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

In the conscious freely moving rat, the intrathecal (i.t.) injection of neuropeptide K (NPK; 0.65 to 6.5 nmol), at T-9 spinal cord level, produced dose-dependent and prolonged (> 3 h) increases in mean arterial blood pressure (MAP) and heart rate (HR). The cardiovascular response to 3.25 nmol NPK was less sustained when injected at T-2 level. The cardiovascular response to 3.25 nmol NPK (T-9 level) was correlated with increases in plasma levels of noradrenaline, adrenaline and neuropeptide Y (NPY), and was significantly reduced by the prior i.v. administration of inhibitors of either alpha-adrenoceptors (1 mg/kg, phentolamine), alpha 1-adrenoceptors (1 mg/kg, prazosin), beta 1-adrenoceptors (1 mg/kg, metoprolol) or angiotensin converting enzyme (10 mg/kg, captopril). The cardiovascular response to NPK was also significantly reduced in rats that had undergone, 48 h earlier, bilateral adrenalectomy or to a greater extent sympathectomy with 6-hydroxydopamine. Whereas NPK-induced release of adrenaline was abolished by adrenalectomy, that of neuropeptide Y and noradrenaline was blunted by either treatment. The results suggest that the cardiovascular effect of i.t. NPK is mediated by the stimulation of the sympathoadrenal system and the release of angiotensin. Sympathetic fibers may play a greater role than the adrenal medulla in the cardiovascular response to NPK. It appears that neuropeptide Y derives from both sympathetic fibers and adrenal medullae. Hence, if released in the spinal cord, NPK may play an important role in cardiovascular and sympathoadrenal regulation.
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PMID:Cardiovascular and sympathoadrenal responses to intrathecal injection of neuropeptide K in the conscious rat. 844 82

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.
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PMID:Chronopharmacology of enalapril in hypertensive patients. 858 61

A soluble 67 kDa angiotensin-converting enzyme (ACE) has been purified by lisinopril-Sepharose affinity column chromatography from adult houseflies, Musca domestica. The dipeptidyl carboxypeptidase activity towards benzoyl-Gly-His-Leu was inhibited by captopril (IC50 50 nM) and fosinoprilat (IC50 251 nM), two inhibitors of mammalian ACE, and was activated by Cl- (optimal Cl- concentration 600 mM). Musca ACE removed C-terminal dipeptides from angiotensin I, bradykinin [Leu5]enkephalin and [Met5]enkephalin and also functioned as an endopeptidase by hydrolysing dipeptideamides from [Leu5]enkephalinamide and [Met5]enkephalinamide, and a dipeptideamide and a tripeptideamide from substance P. Musca ACE was also able to cleave a tripeptide from both the N-terminus and C-terminus of luteinizing hormone-releasing hormone, with C-terminal hydrolysis predominating. Maximal N-terminal tripeptidase activity occurred at 150 mM NaCl, whereas the C-terminal tripeptidase activity continued to rise with increasing concentration of Cl- (0-0.5 M). Musca ACE displays properties of both the N- and C-domains of human ACE, indicating a high degree of conservation during evolution of the substrate specificity of ACE and its response to Cl-.
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PMID:The endopeptidase activity and the activation by Cl- of angiotensin-converting enzyme is evolutionarily conserved: purification and properties of an an angiotensin-converting enzyme from the housefly, Musca domestica. 867 80

Pig kidney aminopeptidase P (AP-P; EC 3.4.11.9) has been purified to homogeneity after its solubilisation from brush border membranes by phosphatidylinositol-specific phospholipase C. The effects of various activators and inhibitors of AP-P activity have been examined with a number of different substrates for the enzyme. The hydrolysis of bradykinin and ArgProPro is inhibited at Mn2+ concentrations above 10(-5) M, whereas the hydrolysis of other substrates (GlyProHyp, beta-casomorphin, substance P) is substantially activated, with 4-10 mM Mn2+ being optimal. The thiol reagent, p-chloromercuriphenylsulphonic acid, inhibits the hydrolysis of GlyProHyp but markedly activates the hydrolysis of bradykinin. A number of inhibitors of angiotensin converting enzyme (ACE; EC 3.4.15.1), previously reported to inhibit the hydrolysis of GlyProHyp, have no effect on the hydrolysis of bradykinin except in the presence of Mn2+. Differences were also observed in the degree of inhibition of GlyProHyp and bradykinin hydrolysis by EDTA and their reactivation by divalent cations. The hydrolysis of GlyProHyp follows Michaelis-Menten kinetics with a Km value of 2.7 mM. Bradykinin inhibits GlyProHyp hydrolysis with an I50 of 1.4 microM. The hydrolysis of bradykinin by AP-P reveals anomalous nonlinear kinetics indicative of negative cooperativity or the presence of more than one active site for this substrate. These results indicate that substrates for AP-P can be divided into 2 groups based on their responses to inhibitors and cation activators.
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PMID:Inhibition and metal ion activation of pig kidney aminopeptidase P. Dependence on nature of substrate. 869 47

