Influence of body temperature on histamine-induced bronchoconstriction in guinea pigs

The effects of body temperature on histamine-induced bronchoconstriction were investigated in anesthetized, paralyzed, and mechanically ventilated guinea pigs. Four groups of guinea pigs were studied with constant body temperatures of 40, 38, 35, and 32 degrees C, respectively. Histamine was infused for 5 min at a rate of 50 ng.kg-1.s-1. Body cooling from 40 to 32 degrees C augmented the bronchomotor responses to histamine, which eventually rose almost fourfold. The enhancement of histamine-induced bronchoconstriction induced by body cooling was not suppressed by pretreating guinea pigs with 5 mg/kg hexamethonium or 5 mg/kg hexamethonium plus 3 mg/kg atropine; neither was the enhancement of histamine-induced bronchoconstriction suppressed in pithed guinea pigs, demonstrating that the autonomic nervous system is not involved in potentiating bronchoconstriction at low body temperatures. These results suggest that, at low body temperatures, increased airway responsiveness to histamine may be because of some direct effect of temperature on bronchial airway smooth muscle.     

Effect of atrial natriuretic peptide on bronchial tone in anesthetized rabbits

The effect of atrial natriuretic peptide (ANP) on histamine-induced bronchoconstriction was studied in vivo (in normoxic and in hypoxic rabbits) and in vitro. Thirty-two anesthetized rabbits, spontaneously breathing room air or 10% O₂, received infusions of ANP (20, 40, or 80 ng/min/kg normoxia; 20 ng/min/kg hypoxia) or the vehicle for 100 min. After 75 min of ANP infusion, bronchoconstriction was induced inhaling histamine; respiratory resistance (Rrs) was measured prior to and until 20 min posthistamine. The results show that the histamine-induced increase in Rrs was significantly reduced by ANP 80 ng/kg/min in normoxia, and by ANP 20 ng/kg/min in hypoxia. In vitro, ANP had no effect on tracheal and bronchial smooth muscle precontracted with histamine or acetylcholine. These results show that ANP can decrease a histamine-induced bronchoconstriction in vivo but not in vitro, suggesting an indirect mechanism of action.     

Influence of tidal volume on histamine-induced bronchoconstriction in guinea pigs

The effects of tidal volume amplitude on bronchopulmonary reactivity were investigated in three groups of 14 anesthetized paralyzed mechanically ventilated guinea pigs. Animals of group 1 served as control; in animals of group 2, both the sympathetic and parasympathetic nervous systems were blocked; in animals of group 3, only the parasympathetic system was blocked. In each group, the animals were randomly divided into two subgroups characterized by their ventilatory pattern: rate of 60/min with a 6-ml/kg tidal volume or rate of 40/min with a 9-ml/kg tidal volume. Bronchopulmonary reactivity to infused histamine was assessed by the respiratory compliance and conductance values measured during bronchoconstriction and expressed as a percentage of the corresponding basal values. In group 1 the animals ventilated with a 9-ml/kg tidal volume were found significantly less reactive than those ventilated with a 6-ml/kg tidal volume. This difference was abolished in groups 2 and 3. These results demonstrate that the effects of increased tidal volume on bronchopulmonary reactivity are vagally mediated and suggest that the decrease observed in histamine-induced bronchoconstriction is mainly due to reflex effects evoked by stretch receptor stimulation.     

Tracheal narrowing during histamine-induced bronchoconstriction

To determine whether tracheal narrowing accompanies histamine-induced bronchoconstriction and whether a cholinergic reflex is involved in the tracheal and bronchial responses, we determined specific pulmonary resistance between the carina and the pleura (sRL) and tracheal volume (Vtr) with an indicator-dilution technique in conscious sheep. Immediately postdelivery of histamine aerosol (7.5 mg histamine base) mean sRL increased by 223% (P less than 0.05), and mean Vtr decreased by 25% (P less than 0.05). The duration of the changes was similar, with a return to base-line values within 60 min. With increasing doses of histamine up to 30 mg, there was a corresponding increase in mean sRL, whereas the maximum effect on Vtr was already reached after 7.5 mg of histamine. Atropine (0.2 mg/kg iv) increased mean Vtr by 77% (P less than 0.05) and blunted the histamine effects on sRL, whereas the histamine effects on Vtr were abolished. Intravenous histamine or carbachol aerosol had similar effects on sRL and Vtr. We conclude that in conscious sheep 1) histamine produces both tracheal and bronchial constriction with a similar time course, 2) there is a base-line vagal tone in the trachea and not the bronchi, 3) the cholinergic reflex component of histamine-induced constriction is greater in the trachea than the bronchi, and 4) this difference between the trachea and bronchi is not due to differential aerosol deposition or cholinergic responsiveness.     

