Effects of diesel exhaust particles on blood pressure in rats.

The effects of diesel exhaust particles (DEP) on pulmonary functions and consequent diseases are well known, but there have been few reports concerning involvement of the cardiovascular system. In order to assess a direct action of DEP on cardiac tissue, the effects on blood pressure of intravenous administration of 12 or 120 mg/kg DEP to anesthetized rats were studied for a 15-min period. DEP (120 mg/kg) significantly lowered blood pressure for 25 s with no signs of arrhythmia or mortality, a phenomenon seen in guinea pigs. After 25 s blood pressure gradually returned to control levels and was maintained for 15 min. The 12-mg/kg DEP concentration did not markedly affect rat blood pressure. Pretreatment with atropine (24 mg/kg) blocked the DEP-induced fall in blood pressure, while pretreatment with propranolol (48 mg/kg) proved ineffective against DEP, suggesting involvement of the parasympathetic system. Data show that the rat is less sensitive to DEP-induced effects on blood pressure and may be a poor model to reflect cardiovascular changes.

Diesel exhaust-induced airway hyperresponsiveness in c-Ha-ras transgenic mice.

Recently the quantity of diesel exhaust (DE) emissions, which contain a variety of chemicals and can induce pulmonary carcinoma in animals, has been increasing in Japan. To assess the toxicity of DE, we evaluated airway hyperresponsiveness after exposure to DE in the rasH2 (CB6F1-TgHras2) mouse, which carries c-Ha-ras genes and shows marked sensitivity to treatment with various genotoxic carcinogens such as methylnitrosourea and dimethylbenzanthracene. We exposed rasH2 mice (n=18) and their nontransgenic littermates (n=19) to room air or 3 mg/m(3) DE for 4 weeks, measured their respiratory resistance (Rrs) during inhalation of acetylcholine (ACh; 0.005, 0.01, 0.02, 0.04, 0.08, 0.16, 0.31, 0.63, 1.28, 2.5, 5, or 10 mg/ml) for 2 min, and calculated the provocative ACh concentration needed to cause a 50% increase (PC(150)) in Rrs. At all doses of ACh, Rrs was significantly higher (P<0.05) in rasH2 mice exposed to DE than in those exposed to room air. In addition, Rrs in the DE-exposed rasH2 animals was significantly higher (P<0.05) at 0.16, 0.31, and 0.63 mg/ml ACh than in DE-exposed nontransgenic littermates. The PC(150) (mean+/-standard error) of DE-exposed rasH2 mice was 3.4+/-1.9 mg/ml, that in rasH2 mice exposed to room air was 10.6+/-2.5 mg/ml, and that in DE-exposed nontransgenic animals was 10.9+/-3.7 mg/ml. In conclusion, DE causes airway hyperresponsiveness in rasH2 mice and may induce the expression of c-Ha-ras genes.

Diesel exhaust (DE) affects the regulation of testicular function in male Fischer 344 rats.

To investigate the effects of diesel exhaust (DE) particles on the reproductive system, male Fischer 344 rats at 13 mo of age were exposed to clean air or DE at particle concentrations of 0.3, 1, or 3 mg/m3 for 8 mo. DE did not markedly affect testicular and body weights. However, DE at 0.3 mg/m3 significantly decreased prostate and coagulating gland weights, accompanied by a reduction in thymus and adrenal gland weight. In contrast, there was a significant rise in the weights of prostate, seminal vesicles, and coagulating glands in the 3 mg/m3 DE group. In rats exposed to 0.3 or 1 mg/m3 DE, serum luteinizing hormone (LH) and testosterone increased significantly, while a rise in testicular testosterone was noted with 3 mg/m3 DE. The concentrations of follicle-stimulating hormone (FSH) and inhibin as well as the sperm head counts were not markedly altered in any treatment group. Positive staining with inhibin-alpha subunit and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were observed in Sertoli cells and Leydig cells, respectively. Immunolocalization of inhibin-alpha subunit and 3beta-HSD was not changed by exposure to DE. In conclusion, DE appears to exert greater effects on accessory glands than on testes in Fischer 344 rats, and the responsiveness of rats is less than that found in mice.

The difference in citric acid-induced cough in congenitally bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs.

