Tachyphylaxis to inhaled aerosolized histamine in anesthetized dogs

Three consecutive dose-response curves to inhaled aerosolized histamine, separated by 1-h intervals, were obtained in 20 anesthetized mongrel dogs. In general, successive histamine dose-response curves shifted progressively rightward. Changes in pulmonary resistance (RL) and dynamic compliance (Cdyn) in response to low concentrations of histamine were reproducible, but responses to high concentrations (sufficient to at least double RL or decrease Cdyn by at least 30%) decreased on successive dose-response curves. The concentration of histamine required to double RL increased significantly (P less than 0.05) from 1.01 mg/ml on the first to 1.62 and 2.02 mg/ml on the second and third dose-response curves. In contrast, consecutive methacholine dose-response curves were not significantly different. Indomethacin pretreatment (5 mg/kg iv) prevented histamine tachyphylaxis, whereas atropine (4 mg iv) did not. However, indomethacin did not alter base-line pulmonary mechanics or histamine responsiveness as measured on the first dose-response curve. We conclude that tachyphylaxis to inhaled aerosolized histamine occurs in anesthetized dogs. Our results are consistent with an important role for endogenous prostaglandins in modulating the airway responses to repeated histamine exposures.     

Differential responses of the airways and pulmonary tissues to inhaled histamine in young dogs

Airway and pulmonary tissue responses to aerosolized histamine were studied in five mongrel puppies (8-10 wk old). Alveolar pressure was measured by use of alveolar capsules and respiratory mechanics calculated during tidal ventilation and flow interruptions. Aerosolized histamine caused an increase in the tissue viscoelastic properties, which was measured as an increase in pulmonary resistance during tidal ventilation. An increase in stress recovery of the pulmonary tissues was measured with the interrupter technique after aerosolized histamine. These data demonstrate that aerosolized histamine caused an increase in the tissue viscoelastic properties. The most reasonable explanation for the mechanism of this increase would seem to be via reflex pathways stimulated by centrally located receptors.     

Activation of histamine H3 receptors inhibits renal noradrenergic neurotransmission in anesthetized dogs

To investigate the possible involvement of histamine H(3) receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H3-receptor agonist, and thioperamide (Thiop), a selective H3-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 microg x kg(-1) x min(-1)) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 microg x kg(-1) x min(-1)) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H1-receptor antagonist) or cimetidine (a selective H2-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.     

Tachyphylaxis to inhaled histamine in asthmatic subjects

The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.     

Respiratory response to partial paralysis in anesthetized dogs

The ability to maintain alveolar ventilation is compromised by respiratory muscle weakness. To examine the independent role of reflexly mediated neural mechanisms to decreases in the strength of contraction of respiratory muscles, we studied the effects of partial paralysis on the level and pattern of phrenic motor activity in 22 anesthetized spontaneously breathing dogs. Graded weakness induced with succinylcholine decreased tidal volume and prolonged both inspiratory and expiratory time causing hypoventilation and hypercapnia. Phrenic peak activity as well as the rate of rise of the integrated phrenic neurogram increased. However, when studied under isocapnic conditions, increases in the severity of paralysis, as assessed from the ratio of peak diaphragm electromyogram to peak phrenic activity, produced progressive increases in inspiratory time and phrenic peak activity but did not affect its rate of rise. After vagotomy, partial paralysis induced in 11 dogs with succinylcholine also prolonged the inspiratory burst of phrenic activity, indicating that vagal reflexes were not solely responsible for the alterations in respiratory timing. Muscle paresis was also induced with gallamine or dantrolene, causing similar responses of phrenic activity and respiratory timing. Thus, at constant levels of arterial CO2 in anesthetized dogs, respiratory muscle partial paralysis results in a decrease in breathing rate without changing the rate of rise of respiratory motor activity. This is not dependent solely on vagally mediated reflexes and occurs regardless of the pharmacological agent used. These observations in the anesthetized state are qualitatively different from the response to respiratory muscle paralysis or weakness observed in awake subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway responses to inhaled ouabain and histamine in conscious guinea pigs