Susceptibility of dopamine D5 receptor targeted mice to cysteamine

BACKGROUND: Recently we demonstrated that gastric mucosa of rats can synthesize, store and release dopamine. Out of five different subtypes, mRNA of D5 (=D1b) dopamine receptor is very abundant in the gastric epithelium. D1 receptor selective dopamine agonists have been shown to protect against experimental gastro-duodenal lesions. AIMS: To test the hypothesis that protective effects of dopamine involve D5 receptors, mucosal lesions were induced in D5 receptor deficient (KO) and wild-type (WT) mice using cysteamine. Morphology and gastric acid secretion of D5 KO mice were also studied. METHODS: Single doses of 600 mg/kg, 300 mg/kg cysteamine or vehicle were administered subcutaneously to fasted animals. After 24 h, number and severity of gastro-duodenal lesions were analyzed. Basal and histamine-induced maximal gastric acid output were measured by a stomach-sac wash-through method. RESULTS: All the KOs in the 600 mg/kg cysteamine group died within 4 h showing symptoms of toxicity while three out of four WTs survived (P<0.05). Mortality after 300 mg/kg cysteamine was significantly higher in KOs versus the WTs: 6/14 versus 2/11, P<0.05. Gastric lesion-index was also significantly higher in KOs (median, middle quartile): four (3-9) versus 0 (0-0), P<0.05. Duodenal lesions did not develop from this single dose of cysteamine in either genotype. Basal and histamine-induced maximal gastric acid output were comparable in the two genotypes. CONCLUSIONS: This study demonstrates that loss of D5 receptor causes mucosal vulnerability and increased toxicity of cysteamine in genetically manipulated mice. Thus, D5 receptor subtype is indeed likely to be involved in protective effects of dopamine in the stomach.     

Effects of a contractile prostaglandin antagonist (L-640,035) upon allergen-induced bronchoconstriction in hyperreactive rats and conscious squirrel monkeys

The effects of an antagonist of contractile prostanoids, L-640,035 (3-hydroxymethyl-dibenzo[b,f]thiepin-5-dioxide) upon antigen-induced bronchoconstriction have been studied in inbred rats with non-specific bronchial hyperreactivity and in conscious squirrel monkeys. L-640,035 was a potent inhibitor of antigen-induced dyspnea (ED50 3.1 mg/kg p.o.) in inbred rats pretreated with methysergide (3 micrograms/kg i.v.) but produced no significant inhibition in untreated rats. Administration of L-640,035 (10 mg/kg p.o.) to conscious squirrel monkeys exposed to aerosols of ascaris antigen markedly inhibited changes in pulmonary resistance (RL) and dynamic compliance (CDYN). At a lower dose (1 mg/kg p.o.) the inhibition of changes in CDYN were similar but the effects on RL were reduced. It was concluded first that contractile prostanoids may be important mediators of antigen-induced bronchoconstriction and secondly that L-640,035 may be effective in human allergic asthma.     

Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors

The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv).     

Some pharmacological effects of prodolic acid, a new anti-inflammatory compound, indicative of inhibition of prostaglandin synthesis.

Prodolic acid, a new non-steroidal anti-inflammatory compound, inhibited bradykinin-induced bronchoconstriction but did not affect histamine-induced bronchoconstriction in the guinea pig. Prodolic acid potentiated the responses of the isolated rabbit vas deferens and portal vein to electrical stimulation without altering the response to noradrenaline. The potentiating effects of prodolic acid on the vas deferens were reversible but the potentiating effects in the portal vein were frequency-dependent. It is concluded that these effects of prodolic acid are probably related to its ability to inhibit prostaglandin biosynthesis.     

