Takashi Aikawa

Treatment of status asthmaticus with intravenous magnesium sulfate

The bronchodilating effect of magnesium sulfate (MgSO4) was studied in two patients with status asthmaticus, who were intubated and mechanically ventilated by a respirator. Airway resistance was continuously monitored by the respiration-controlled interruption technique. After administration of 0.5 mmol/min MgSO4 intravenously, airway resistance decreased from 17 to 9, and from 13 to 8 mmHg/L/s in the two patients, respectively, and piping rales diminished or disappeared. We conclude that while corticosteroid therapy requires several hours to demonstrate significant effects in status asthmaticus, MgSO4 is of great benefit in the rapid improvement of airflow obstruction.

K channels of human alveolar macrophages

The activation of macrophages has been reported to be associated with Ca-activated K permeability change. In order to study this permeability change in human alveolar macrophages, we examined alveolar macrophages electrophysiologically at a single channel level. We observed two types of Ca-activated K channel currents having conductances of 218 +/- 2 and 32 +/- 0.6 picosiemens in symmetrical 154 mmol/L KCl solutions. The characteristics, such as voltage dependency and Ca sensitivity, as well as channel conductance, were different between these two types of channel currents. Quinine (a blocker of Ca-activated K conductance), 0.5 mmol/L, reduced these channel currents by 45 +/- 8% and 31 +/- 8%. Quinine, 0.5 mmol/L, also inhibited chemiluminescence and leukotriene B4 release by 82 +/- 6 to 88 +/- 3% and 88 +/- 2%, respectively. These results suggest the presence of two types of Ca-activated K channels, which may be related to the release of inflammatory mediators from human alveolar macrophages.

Inhibitory actions of prostaglandin E1 on non-adrenergic non-cholinergic contraction in guinea-pig bronchi.

We have investigated the effect of prostaglandin E1 (PGE1) on non‐adrenergic, non‐cholinergic (NANC) contraction in guinea‐pig bronchial strips. PGE1 (10 nM to 10 μm) did not alter baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration‐dependent fashion (‐log EC50 was 6.60 ± 0.10M and maximum inhibition was 88.7 ± 2.9%). PGE1 (>0.3 μm) also reduced the contraction induced by substance P (1 μm). Removal of epithelium did not alter the effects of PGE1 on NANC contraction. These results suggest that PGE1 exerts both pre‐ and post‐junctional inhibitory actions on NANC contraction.

Evidence that an atypical β-adrenoceptor mediates the prejunctional inhibition of non-adrenergic non-cholinergic contraction in guinea-pig bronchi

We investigated the effect of the putative beta 3 agonist BRL 35135 on non-adrenergic non-cholinergic (NANC) contractions in guinea-pig bronchial strips. BRL 35135 (10(-9) to 10(-6) M) did not alter the baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration-dependent fashion without having a significant effect on the contraction induced by substance P (10(-6) M). BRL 35135 (10(-6) M) also reduced the contraction induced by capsaicin (10(-7) M). Likewise, BRL 37344 (10(-9) to 10(-6) M) reduced NANC contractions induced by EFS in a concentration-dependent fashion. While BRL 37344 up to concentrations of 10(-8) M did not alter the contraction induced by SP (10(-6) M), BRL 37344 (10(-8) M) significantly inhibited NANC contractions induced by EFS and capsaicin (10(-7) M), (P less than 0.01). The inhibitory effect of BRL 35135 (10(-6) M) on NANC contractions induced by EFS was not significantly altered by the non-selective beta-adrenoceptor antagonists, propranolol and pindolol (P greater than 0.10), by the beta 1-selective antagonists, atenolol and metoprolol (P greater than 0.20) (10(-8) to 10(-6) M), or by the alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5) M) (P greater than 0.50). These results suggest that beta 3 agonists exert a prejunctional inhibitory action on NANC contractions.

