cp-99994 and icatibant

We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of losartan (5mM), lisinopril (1mM), bradykinin (0.05 mM), HOE-140 (0.2mM, a bradykinin B2 receptor antagonist) and CP-99,994 (1mM, an NK1 receptor antagonist) were performed into the caudal nucleus tractus solitarii, the predominant site of termination of cough-related afferents. Lisinopril, but not losartan increased the cough number. This effect was reverted by HOE-140 or CP-99,994. Cough potentiation was also induced by bradykinin. The results support for the first time a central protussive action of lisinopril mediated by an accumulation of bradykinin and substance P.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Citric Acid; Cough; Lisinopril; Male; Microinjections; Neurokinin-1 Receptor Antagonists; Peptidyl-Dipeptidase A; Physical Stimulation; Piperidines; Rabbits; Receptor, Bradykinin B2; Receptors, Neurokinin-1; Reflex; Solitary Nucleus

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

Topics: Administration, Inhalation; Adrenergic beta-Antagonists; Airway Resistance; Animals; Asthma; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Citric Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Piperidines; Receptors, Neurokinin-2

We have investigated the effects of CP-99,994 [(+)-(2s,3s)-3-(2-methoxybenzylamino)-2-phenylpiperidine], a tachykinin NK1 receptor antagonist, HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4 H-benzo[4,5]cycloheptal[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell-stabilizing properties, on microvascular leakage induced by gaseous formaldehyde. Extravasation of Evans blue dye into airway tissues was used as an index of airway microvascular leakage. Leakage of dye in the trachea and main bronchi increased significantly in a concentration-dependent fashion after 10 min inhalation of formaldehyde (5-45 parts per million (ppm)). The airway response induced by 10 min inhalation of 15 ppm formaldehyde (trachea: 119.5 +/- 13.9 ng/mg, n = 7; main bronchi: 139.6 +/- 7.9 ng/mg, n = 7) was abolished by the administration of CP-99,994 (3 and 6 mg/kg i.v.), but not by the administration of HOE 140 (0.65 mg/kg i.v.) nor ketotifen (1 mg/kg i.v.). The increase in vascular permeability induced by formaldehyde in the rat airway was mediated predominantly by NK1 receptor stimulation. Activation of bradykinin receptors and mast cells did not appear to play an important role in this airway response.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Bronchi; Capillary Leak Syndrome; Capillary Permeability; Formaldehyde; Histamine H1 Antagonists; Ketotifen; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Specific Pathogen-Free Organisms; Trachea

1. The effect of bradykinin, capsaicin, substance P and low pH medium on plasma extravasation in the guinea-pig conjunctiva has been studied. Evans blue dye was measured in the conjunctiva after local instillation of the agents into the conjunctival sac. 2. Bradykinin (2-50 nmol), capsaicin (20-50 nmol) and substance P (0.5-5 nmol) caused a dose-dependent increase in plasma extravasation with the following order of potency: substance P > bradykinin = capsaicin. The effect of capsaicin (50 nmol) and substance P (5 nmol) was abolished by the tachykinin NK1 receptor antagonist, CP-99,994 (8 mumol kg-1, i.v.) (P < 0.01), whereas CP-100,263 (8 mumol kg-1, i.v.) the inactive enantiomer of CP-99,994 was without effect. CP-99,994 inhibited by 70% (P < 0.01) the effect of bradykinin. 3. The kinin B2 receptor antagonist, Hoe 140 (icatibant, 10 nmol kg-1, i.v.) abolished the response to bradykinin (50 nmol) (P < 0.01), but did not affect the responses to capsaicin (50 nmol) or substance P (5 nmol). Plasma extravasation induced by low pH medium (pH 1) was abolished by CP-99,994 (P < 0.01) and by Hoe 140 (P < 0.01). 4. The present findings suggest that: endogenous or exogenous tachykinins increase plasma extravasation in the guinea-pig conjunctiva by activation of NK1 receptors; bradykinin-induced plasma extravasation is mediated by tachykinin release from sensory nerve endings; low pH media cause plasma extravasation via release of kinins that by activation of B2 receptors release tachykinins from sensory nerve endings.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Capsaicin; Conjunctiva; Guinea Pigs; Hydrogen-Ion Concentration; Male; Neuritis; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Bradykinin; Substance P; Tachykinins