Cough elicitation and major physiological factors influencing cough occurrence were investigated in congenitally bronchial-hypersensitive (BHS) and -hyposensitive (BHR) guinea pigs exposed to citric acid (0.3 M) aerosol for 10 min. The number of cough in BHS was significantly larger than in BHR, while the latency to cough in BHS was significantly shorter than in BHR. Pretreatment with atropine (0.2%), lidocaine (2%) or salbutamol (0.1%) aerosol and desensitization of C-fibers with capsaicin (100 mg/kg) decreased the cough numbers in both BHS and BHR. The salbutamol, atropine and capsaicin pretreatments prolonged the cough latency in BHS, but only salbutamol prolonged the latency in BHR. After salbutamol pretreatment all BHR guinea pigs exhibited cough, while 66.7% of BHS guinea pigs exhibited it. Vagal blocking by atropine suppressed coughing in both BHS and BHR. Only a small number (33.3%) of BHR guinea pigs and no BHR guinea pigs exhibited a cough response after capsaicin and lidocaine pretreatment whereas many BHS guinea pigs still produced cough after such pretreatment. The present study demonstrated that the cough responsiveness to citric acid aerosol was significantly higher in BHS than in BHR. It was revealed that airway smooth muscle contraction and functional and/or morphological development of airway nervous receptors, especially C-fiber endings, contributed to aggravation of coughing in BHS.

Airway responsiveness to acetylcholine in congenitally bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs in vivo and in vitro.

The characteristics of airway responsiveness to acetylcholine (ACh) in congenitally bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs were clarified in vivo and in vitro. We measured the change in ventilatory mechanics in response to ACh inhalation by means of the bodyplethysmograph and the contractile responses of isolated trachea to ACh and carbachol (CCh). Further, muscarinic receptor subtypes involved these responses were identified. The basal values for ventilatory mechanics in BHS were not significantly different from those in BHR. Respiratory resistance to ACh was progressively increased in a time- and dose-dependent manner in BHS. The contractile responses of tracheal smooth muscle to ACh in BHS were significantly greater than those in BHR, but CCh-induced responses in BHS and BHR were similar. ACh- and CCh-induced contractions were mediated via M3 receptors. These results suggested that the falling-down of BHS in response to ACh inhalation was caused by the strong constriction of the airway and the reduction in ventilation. Moreover, the airway hyperresponsiveness to ACh in BHS might be partly dependent on the change in acetylcholinesterase activity.

Histamine-induced airway contraction in congenitally bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs.

Airway hyper-responsiveness is known as an important pathogenesis of asthma. In the present study, the airway responsiveness to aerosolized and injected histamine in congenitally bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs was investigated. In addition, the role of the vagal reflex in histamine-induced airway contraction was evaluated by vagal blocking with atropine inhalation or bilateral vagotomy. A significantly higher bronchoconstrictive reaction, i.e., a decrease in tidal volume (VT) and an increase in respiratory resistance (Rrs), to histamine-inhalation was observed in BHS than in BHR. A noticeably lower reduction in VT was noted after atropine pretreatment for both BHS and BHR, whereas an increase in Rrs was inhibited only in BHS. The intravenous injection of histamine caused a noticeable bronchoconstrictive reaction in both BHS and BHR with a dose-dependent relationship, but no significant differences were observed and the bilateral vagotomy failed to induce any difference between the two animal groups. These results demonstrated that the airway responsiveness to histamine is considerably different in BHS from that in BHR, but the difference is largely dependent on the route of administration of histamine. The important role of the vagal reflex on the elicitation of airway contraction was elucidated in both animal groups, and it appeared that the BHS possessed relatively higher dependency on the vagal reflex mechanism than the BHR.

Bradykinin-induced airway contraction in two lines of guinea pigs with congenitally different airway sensitivity.

The airway responsiveness to bradykinin (0.1, 1 and 10 microg/kg, i.v.) was examined in two lines of guinea pigs, BHS (bronchial hypersensitive) and BHR (bronchial hyposensitive) lines, with different airway sensitivity to inhalation of acetylcholine (ACh)-aerosol. Normal Hartley strain guinea pigs were used as a control group. The airway contraction was measured by recording intratracheal pressure (P[IT]) and respiratory airflow (V) under the condition of artificial ventilation in anesthetized guinea pigs. The results show airway responsiveness to bradykinin in BHS guinea pigs to be significantly greater than in BHR and normal Hartley strain guinea pigs.