Vascular permeability and airway narrowing during late asthmatic response in dogs treated with metopirone

Recently, we have developed an animal model of late asthmatic response (LAR) by treating naturally sensitized dogs to Ascaris suum antigen with the cortisol-synthesizing inhibitor, Metopirone. By using this animal model, we examined the contribution of edema in the airway wall to the development of LAR. To study whether airway microvascular leakage is increased in association with LAR, we performed antigen challenge in dogs treated with Metopirone. We measured the amount of extravasated Evans blue (EB) dye from the esophagus, trachea, and large and small bronchi 8 hours after the antigen challenge in dogs demonstrating immediate asthmatic response alone (IAR) and in dogs demonstrating both IAR and LAR. Airway responses to A. suum antigen were assessed by changes in respiratory resistance measured with the force oscillation technique at 3 Hz. EB dye extravasation did not increase significantly from that of control in any tissues in IAR (P greater than 0.10), but in LAR, it increased significantly from that of control (p less than 0.01) and IAR (p less than 0.05) in large and small bronchi. Histologic assessment of vascular permeability revealed that Monastral blue-labeled leaking vessels were only in sections from LAR, and leaking vessels were limited to small vessels (10 to 25 microns) in the trachea, large (diameter, greater than 5 mm) and small bronchi (2 to 4 mm in diameter), and bronchiole. The permeability index defined as the ratio of area of small vessels labeled with Monastral blue to that of the total small vessels in the walls was highest in the small bronchi. LAR significantly increased submucosal thickness of the small bronchi (p less than 0.05) compared with that in IAR. Both EB dye extravasation and permeability index in large and small bronchi also significantly increased during IAR within 3 minutes after the antigen challenge (p less than 0.05), but IAR did not alter the submucosal thickness of the small bronchi. These results imply that the increase in vascular permeability and submucosal thickness, especially in small bronchi, may be an important factor in the pathogenesis of LAR.

Effects of Qing-Fei-Tang (Seihai-to) and Baicalein, Its Main Component Flavonoid, on Lucigenin-Dependent Chemiluminescence and Leukotriene-Dependence Chemiluminescence and Leukotriene B4 Synthesis of Human Alveolar Macrophages

A traditional Chinese remedy, Qing-Fei-Tang (Seihai-to, T90), has been used for treatment of chronic respiratory diseases with long-lasting cough and sputum, e.g. chronic bronchitis. We examined the effect of T90 and its main component flavonoid, baicalein, on the lucigenin-dependent chemiluminescence (CL) and leukotriene B4 (LTB4) synthesis of human alveolar macrophages (AM). AM were obtained by bronchoalveolar lavage from patients with various respiratory diseases, including sarcoidosis, idiopathic pulmonary fibrosis, bronchial asthma, chronic bronchitis and lung cancer. CL were observed by stimulating 1 x 10(5) AM with phorbol myristate acetate in the presence of lucigenin. LTB4 were generated by incubating 1 x 10(6)/ml AM with Ca ionophore A23187 for 30 min and determined by reverse phase high performance liquid chromatography and radioimmunoassay. T90 (0.2-2.0 mg/ml) and baicalein (0.1-100 microM) inhibited both CL and LTB4 production of AM in a dose-dependent fashion. These inhibitory effects were not due to cytotoxic effects of the procedure because neither 2 mg/ml T90 nor 100 M baicalein affected the viability of AM nor lactate dehydrogenase release from AM. These results suggest that T90 exerts its effect on inflammatory lung diseases through the anti-inflammatory action, i.e. inhibiting the oxidative and arachidonate metabolism of local inflammatory lung cells.

The role of cyclic AMP in non‐adrenergic non‐cholinergic contraction in guinea‐pig bronchi

