiomerD-NAME (1 mmol/kg ip), incontrast, had no effect. TheL-NAME-induced airwayhyperresponsiveness was still observed in animals pretreated withpropranolol (1 mg/kg iv) and atropine (1 mg/kg iv). Pretreatment withthe ganglionic blocker hexamethonium (2 mg/kg iv) completely abolishedenhancing effect of L-NAME on airway responsiveness. Bilateral cervical vagotomy did not alter theL-NAME-induced airwayhyperresponsiveness, whereas sympathetic stellatectomy completelyabolished it. Results suggest that NO that was presumably derived fromthe sympathetic nervous system regulates airway responsiveness tohistamine in guinea pigs.