Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitussive effects of SR 48968, a non-peptide tachykinin NK2 receptor antagonist, were investigated on citric acid-induced cough in the unanesthetized guinea-pig and compared with the effects of codeine. SR 48968 (0.01-0.3 mg/kg i.p.) inhibited in a dose-dependent manner the number of coughs induced by inhalation of an aqueous solution of citric acid with an ED50 of 0.1 mg/kg (0.17 mumol/kg). Under similar conditions, the codeine ED50 was 8 mg/kg (27 mumol/kg). Naloxone, an opioid receptor antagonist, abolished the effects of codeine but did not modify the effects of SR 48968. These data suggest that NK2 receptor stimulation might play an important role in the regulation of the cough reflex and that SR 48968 could be a potential antitussive agent.
 ...
PMID:Antitussive effect of SR 48968, a non-peptide tachykinin NK2 receptor antagonist. 811 16

gamma-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the mammalian CNS, is also found in peripheral tissues, including the lung. Recent pharmacological studies using selective ligands for GABAA and GABAB receptors demonstrate that of these two, the GABAB receptor is the important receptor subtype controlling lung functions. GABAB agonists inhibit a variety of responses in the airways, including neuronally induced cholinergic- and tachykinin-mediated smooth muscle contraction, microvascular leakage, anaphylactic bronchospasm and cough. Because these conditions are seen in certain respiratory diseases, such as asthma, a selective GABAB agonist may have therapeutic potential for the treatment of this respiratory disorder.
 ...
PMID:GABAB receptors in the lung. 838 86

In order to create a new drug for the treatment of respiratory diseases, such as asthma and chronic bronchitis, having a novel therapeutic mechanism, we have been trying to develop new compounds with neurokinin (NK)-receptor antagonistic effects. We used [3H]-substance P binding to guinea pig lung membrane for the first screening system and successfully discovered FK224 from a fermentation product and FK888 from chemical design studies using an octapeptide antagonist (D-Pro4,D-Trp7,9,10) SP4-11 as the parent compound. FK224 and FK888 showed different selectivities against the NK-receptor subtypes (NK1, NK2, NK3); FK888 was a highly potent NK1-selective antagonist, and FK224 was a NK1 + NK2 dual receptor antagonist. Neither compound had any activity on the NK3 receptor. In the in vivo experiments, FK224 and FK888 significantly inhibited the constriction and plasma extravasation in the airway induced by agonist injection. These compounds also showed inhibitory effects on the airway response induced by capsaicin and antidromic stimulation of vagus nerves. Furthermore, FK224 and FK888 were effective on the mucus secretion in the airway and the cough reflex induced by citric acid challenge. There were some differences in the effects of FK224 and FK888 in the in vivo experiments, and it was suggested that the NK1 receptor and NK2 receptor were mainly involved in neurogenic inflammation and airway constriction, respectively. FK224 and FK888 are now undergoing clinical studies to test the effectiveness of a NK antagonist in human respiratory diseases.
 ...
PMID:[Discovery and pharmacological properties of selective neurokinin-receptor antagonists, FK224 and FK888]. 852 64

To examine the mechanisms of an angiotensin-converting enzyme (ACE) inhibitor-induced cough in perimenopausal and postmenopausal women, cough responses to aerosols of capsaicin and citric acid were examined in four groups of female guinea pigs treated orally with danazol (D) (an agent decreasing plasma estrogen levels), cilazapril (C) (an inhibitor of ACE), both danazol and cilazapril (C+D), or without either drug (control group) for 4 to 5 wk. Capsaicin caused dose-dependent increases in the number of coughs in all four groups. C or D alone shifted dose-response curves to capsaicin (from 10(-7) M to 10(-3) M) to lower concentrations compared with the control, and C+D further shifted them. Likewise, the number of coughs induced by citric acid (3 x 10(-1) M; 2 min) was highest in animals treated with C+D and significantly higher in animals treated with C or D than in the control group. Aerosols of a selective substance P (SP) receptor antagonist FK 888 (10(-5) M; 2 min) inhibited capsaicin-induced cough in all four groups, and dose-response curves to capsaicin did not differ significantly at any concentrations among the four groups in the presence of FK 888 (p > 0.10). D decreased cyclic AMP levels in the trachea, irrespective of the combination of C. A beta 2-adrenoceptor agonist, procaterol, which is thought to inhibit SP release by elevation of cyclic AMP in sensory nerves, dose-dependently inhibited the number of coughs induced by capsaicin (10(-3) M) in animals treated with D. The present study suggests that SP is a common mechanism mediating increases in the sensitivity of cough reflex induced by both ACE inhibition and a decrease in plasma estrogen levels, and the additive effects of the two events may explain the high incidence of cough during ACE inhibitor therapy in perimenopausal and postmenopausal women.
 ...
PMID:Angiotensin-converting enzyme inhibitor and danazol increase sensitivity of cough reflex in female guinea pigs. 856 37

