Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.
 ...
PMID:Tachykinin-induced dyspnea in conscious guinea pigs. 137 29

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic construction of guinea-pig tracheal smooth muscle. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on constriction induced by the non-immunological mast cell degranulator-compound 48/80. Phosphoramidon produced significant leftward shift of the compound 48/80 concentration-response curve with corresponding decrease in the EC50 value from 51 (28-80) micrograms/ml to 42 (20-72) micrograms/ml. When added during the compound 48/80-induced constriction, phosphoramidon significantly increased the magnitude of this constriction by 69.7% after 30 min, and 78.9% after 45 min. Phosphoramidon was ineffective in tracheal rings from tachykinin-depleted guinea pigs. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) and leukotriene receptor antagonist (ICI 198.615, 5 microM) significantly diminished the contractile response to compound 48/80 and prevented a phosphoramidon-dependent increase of this constriction. These results suggest that compound 48/80 induces the release of tachykinins by the stimulatory activity of histamine and leukotrienes. Anaphylactic release of tachykinins would therefore not depend directly on the antigen-antibody reaction.
 ...
PMID:Inhibition of neutral endopeptidase potentiates compound 48/80-induced constriction of guinea-pig tracheal smooth muscle. 754 50

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.
 ...
PMID:Phosphoramidon augments contraction of guinea pig tracheal smooth muscle induced by histamine and leukotriene-D4. 811 Dec 47

In vertebrates the effects of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidase 24.11 (enkephalinase), which cleaves the Gly-Phe bonds in both methionine- and leucine-enkephalin. SCH 34826 ((S)-N-[n-[1-[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine-B-alanine) is a potent, highly specific, enkephalinase inhibitor that has marked analgesic effects in mammals. The present study examined the effects of SCH 34826 on opioid-mediated aversive thermal (nociceptive) response of an invertebrate, the land snail, Cepaea nemoralis. SCH 34828 had significant, dose-related antinociceptive effects in Cepaea that were reduced by naloxone and completely blocked by the specific data opiate antagonist, ICI-174,864, and only weakly affected by the specific kappa opiate antagonist nor-binaltrophimine. These findings with SCH 34826 suggest that an enkephalinase similar to that in vertebrates is present and involved in the mediation of opioid (enkephalin) activity in the snail, Cepaea.
 ...
PMID:Antinociceptive effects of the enkephalinase inhibitor, SCH 34826, in the snail, Cepaea nemoralis. 823 22

The effects of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidase 24.11 ("enkephalinase"), which cleaves the Gly-Phe bonds in Met- and Leu-enkephalin. SCH 34826 [(S)-N-[n-[1-[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]carbonyl]-2-phenylethyl]-L-phenyl-alanine-B-alanine] is a potent, highly specific, enkephalinase inhibitor that has marked analgesic effects in laboratory rodents. The present study compared the effects of SCH 34826 on nociception and restraint stress-induced opioid analgesia in reproductive adult male and female deer mice, Peromyscus maniculatus. SCH 34826 had significantly greater antinociceptive actions and facilitatory effects on stress-induced analgesia in male than female mice. These antinociceptive effects of SCH 34826 were reduced by the general opioid antagonist naloxone and completely blocked by the specific delta opioid receptor antagonist, ICI 174,864, and nonsignificantly affected by the mu and kappa opioid receptor antagonists, beta-funaltrexamine and nor-binaltorphimine, respectively. These results show that there are sex differences in the effects of the enkephalinase inhibitor, SCH 34826, on opioid-mediated antinociception and that these sex differences are associated with delta opioid mechanisms.
 ...
PMID:Sex differences in the antinociceptive effects of the enkephalinase inhibitor, SCH 34826. 830 54

Bradykinin has been implicated as a mediator of the acute pathophysiological and inflammatory consequences of respiratory tract infections and in exacerbations of chronic diseases such as asthma. Bradykinin may also be a trigger for the coughing associated with these and other conditions. We have thus set out to evaluate the pharmacology of bradykinin-evoked coughing in guinea pigs. When inhaled, bradykinin induced paroxysmal coughing that was abolished by the bradykinin B2 receptor antagonist HOE 140. These cough responses rapidly desensitized, consistent with reports of B2 receptor desensitization. Bradykinin-evoked cough was potentiated by inhibition of both neutral endopeptidase and angiotensin-converting enzyme (with thiorphan and captopril, respectively), but was largely unaffected by muscarinic or thromboxane receptor blockade (atropine and ICI 192605), cyclooxygenase, or nitric oxide synthase inhibition (meclofenamic acid and N(G)-nitro-L-arginine). Calcium influx studies in bronchopulmonary vagal afferent neurons dissociated from vagal sensory ganglia indicated that the tachykinin-containing C-fibers arising from the jugular ganglia mediate bradykinin-evoked coughing. Also implicating the jugular C-fibers was the observation that simultaneous blockade of neurokinin2 (NK2; SR48968) and NK3 (SR142801 or SB223412) receptors nearly abolished the bradykinin-evoked cough responses. The data suggest that bradykinin induces coughing in guinea pigs by activating B2 receptors on bronchopulmonary C-fibers. We speculate that therapeutics targeting the actions of bradykinin may prove useful in the treatment of cough.
 ...
PMID:Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs. 2700 Aug 1