A possible role for PAF in allergen-induced late responses: modification by a selective antagonist

We determined whether platelet-activating factor (PAF) plays a role in allergen-induced airway responses by studying the effects of a selective PAF antagonist WEB-2086 on antigen-induced early and late airway responses in allergic sheep. In seven sheep, inhaled Ascaris suum produced significant early (282%) and late (176%) increases in specific lung resistance (sRL). WEB-2086 (1 mg/kg iv) given 20 min before antigen challenge did not affect the early response, but the peak late increase in sRL was only 37% over base line (P less than 0.05 vs. control). To study the mechanism by which PAF contributes to antigen-induced responses, we evaluated the effects of pharmacological probes on PAF-induced bronchoconstriction. Inhaled PAF (dose range 75-700 micrograms) caused reproducible (r = 0.781, P less than 0.05) increases in sRL in eight sheep. The PAF-induced bronchoconstriction was blocked by WEB-2086 (1 mg/kg iv) and by the leukotriene antagonist FPL-55712 (30 mg by aerosol); however, neither the cyclooxygenase blocker indomethacin (2 mg/kg iv) nor the histamine H1-antagonist chlorpheniramine (2 mg/kg iv) blocked the PAF response. WEB-2086, however, did not block bronchoconstriction induced by aerosol leukotriene D4, indicating that PAF acts indirectly through leukotrienes. Finally, we determined whether PAF could induce late airway responses. Inhaled PAF produced an immediate increase in sRL in all seven sheep tested, but late airway responses were observed in only three of the seven sheep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin-induced vascular and bronchial effects in pig airways: role in acute allergic responses.

The effects of endothelin (ET) agonists on airway mechanics and bronchial blood flow were studied as well as the effects of mixed ET-receptor antagonist bosentan on allergen-induced airway reactions in the pig. ET agonists [ET-1, ET-3, and the ET(B) receptor-selective agonist Sarafotoxin 6c (Sf6c)] were given as intravenous injections (0.4-200 pmol/kg) to eight anesthetized pigs. Bosentan (10 mg/kg iv) was then administered, and the injections were repeated. Only Sf6c caused a significant increase in airway resistance, and this response was blocked by bosentan. Sf6c and ET-1 (200 and 400 pmol/kg, respectively) were also given as aerosols to five pigs. Sf6c, but not ET-1, caused bronchoconstriction via this route. All agonists (intravenous) caused increases in bronchial vascular conductance, an effect that was blocked by an NO-synthase inhibitor (N(G)-nitro-L-arginine) but unaffected by a cyxlooxygenase inhibitor (diclofenac). Fourteen pigs were sensitized with ascaris suum antigen. Under anesthesia, eight pigs were pretreated with bosentan, and six pigs were controls. They were all challenged with allergen aerosol resulting in acute bronchoconstriction and elevation of ET-1 in bronchoalveolar lavage fluid. Bosentan did not affect the maximal acute airway obstruction but markedly increased baseline bronchial vascular conductance, suggesting a basal vascular tone regulated by ETs. In conclusion, ETs induce bronchoconstriction primarily via the ET(B) receptor in the pig. However, ETs are probably not involved in the allergen-induced acute bronchoconstriction in this model.     

Mechanisms of metabisulfite-induced bronchoconstriction: evidence for bradykinin B2-receptor stimulation.

Sodium metabisulfite (MBS) is a food preservative that can trigger bronchoconstriction in asthmatic subjects. Previous studies designed to identify the mechanisms involved in this response have yielded conflicting results. We noted certain similarities between the pharmacology of MBS-induced airway responses and those elicited by bradykinin (BK), another provocating agent in asthmatic subjects. Therefore we used allergic sheep to determine whether MBS-induced bronchoconstriction 1) had a pharmacology similar to that previously seen with BK in this model, including protection by a BK B2-receptor antagonist, NPC-567, and 2) was associated with increased concentrations of immunoreactive kinins in bronchoalveolar lavage. We measured specific lung resistance before and immediately after inhaled buffer and increasing concentrations of MBS (30 breaths of 25, 50, and 100 mg/ml) and calculated the concentration producing 100% increase in specific lung resistance over baseline (PC100). In seven sheep, geometric mean control PC100 was 33.1 mg/ml. Pretreatment with either the anticholinergic agent ipratropium bromide (180 micrograms; PC100 87.1 mg/ml) or the antiasthma drug nedocromil sodium (1 mg/kg aerosol; PC100 97.7 mg/ml) blocked the MBS-induced bronchoconstriction (P less than 0.05), whereas the histamine H1-receptor antagonist chlorpheniramine (2 mg/kg iv) was ineffective. Furthermore the MBS-induced bronchoconstriction was not affected by the neutral endopeptidase inhibitor thiorphan (40 breaths of a 1 mg/ml solution) or the angiotensin-converting enzyme inhibitor enalaprilat (2.5 mg aerosol). In six sheep the MBS-induced bronchoconstriction was completely blocked by NPC-567 (20 breaths, 5 mg/ml aerosol): after treatment with NPC-567 mean PC100 was 100 mg/ml compared with 57.5 mg/ml in the control trial (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a contractile prostaglandin antagonist (L-640, 035) upon allergen-induced bronchoconstriction in hyperreactive rats and conscious squirrel monkeys

