P. D. Graf

Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs.

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.

Modulation of cholinergic neurotransmission in canine airways by thromboxane mimetic U46619

Abstract We studied the effect of a thromboxane A 2 -mimetic, U46619, on the contractile responses of canine bronchial smooth muscle to cholinergic stimulation in vitro. U46619 (3 × 10 −10 M), at a concentration that did not cause contraction, enhanced the effect of electrical field stimulation at all frequencies; histamine (10 −7 M) and prostaglandin F 2α (10 −7 M) did not. U46619 (3 × 10 −10 M) did not affect methacholine-induced contractions. U46619 may therefore increase the prejunctional release of acetylcholine.

Mast cell chymase potentiates histamine-induced wheal formation in the skin of ragweed-allergic dogs.

Skin mast cells release the neutral protease chymase along with histamine during degranulation. To test the hypothesis that chymase modulates histamine-induced plasma extravasation, we measured wheal formation following intradermal injection of purified mast cell chymase and histamine into the skin of ragweed-allergic dogs. We found that chymase greatly augments histamine-induced wheal formation. The magnitude of the potentiating effect increases with increasing doses of chymase and becomes maximal approximately 30 min after administration. Injection of chymase without histamine does not evoke wheal formation. The chymase potentiation of histamine-induced skin responses is prevented completely by pretreatment with the H1-receptor antagonist pyrilamine, and is prevented by inactivation of chymase with soybean trypsin inhibitor, suggesting that both histamine and preserved catalytic activity are required for the effects of chymase. To examine the effects of histamine and chymase released in situ in further experiments, we measured wheal size following local degranulation of mast cells by intradermal injection of ragweed antigen or compound 48/80. We found that pretreatment with either soybean trypsin inhibitor or pyrilamine markedly reduces ragweed antigen- or 48/80-induced wheal formation, supporting the results obtained by injection of exogenous chymase and histamine. These findings suggest a novel and important proinflammatory role for chymase in modulating the effects of histamine on vascular permeability during mast cell activation.

Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs.

1 In the present study, we have investigated the role of kinins in allergen‐induced bronchoconstriction. 2 Anaesthetized guinea‐pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 μmol kg−1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 μmol kg−1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 μmol kg−1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mm, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10μm, 40 breaths). On the other hand, a combination of the NK1 (CP‐96,345, 2 μmol kg‐1, i.v.) and NK2 (SR 48968, 0.3 μmol kg−1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea‐pig airways. 3 Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea‐pigs pretreated with atropine (1.4mmol kg−1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 μmol kg−1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4 Pretreatment with a combination of NK1 (CP‐96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin‐induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen‐induced bronchoconstriction. 5 These findings confirm that activation of sensory nerves to release tachykinins in guinea‐pig airways contribute to antigen‐induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.

The Effects of Halothane and Cyclopropane on Total Pulmonary Resistance in the Dog

The authors compared the effects of halothane and cyclopropane on total pulmonary resistance (RL) in dogs before (unstimulated) and during airway constriction produced by histamine or vagal nerve stimulation. In two dogs, direct measurements of airway diameter were obtained from bronchograms and com

Regulation of Pulmonary Capillary Blood Volume by Pulmonary Arterial and Left Atrial Pressures

We used single-breath CO diffusing capacity to study the effect of changes in pulmonary arterial and left atrial pressures on pulmonary capillary blood volume in 15 supine dogs whose lungs were perfused with a nonpulsatile pump. Effect of pulmonary arterial pressure: When left atrial pressure measured relative to the bottom of the lungs ≤ alveolar pressure, increasing pulmonary arterial pressure increased diffusing capacity markedly (mean, 0.71 ml/min × mm Hg per mm Hg change in pulmonary arterial pressure). When left atrial pressure ≥ alveolar pressure plus the height of the lungs, increasing pulmonary arterial pressure had less effect on diffusing capacity, although blood flow was increased through a wide range (mean, 0.22 ml/min × mm Hg CO per mm Hg increase in pulmonary arterial pressure). Effect of left atrial pressure: At zero flow, increasing left atrial pressure increased diffusing capacity markedly; when pulmonary arterial pressure was high, increasing left atrial pressure had no significant effect on diffusing capacity. Increasing bronchial arterial pressure from 0 to 150 mm Hg or inhaling 10.5% CO2 had no effect on diffusing capacity. Injection into the pulmonary artery of glass microspheres decreased diffusing capacity only when left atrial pressure was low; their effect was exaggerated when pulmonary arterial pressure was high in the control state.

Bronchial smooth muscle responses evoked by toluene diisocyanate are inhibited by ruthenium red and by indomethacin

We have investigated the ability of ruthenium red, an inorganic dye with Ca2+ entry-blocking properties and a selective antagonist of capsaicin, and of indomethacin, a cyclooxygenase inhibitor, to inhibit bronchial smooth muscle responses evoked by toluene diisocyanate in guinea pigs. Previous exposure of isolated guinea pig bronchi to ruthenium red significantly decreased the response produced by toluene diisocyanate. Further, the response to toluene diisocyanate was significantly decreased by pretreatment with indomethacin. These findings provide evidence that toluene diisocyanate-induced contractions of guinea pig bronchi are produced indirectly by generation of a prostanoid that activates capsaicin-sensitive afferents via a ruthenium red-sensitive mechanism.

Powdered Tantalum as a Medium for Human Laryngography

Abstract Powdered tantalum was used as a contrast agent for laryngography 7 times in 5 subjects: 3 healthy and 2 with laryngeal carcinoma. It was inhaled by the mouth in 3 cases without topical anesthesia and insufflated selectively into the upper airways by cathether in the others. The laryngeal structures were outlined with sharp contrast and fine mucosal detail in all cases. Coughing, swallowing, or phonation did not significantly affect the roentgen appearance. No adverse effects were observed.

Effect of macrophage stimulation on parasympathetic airway contraction in dogs.

The effect of lung macrophages stimulated with calcium ionophore on parasympathetic contractile response of canine bronchial rings was studied. Macrophages augmented the contraction induced by electrical field stimulation, an effect that was inhibited by indomethacin and by SQ29548, a thromboxane A2 receptor antagonist, but had no effect on the contractile response to exogenous acetylcholine. These results suggest that macrophage-derived thromboxane A2 facilitates cholinergic neurotransmission prejunctionally in airway smooth muscle.

Powdered Tantalum as a Contrast Agent for Tracheobronchography in the Pediatric Patient

Abstract Powdered metallic tantalum was used as a contrast agent for bronchography or tracheography in 15 studies on 13 patients (age, 13 days to 16 years). Tantalum proved to be an excellent medium, providing better mucosal detail and opacification than other contrast media, without obstructing airways. None of the patients had local or systemic reactions to tantalum. Because of its inertness and the small quantities required, tantalum may enable more extensive use of bronchography in the pediatric patient.