Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea pigs. Ten minutes after the injection of l-NAME (50 mg/kg intravenously) or l-NMMA (50 mg/kg intravenously), baseline heartbeat frequency was unchanged (Table ). Of particular interest for the present study is the observation that the moderate bronchoconstriction induced by aerosolized bradykinin (BK) in anesthetized guinea pigs is markedly potentiated by inhibition of the l-arginine (l-Arg) NO-pathway (6). 1. By continuing to browse SR 48968 {(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl] benzamide} was kindly provided by Dr. X. Emonds-Alt (Sanofi Recherche, Montpellier, France). l-Arg, d-Arg, l-NAME, d-NAME, l-NMMA, d-NMMA, capsaicin, and atropine were obtained from Sigma Chemical Co. (St. Louis, MO). Involvement of kinins was indicated by the observation that a kinin B2-receptor antagonist, HOE 140, abolished bronchoconstriction induced by cold air (10). If tachykinins play a role in HIB in human subjects with exercise-induced asthma, or in the worsening of this condition when these subjects breathe cold air, the recently discovered nonpeptide tachykinin receptor antagonists may be of some benefit in this pathology. Inhalation of cold air worsens symptoms of exercise-induced asthma (27), and asthma-like symptoms are more common in cross-country skiers (breathing large volumes of cold air) than in the general population (28). The activity of iNOS is stimulated during inflammation by bacterial endotoxins (e.g., lipopolysaccharide) and cytokines such as tumor necrosis factor (TNF) and interleukins. Second, the increase in Rl caused by cold-air inhalation in the presence of l-NAME was reversed by l-Arg in a stereospecific manner. Entries are mean ± SEM of at least five experiments. Entries are mean ± SEM of at least five experiments. When NO forms, it has a half-life of only a few seconds, in large part because superoxide anion has a high affinity for NO (both molecules have an unpaired electron making them highly reactive). Under normal, basal conditions, the activity of iNOS is very low. Endogenous nitric oxide modulates potassium-induced changes in guinea pig airway tone. Evidence that epithelium-derived relaxing factor released by bradykinin in guinea pig trachea is nitric oxide. The nebulized 0.9% saline was mixed with cold air after the air had passed through the coiled tubing immersed in dry ice. We also investigated the ability of BK and of the selective tachykinin NK2-receptor agonist, [βAla8]neurokinin A (4-10) ([βAla8]NKA [4–10]) (11) to increase cyclic 3′,5′-guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle. The activity of cNOS is calcium- and calmodulin-dependent. Apparently, kinins do not contribute directly to smooth-muscle contraction, but instead excite sensory nerves, thus releasing the proinflammatory tachykinins (23), which cause bronchoconstriction via activation of NK2-receptors. Effect of HOE 140 on bradykinin-induced bronchoconstriction in anaesthetized guinea-pigs. The transpulmonary pressure (defined as the pressure difference between the intratracheal and the esophageal pressures) was measured with a differential pressure transducer (Model DP7; Valydine Engineering Corp.). increased cGMP= bronchoconstriction. Values are mean ± SEM of five experiments. This physiologic finding was recently confirmed by neurochemical findings that dorsal-root-ganglion neurons in culture release substance P (SP) after exposure to hypertonic media, but not to a physiologic solution maintained at a low temperature (21). Pretreatment with l-Arg but not with d-Arg abolished the increase in Rl induced by inhalation of cold air for 5 min in guinea pigs pretreated with l-NAME (Figure 2c). Cold-air inhalation for periods longer than 5 min was shown to increase Rl in anesthetized and atropinized guinea pigs (10). Capsaicin increases airflow resistance in guinea pigs. This enzyme catalyzes the dephosphorylation of GTP to cGMP, which serves as a second messenger for many important cellular functions, particularly for signalling smooth muscle relaxation. Further studies may elucidate whether NO is involved in the modulation of bronchoconstriction induced in asthmatic subjects by agents that might increase kinin levels in the airways. Bradykinin effects in guinea pig tracheal epithelial cells are mediated through a B. Endogenous nitric oxide counteracts antigen-induced bronchoconstriction. The Vt was adjusted to maintain normal arterial blood gases as described previously (12). The novel mechanism that we have described in this report is the involvement of the l-Arg–NOS pathway in the modulation of bronchoconstriction induced by inhalation of cold air in guinea pigs. increased by beta2-adrenoreceptors, decreased by alpha adrenergic stimulation: Term. Bronchoconstriction induced by inhalation of cold air for 10 min was proposed to be mediated entirely by tachykinins released from sensory nerve endings, because it was blocked by pretreatment with the selective antagonist of NK2-receptors SR 48968 (10). BK increased cyclic guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle in vitro, whereas the selective tachykinin NK2-receptor agonist [ β Ala8]neurokinin A (4-10) was without effect. This involvement of kinins in the release of NO that follows cold-air inhalation is supported by a large body of evidence: bronchoconstriction induced by aerosolized BK is exaggerated by aerosolized (16) or intravenous NOS inhibitors; epithelium-dependent relaxation induced by BK in tracheal-tube preparations of guinea pigs was changed to contraction by l-NAME or l-NMMA (8); BK, via B2-receptor stimulation, increased cGMP in strips of guinea pig trachealis in vitro. These data should have direct relevance to a better understanding of the causes of PPHN, and allow the design of safer, more effective treatments. Capsaicin was dissolved in a solution containing 10% ethanol, 5% Tween 80, and 85% of 0.9% NaCl. The amplified signal from the transducer (Module M2102B; Electronics for Medicine) was displayed continuously on a video monitor (Model OM; Electronics for Medicine) and recorded with an oscillographic recorder (Model DASH-8; Astro-Med). Effect of inhalation of cold air (hatched columns) on the maximum increase in total pulmonary resistance (Rl) in guinea pigs anesthetized, artificially ventilated, and pretreated with atropine (1.4 μmol/kg intravenously). Because we found that this inhalation of cold air after inhibition of the l-Arg NOS pathway caused significant bronchoconstriction, we addressed the following questions: (1) Are kinins and tachykinins involved in the bronchoconstriction induced by short lasting inhalation of cold air; and (2) Is bronchorelaxant NO released by kinins, tachykinins, or cold air alone. 1992. It differs, in part, from cNOS in that its activation is calcium independent. PDE IV (cAMP specific) was Pretreatment with the tachykinin NK2-receptor antagonist SR 48968 (0.3 μmol/kg intravenously) blocked completely the bronchoconstriction produced by inhalation of cold air for 5 min after pretreatment with l-NAME (Figure 3a). The pathophysiologic relevance of the findings in the present study is unknown. It may further explain why some infants with PPHN do not respond initially, or do not maintain their response to inhaled NO. The temperature of cold air recorded at the distal end of the cannula prior to insertion in the trachea was 10° C when the room temperature was 26° C. To maintain a constant humidification of inhaled air, cold air was inhaled with a mist of nebulized 0.9% saline (Pulmo-Sonic 25; DeVillbiss, Somerset, PA).
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