The effects of an antagonist of contractile prostanoids, L-640,035 (3-hydroxymethyl-dibenzo[b,f]thiepen-5-dioxide) upon antigen-induced bronchoconstriction have been studied in inbred rats with non-specific bronchial hyperreactivity and in conscious squirrel monkeys. L-640,035 was a potent inhibitor of antigen-induced dyspnea (ED₅₀ 3.1 mg/kg p.o.) in inbred rats pretreated with methysergide (3 μg/kg i.v.) but produced no significant inhibition in untreated rats. Administration of L-640,035 (10 mg/kg p.o.) to conscious squirrel monkeys exposed to aerosols of ascaris antigen markedly inhibited changes in pulmonary resistance (R_L) and dynamic compliance (C_DYN). At a lower dose (1 mg/kg p.o.) the inhibition of changes in C_DYN were similar but the effects on R_L were reduced. It was concluded first that contractile prostanoids may be important mediators of antige-induced bronchoconstriction and secondly that L-640,035 may be effective in human allergic asthma.     

Inhibitory activity of nociceptin/orphanin FQ on capsaicin-induced bronchoconstriction in the guinea-pig

In vivo studies were conducted in the guinea-pig to investigate the activity of the selective ORL1 receptor agonist nociceptin/orphanin FQ against capsaicin-induced bronchoconstriction, a response mediated by the release of tachykinins from pulmonary sensory nerves. Anesthetized guinea-pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph, and pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were monitored. Intravenous administration of nociceptin/orphanin FQ (0.3 mg/kg) inhibited the capsaicin-induced bronchoconstriction. The new nonpeptide ORL1 receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) administered intravenously (1 mg/kg) produced a significant blockade of the inhibitory effect of nociceptin/orphanin FQ (0.3 mg/kg) on capsaicin-induced bronchoconstriction, whereas the nonselective opioid receptor antagonist naloxone (1 mg/kg) had no effect. Nociceptin/orphanin FQ (0.3 mg/kg) did not affect the bronchoconstriction induced exogenously by the tachykinin NK2 receptor agonist [beta-ala8]-neurokinin A (4-10). We conclude that nociceptin inhibits in vivo capsaicin-evoked tachykinin release from sensory nerve terminals in the guinea-pig by a prejunctional mechanism. This inhibitory action does not involve activation of opioid receptors.     

Antagonism of peptidoleukotrienes and inhibition of systemic anaphylaxis by RG 12525 in guinea pigs

RG 12525 was determined to be a specific, competitive and orally effective antagonist of the peptidoleukotrienes, LTC4, LTD4 and LTE4, in several assays utilizing guinea pigs. In vitro, RG 12525 competitively inhibited 3H-LTD4 binding to lung membranes (Ki = 3.0 +/- 0.3 nM) and competitively antagonized the spasmogenic activity of LTC4, LTD4 and LTE4 on lung strips (KB values = 3 nM) with greater than 8000 fold selectivity. In vivo, RG 12525 orally inhibited LTD4 induced wheal formation (ED50 = 5 mg/kg with a t1/2 = 10 hrs at 9 mg/kg), LTD4 induced bronchoconstriction (ED50 = 0.6 mg/kg), and anaphylactic death (ED50 = 2.2 mg/kg with a t1/2 = 7 hrs at 10 mg/kg) and antigen induced bronchoconstriction (ED50 = 0.6 mg/kg). RG 12525 represents a significant improvement in receptor affinity and oral efficacy and thus, is a valuable pharmacological tool to evaluate peptidoleukotrienes in allergic diseases.     

Teratogenicity of the antiallergic Sm 857 SE in rats versus rabbits

Sm 857 SE is an antiallergic drug chemically described as 11-Oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral-costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of 14C-Sm 857 SE in the rat fetus.     

Dysfunction of M2-muscarinic receptors in pulmonary parasympathetic nerves after antigen challenge.