Tracheal Na+-K+-ATPase activity is positively correlated with in vivo airway responsiveness to histamine. We wondered whether this were a chance association or whether it was directly related to the mechanism of hyperreactivity. Therefore, we obtained dose-response curves to aerosols of histamine and ouabain in guinea pigs to determine whether an in vivo relationship existed between the excitatory effects of histamine and the enzyme-inhibiting effect of ouabain. Airway responsiveness to ouabain was measured as the ouabain concentration producing a 30% decrease in specific airway conductance (ED30) or that producing a half-maximal response (ED50). Responsiveness to histamine was measured either as ED30 or as ED50. Significant positive correlations were noted between the log ED50 of ouabain and log histamine ED30 or ED50 (r = 0.81 and 0.83, respectively; P less than 0.001), and between log ouabain ED30 and log histamine ED30 and ED50 (r = 0.76 and 0.77, respectively; P less than 0.002). Pretreatment with ouabain increased airway responsiveness to histamine (P less than 0.05). We suggest that in hyperreactive airways Na+-K+-ATPase serves a homeostatic function of preventing Na+ and Ca2+ loading of the cell and that it is not directly responsible for the hyperreactivity.     

Distribution of pulmonary responsiveness to aerosol histamine in dogs

Dose-response curves to aerosol histamine in 102 anesthetized, intubated, spontaneously breathing dogs revealed a spectrum of airway responsiveness with a greater than 40-fold difference between the most and the least sensitive animals. The frequency distribution of responses fits a log normal distribution. No correlation was found between sex, age, or control values of dynamic compliance (Cdyn) and lung resistance (RL) and the dose of histamine required to cause a response. Repetitive studies in 17 dogs observed for up to 20 mo showed that the dose at which an individual dog would respond was reproducible within a narrow range and that the differences between dogs were highly significant (P greater than 0.001). The long-term reproducibility of the response to aerosol histamine in individual dogs suggests that short-term reversible airway insults are not responsible for the range in responses noted between animals.     

Nonhomogeneity of lung response to inhaled histamine assessed with alveolar capsules

To assess the homogeneity of airway responses to inhaled histamine we examined regional alveolar pressure excursions (PA) arising from small-amplitude oscillations applied at the airway opening (Pao). In five anesthetized and vagotomized dogs the sternum was split and the anterior right lung field exposed. PA was sampled using four capsules affixed to the right apical and middle lobes while lung impedance (ZL) and airway impedances (Zaw) were measured during conventional tidal breathing and during forced oscillations (2-60 HZ at 10 cmH2O distending pressure). During tidal breathing after exposure to aerosol histamine regional PA's could be separated into three groups by plotting Lissajous figures of PA vs. Pao: PA in phase with Pao (no looping), PA lagging Pao (moderate looping), and PA decreasing while Pao was increasing and vice versa (paradoxical looping), suggesting unresponsive, responsive, and closed pathways, respectively, between the airway opening and specific alveolar zones. During high-frequency oscillation the corresponding PA spectra were markedly different from control spectra and revealed resonant amplification, overdamped resonance, and marked attenuation, respectively. With induced bronchospasm resonant amplification of PA was damped on average. However, the more obstructed and closed pathways were protected from resonant amplification, and the more open (nonlooping) pathways were subjected to resonant amplification greater than in the control state. In spite of this markedly nonhomogeneous behavior, frequency dependence of ZL was consistent with the model by Mead (J. Appl. Physiol. 26: 670-673, 1969), which ignores nonhomogeneity of peripheral compartments. These data demonstrate that the response of airways to inhaled histamine is nonhomogeneous but that frequency dependence of ZL above 2 Hz is not sufficient to characterize this nonhomogeneity.