We investigated the effect of imidapril, a novel angiotensin-converting enzyme (ACE) inhibitor, on augmentation of airway microvascular leakage induced by bradykinin (BK) and substance P (SP) in guinea pigs and compared it with those of enalapril and captopril. The three ACE inhibitors significantly potentiated BK- and SP-induced airway microvascular leakage in a dose-dependent manner. In spite of the compatible or higher ACE inhibitory activity of imidapril, its potentiating activity in BK-induced leakage was lower than those of enalapril and captopril both by single administration (0.3-30 mg/kg, p.o.) and repeated administration for eight days (0.1-10 mg/kg/day, p.o.). The potentiating activities of the three ACE inhibitors were suppressed by pretreatment with a BK2-receptor antagonist, but not by neurokinin 1 and neurokinin 2 antagonists, suggesting that neurokinins may not be involved in BK-induced leakage under the conditions used. On the other hand, the potentiating effect of imidapril in SP-induced leakage was weaker than those of enalapril and captopril only after single high doses. The present study shows that the ACE inhibitors have different activity in potentiation of the airway microvascular leakage induced by BK, which may be ascribable to the difference in their inhibition of BK hydrolysis. This evidence may partly explain the smaller incidence of dry cough induced by imidapril compared with other ACE inhibitors when clinically used as antihypertensive drugs.
 ...
PMID:Difference among angiotensin-converting enzyme inhibitors in potentiating effects on bradykinin-induced microvascular leakage in guinea pig airways. 856 47

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.
 ...
PMID:Chronopharmacology of enalapril in hypertensive patients. 858 61

Fenspiride is a nonsteroidal anti-inflammatory agent, which we have previously shown to have an in vivo antibronchoconstrictor action in guinea pigs. We have currently studied this action using the constrictors Substance P, neurokinin A, citric acid and capsaicin in anaesthetized guinea-pigs. Fenspiride has also been reported to produce a subjective improvement in cough in patients. We have used a conscious guinea-pig model of cough as a more definitive method to study the effect of fenspiride on capsaicin- and citric acid-induced cough. Aerosolized fenspiride (1 mg.mL-1) caused a 58% reversal of capsaicin-induced bronchoconstriction; and i.v. fenspiride (1mg.kg-1) a 45% reversal of citric acid induced bronchoconstriction. Substance P- and neurokinin A-induced bronchoconstriction were unaffected by 1 mg.kg-1 i.v. fenspiride. Aerosolized fenspiride (1, 3 and 10 mg.mL-1) administered for 4 min reduced citric acid (300 mM) induced cough, but 0.1 mg.mL-1 was without effect. Pretreatment with aerosolized fenspiride (10 mg.mL-1) caused a shift in the citric acid dose response curve to the right. For citric acid-induced cough, the duration of action of aerosolized fenspiride (10 mg.mL-1) was found to be 5 and 15 min post-treatment. Aerosolized capsaicin (30 microM) induced cough was also reduced by 3 and 10 mg.mL-1 aerosolized fenspiride, but no significant effect was found with 1 mg.mL-1. We conclude that aerosolized fenspiride reduces capsaicin- and citric acid-induced bronchoconstriction as well as induced cough in guinea-pigs in vivo. Whether a pathway common to both cough and bronchoconstriction is the site of action of fenspiride remains to be established. We postulate that fenspiride, acting as an antitussive and antibronchoconstrictor agent, would be beneficial in the clinical situation for those patients with hyperresponsive airways.
 ...
PMID:Antitussive and antibronchoconstriction actions of fenspiride in guinea-pigs. 858 25

Angiotensin converting enzyme (ACE) -inhibitors inhibit degradation of inflammatory mediators substance P (SP) and bradykinin, which may further stimulate the synthesis of prostaglandins. The resulting increase in inflammatory mediators in tissues is suggested to be the reason for the dry cough, involving sensory C-fiber activation, among patients receiving ACE-inhibitor therapy. In the present study, the effect of an ACE-inhibitor, captopril, on ocular irritative responses was studied in the rabbit. Intravenous captopril decreased markedly the blood pressure and the intraocular pressure (IOP) modestly. Topical neutral formaldehyde elicits an irritative response in the eye mediated through sensory neuropeptides SP and calcitonin gene-related peptide (CGRP). Following topical neutral formaldehyde, the increase in IOP and breakdown of the blood-aqueous barrier were inhibited by captopril, while miosis was not affected. Cyclic AMP (cAMP) content in the aqueous humour was increased by captopril, and this increase was inhibited by indomethacin. Following YAG-laser anterior capsulotomy, captopril inhibited the increase in IOP, breakdown of the blood-aqueous barrier and miosis. The present study demonstrates that use of short-term administration of captopril prior to sensory nerve stimulation or YAG laser anterior capsulotomy does not enhance the ocular responses to these stimuli in the rabbit. In the present study, captopril inhibited these responses, at least partly by decreasing the blood pressure.
 ...
PMID:Effect of captopril on ocular irritative response to topical neutral formaldehyde and YAG-laser capsulotomy in the rabbit. 859 Feb 56

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.
 ...
PMID:The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics. 866 34

We compared the effects of a tachykinin NK1 receptor antagonist, FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N -phenylmethyl-3-(2-naphthyl)-L-alaninamide), and a tachykinin NK2 receptor antagonist, SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide]), on citric acid-induced cough and bronchoconstriction in conscious guinea pigs. FK888 and SR48968 inhibited the cough dose dependently. Combination of FK888 and SR48968 showed a small additive effect compared with that of FK888 or SR48968 alone. SR48968 but not FK888 inhibited the bronchoconstriction dose dependently. These results indicate that tachykinin NK1 receptors as well as tachykinin NK2 receptors are involved in the citric acid-induced cough response. The antitussive activity of the tachykinin NK1 receptor antagonist appeared not to depend on the anti-bronchoconstrictor effects.
 ...
PMID:Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs. 873 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>