The effect of antigen challenge on the function of neuronal M2-muscarinic autoreceptors in the lungs was studied in anesthetized guinea pigs. Guinea pigs were injected intraperitoneally with saline (control group) or ovalbumin (10 mg/kg) on days 1, 3, and 5. One group of sensitized animals was challenged on days 20-25 with aerosolized ovalbumin for 5 min/day (challenged group), while another group of the sensitized animals was not challenged (sensitized group). On day 26 the animals were anesthetized, paralyzed, tracheostomized, and artificially ventilated. Pulmonary inflation pressure (Ppi), tidal volume, blood pressure, and heart rate were recorded. Both vagus nerves were cut, and electrical stimulation of the distal portions caused bronchoconstriction (measured as an increase in Ppi) and bradycardia. In the control group, pilocarpine (1-100 micrograms/kg iv) attenuated vagally induced bronchoconstriction by stimulating inhibitory M2-muscarinic receptors on parasympathetic nerves in the lungs. Conversely, blockade of these receptors with the antagonist gallamine (0.1-10 mg/kg iv) produced a marked potentiation of vagally induced bronchoconstriction. These results confirm previous findings. In the challenged guinea pigs, pilocarpine did not inhibit vagally induced bronchoconstriction. Furthermore, gallamine did not potentiate vagally induced bronchoconstriction to the same degree as in the controls. In the group of animals that was sensitized but not challenged, the potentiation of vagally induced bronchoconstriction by gallamine was identical to the controls. There was no increase in baseline Ppi in the sensitized or challenged animals compared with the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary and cardiovascular changes in hyperreactive rats from citric acid aerosols

Administration of aerosols of citric acid to anesthetized spontaneously breathing hyperreactive rats produced reversible increases in respiratory rate (f) and pleural pressure (Ppl) accompanied by hypotension and bradycardia. In contrast, Fischer rats, which do not have bronchial hyperreactivity, failed to respond to citric acid aerosols. The effects of various treatments on citric acid-induced changes in f, Ppl and blood pressure were studied. Vagotomy, cromolyn sodium (1 and 10 mg/kg iv), mecamylamine, (2 mg/kg iv), FPL-55712 (3 mg/kg iv), and BW 755C (10 mg/kg iv) inhibited markedly the responses to citric acid, whereas atropine (2 mg/kg iv) produced weak inhibition. Methysergide (1 mg/kg iv), indomethacin (1 mg/kg iv), and a prostanoid antagonist, L-640,035, (5 mg/kg iv) were completely ineffective. The results suggest that citric acid-induced bronchoconstriction in hyperreactive rats may be reflex mediated and that leukotrienes may be involved in the response.     

Mechanisms of organophosphate insecticide-induced airway hyperreactivity

It has been suggested that pesticide exposure may be a contributing factor underlying the increased incidence of asthma in the United States and other industrialized nations. To test this hypothesis, airway hyperreactivity was measured in guinea pigs exposed to chlorpyrifos, a widely used organophosphate pesticide. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively. Mechanisms by which chlorpyrifos may cause airway hyperreactivity include inhibition of acetylcholinesterase (AChE) or dysfunction of M3 muscarinic receptors on airway smooth muscle or of autoinhibitory M2 muscarinic receptors on parasympathetic nerves in the lung. AChE activity in the lung was significantly inhibited 24 h after treatment with 390 mg/kg of chlorpyrifos, but not 7 days after injection of 70 mg/kg of chlorpyrifos. Acute exposure to eserine (250 microg/ml) also significantly inhibited lung AChE but did not potentiate vagally induced bronchoconstriction. Neuronal M2 receptor function was tested using the M2 agonist pilocarpine, which inhibits vagally induced bronchoconstriction in control animals. In chlorpyrifos-treated animals, pilocarpine dose-response curves were shifted significantly to the right, demonstrating decreased responsiveness of neuronal M2 receptors. In contrast, chlorpyrifos treatment did not alter methacholine-induced bronchoconstriction, suggesting that chlorpyrifos does not alter M3 muscarinic receptor function on airway smooth muscle. These data demonstrate that organophosphate insecticides can cause airway hyperreactivity in the absence of AChE inhibition by decreasing neuronal M2 receptor function.     

Low frequency-dependent mechanism of the M2 receptor function on vagally mediated bronchoconstriction in rabbits in vivo.

The present study was carried out to investigate whether there is the difference between low and high frequencies of vagal stimulation on the functional appearance of M2 receptors in the rabbit. The animals were anesthetized, artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose-dependent. Although administration of methoctramine (50 and 300 microg/kg), a selective M2 receptor antagonist, had no significant effect on ACh-induced bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn responses to vagal stimulation at 5-15 Hz but did not potentiate bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D-Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5-15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz. Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results suggest that M2 receptors function as the inhibitory receptors in the bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15 Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at a higher frequency (30 Hz) results in the release of SP from the lungs.     

Enalapril and diltiazem co-administration and respiratory side effects of enalapril

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.