1 We investigated the role of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) in non‐adrenergic non‐cholinergic (NANC) contraction in guinea‐pig bronchial strips. 2 Forskolin (3 nm to 1 μm) reduced NANC contraction induced by electrical field stimulation (EFS) in a concentration‐dependent fashion (–log EC50 was 7.22 ± 0.12 m and maximum inhibition was 100 ± 0.01%). However, forskolin (< 1 μm) did not alter the contraction induced by substance P (SP, 1 μm). 3 Dibutyryl cyclic AMP (1 mm) also reduced NANC contractions induced by EFS (100 ± 0.01%) without significant effect on SP (1 μm)‐induced contractions. In contrast, dibutyryl cyclic GMP (1 mm) was without effect against either NANC or SP‐induced contractions. 4 Both the β2‐adrenoceptor agonist, procaterol (0.1 nm to 3 nm) and theophylline (100 nm to 1 mm) concentration‐dependently reduced EFS‐induced NANC contractions without significant effect on SP (1 μm)‐induced contractions. 5 In contrast to forskolin, procaterol and theophylline, both sodium nitroprusside and cromakalim inhibited the EFS‐induced contractions only at those concentrations that similarly reduced the contractions induced by SP (1 μm). 6 These results suggest that cyclic AMP may mediate pre‐junctional inhibition of NANC contractions in guinea‐pig bronchi.

Conditioned enhancement of cough response in awake guinea pigs.

To determine whether psychological factors affect the cough response, we employed a classical conditioning procedure in which capsaicin challenge was paired with the presentation of an odor in awake guinea pigs. On days 1-4, animals received combined administrations of the unconditioning stimulus, capsaicin aerosols, and the conditioning stimulus, camphor aerosols (group 1), capsaicin and saline aerosols (group 2), and camphor and saline aerosols (group 3), and the number of coughs was counted. On day 5, all groups received camphor and saline aerosols. A significant number of coughs (p < 0.01) was observed only in group 1 when the animals were exposed to the odor alone on day 5. This suggests that associative learning enhances the cough response.

Rivastigmine dermal patch solves eating problems in an individual with advanced Alzheimer's disease.

trial. Lancet 2005;366:455–462. 3. Burstein HJ, Winer EP. Aromatase inhibitors and arthralgias: A new frontier in symptom management for breast cancer survivors. J Clin Oncol 2007;25:3797–3799. 4. Donnellan PP, Douglas SL, Cameron DA et al. Aromatase inhibitors and arthralgia. J Clin Oncol 2001;19:2767. 5. Mao JJ, Stricker C, Bruner D et al. Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer 2009;115:3631–3639. 6. Greising SM, Baltgalvis KA, Lowe DA et al. Hormone therapy and skeletal muscle strength: A meta-analysis. J Gerontol A Biol Sci Med Sci 2009;64A:1071–1081. 7. Lowe DA, Baltgalvis KA, Greising SM. Mechanisms behind estrogen’s beneficial effect on muscle strength in females. Exerc Sport Sci Rev 2010;38:61– 67.

Inhibitory actions of prostaglandin E1 on neurogenic plasma extravasation in rat airways

To determine whether neurogenic inflammation can be inhibited by prostaglandin E1 (PGE1), that is suggested to have an inhibitory effect on neuropeptide release from airway sensory nerves, we examined plasma extravasation in the airways of anesthetized rats in vivo with Evans blue due as a marker. Neurogenic inflammation was produced by an i.v. injection of capsaicin (100 micrograms/kg) or by antidromic electrical stimulation of the right vagus nerve (4 Hz, 1 ms, 4 V for 1 min). Capsaicin injection significantly increased leakage of dye in the trachea and main bronchi. Similar increases in leakage were seen in the trachea and right bronchus on electrical stimulation of the right vagus nerve. PGE1 (1-1000 micrograms/kg) inhibited the leakage induced by capsaicin in the trachea and bronchi concentration dependently with complete inhibition at a concentration of 1000 micrograms/kg. Likewise, PGE1 (1000 micrograms/kg) significantly inhibited electrical stimulation-induced leakage in the trachea and right bronchus (P less than 0.01). I.v. substance P (SP; 1 microgram/kg) increased Evans blue dye extravasation in the same way as the leakage induced by capsaicin and electrical stimulation but PGE1 (1000 micrograms/kg) failed to inhibit SP-induced leakage in the trachea and main bronchi (P greater than 0.20). These results suggest that PGE1 inhibits neurogenic plasma leakage by presynaptic inhibition of the release of neuropeptides from sensory nerves.