neurokinin-a and Airway-Obstruction

(-)-Δ(9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo. Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol. Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs. (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (-)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions. In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction. In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders.

Topics: Airway Obstruction; Animals; Arachidonic Acids; Bronchi; Cannabidiol; Cannabinoids; Carbachol; Endocannabinoids; Female; Guinea Pigs; Histamine; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Neurokinin A; Ovalbumin; Phenylmethylsulfonyl Fluoride; Polyunsaturated Alkamides

The purpose of the study was to compare in vitro airway responses to neurokinin A & B (NKA and NKB) and expression of NK-2 receptors in airways of horses affected and unaffected with recurrent airway obstruction (RAO). Neurokinin-A, an inflammatory mediator belonging to the tachykinin family of neuropeptides, causes bronchoconstriction by binding to NK-2 receptors. Neurokinin-B is a lesser-known neuropeptide that acts on NK-3 receptors. Horses were placed into RAO-affected and RAO-unaffected groups based on their history, clinical scoring, and pulmonary function testing. Lung tissue from each lobe was collected for immunohistochemical staining for NK-2 receptors. Cumulative concentration-response relationships were determined on bronchial rings (4-mm wide) collected and prepared from the right diaphragmatic lung lobe to graded concentrations (half log molar concentrations 10(-7)M to 10(-4)M) of NKA and NKB. The results showed that NKA caused significantly greater contraction than NKB in both groups. In RAO-affected horses, both agents produced significantly greater bronchial contractions than those in the RAO-unaffected horses. Immunohistochemical staining showed that the overall NK-2 receptor distribution was significantly increased in bronchial epithelium and smooth muscles of bronchi and pulmonary vessels of RAO-affected than RAO-unaffected horses. The findings indicate that NK-2 receptors are up-regulated in RAO, suggesting that NK-2 receptor antagonists may have some therapeutic value in controlling the progression of airway hyperreactivity in horses affected with RAO.

Topics: Airway Obstruction; Animals; Antibodies; Bronchi; Bronchial Hyperreactivity; Horse Diseases; Horses; Immunohistochemistry; Muscle, Smooth; Neurokinin A; Neurokinin B; Nose; Receptors, Neurokinin-2; Recurrence; Respiratory Physiological Phenomena

1. To study the effect of maturation on substance P (SP)- and neurokinin A (NKA)-induced airflow obstruction and airway microvascular leakage (MVL), we have measured changes in both lung resistance (RL) and extravasation of Evans blue dye in anaesthetized immature (aged 14 +/- 1 days) and adult guinea-pigs (aged 80 +/- 3 days). 2. RL and its recovery after hyperinflation at 5 min were measured for 6 min after i.v. SP (0.2, 1 and 30 nmol kg-1), NKA (1 and 10 nmol kg-1) or vehicle (0.9% NaCl). After measurement of RL, MVL in trachea, main bronchi and intrapulmonary airways was also examined. 3. The order of potency in inducing airflow obstruction did not change with age (NKA > SP) but immature animals required a larger dose of SP or NKA than adults to cause a significant increase in RL. 4. The order of potency in inducing airway microvascular leakage was SP > NKA in both immature and adult animals. The amount of extravasated dye after SP was significantly less in immature airways, especially in central airways. 5. Phosphoramidon (2.5 mg kg-1), a neutral endopeptidase (NEP) inhibitor, significantly increased RL after 0.2 nmol kg-1 SP only in adult airways. Phosphoramidon enhanced the dye extravasation after 0.2 nmol kg-1 SP in both immature and adult airways with a significantly greater amount of dye in adult animals, suggesting that mechanisms other than changes in NEP activity may be responsible for this age-related difference. 6. RL after hyperinflation following SP was not correlated with the degree of extravasation of Evans blue dye in immature animals, whereas it was closely correlated in adult animals. 7. SP and NKA may be less potent in causing both bronchoconstriction and microvascular leakage in immature airways. 8. Airway oedema caused by microvascular leakage may contribute less in immature airways to airflow obstruction after SP or NKA.

Topics: Aging; Airway Obstruction; Airway Resistance; Animals; Blood Pressure; Bronchoconstriction; Capillary Permeability; Evans Blue; Glycopeptides; Guinea Pigs; Lung; Male; Neprilysin; Neurokinin A; Pulmonary Ventilation; Substance P