Angiotensin-converting enzyme (ACE; EN 3.4.15.1) is a peptidyl dipeptide hydrolase that removes the carboxyl terminal His-Leu from angiotensin I to produce the octapeptide angiotensin II. In addition, ACE inactivates bradykinin, a vasodilator peptide/mediator of inflammation, as well as substance P, enkephalins and endorphins. Because of the importance of ACE and its active site-directed inhibitors in the pathogenesis and treatment of cardiovascular disorders such as hypertension and heart failure, ACE purification and assay are of clinical and commercial, as well as scientific interest. This review summarizes the historical development of ACE purification and assay methods and presents some innovative high-performance liquid chromatography-based techniques developed in our own laboratory for high yield and efficient purification and sensitive and specific assay of ACE.
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PMID:Purification and assay methods for angiotensin-converting enzyme. 881 75

1. The effect of pretreatment with bacterial endotoxin (LPS, 10 micrograms, i.v., 24 h) on the bradykinin B1 and B2 receptor-induced oedema in the rat paw, and the interaction of B1-mediated responses with other inflammatory mediators, was investigated. 2. Intraplantar (i.pl.) injection of the selective B1 agonist, des-Arg9-BK (DABK, 100 nmol) in naive animals pretreated with the angiotensin converting enzyme inhibitor, captopril caused a small increase in paw volume (0.04 +/- 0.003 ml, mean +/- s.e. mean, n = 6), while the B2-selective agonist, tyrosine8-bradykinin (T-BK, 3 nmol) induced marked oedema (0.36 +/- 0.02 ml). However, i.pl. injection of DABK (3-300 nmol) in rats pretreated with LPS (24 h beforehand) resulted in a marked dose- and time-related increase in paw volume, with mean ED50 of 24.1 nmol. In contrast, oedema caused by T-BK (3 nmol) was reduced by 79 +/- 4% in animals treated with LPS when compared with naive animals. 3. Oedema caused by prostaglandin E2 (PGE2, 10 nmol) was unaffected by LPS treatment, while oedema induced by histamine (100 nmol), 5-hydroxytryptamine (5-HT, 10 nmol) and substance P (SP, 3 nmol) was reduced (P < 0.05). 4. The selective B1 antagonist, des-Arg9[Leu8]-BK (100-300 nmol), produced dose-dependent inhibition of DABK (100 nmol)-induced paw oedema in LPS-treated animals with mean IC50 of 134 nmol, while the selective B2 antagonists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect. 5. Treatment of animals with dexamethasone (0.5 mg kg-1, s.c.) 24 or 48 h prior to LPS injection resulted in a graded inhibition of DABK (100 nmol)-induced oedema formation (58 +/- 3 and 82 +/- 2%, respectively), and almost reversed to control value oedema formation induced by T-BK (3 nmol) in LPS-pretreated rats. Cycloheximide (1 mg kg-1, s.c.) or indomethacin (2 mg kg-1, i.p.) pretreatment 24 and 1 h prior to LPS injection, respectively, markedly inhibited DABK (100 nmol)-induced paw oedema (98 +/- 2 and 50 +/- 4%, respectively). 6. Intraplantar injection of submaximal dose of DABK (10 nmol) in LPS-treated rats produced modest paw oedema (0.09 +/- 0.03 ml). However, i.pl. injections of PGE2, prostacyclin (PGI2), calcitonin-gene-related peptide (CGRP), SP, 5-HT, or platelet activating factor (PAF) (each 1 nmol), which alone caused little or no paw oedema, resulted in a potentiation of the DABK-induced oedema. The increases in paw volume (in ml) were: PGE2 + DABK (0.31 +/- 0.03), PGI2 + DABK (0.39 +/- 0.02), CGRP+DABK (0.35 +/- 0.04), DABK+SP (0.33 +/- 0.04), DABK + 5-HT (0.40 +/- 0.02) and DABK+PAF (0.38 +/- 0.016) ml. In contrast, histamine (1 nmol) was ineffective in potentiating the response to DABK. 7. The selective B1 receptor antagonist, DALBK (100-300 nmol), produced dose-dependent inhibition of paw oedema potentiation induced by co-injection of DABK and other mediators with mean ID50S (nmol) of: 180, 160, 139 and 135 in the presence of PGE2, PGI2, SP and 5-HT, respectively. 8. These results demonstrate that DABK-induced increase in paw volume in LPS-treated rats is probably mediated by induction of B1 receptors, associated with downregulation of B2 receptors. The induction of B1 receptors by LPS is sensitive to dexamethasone and cycloheximide treatment and requires activation of cyclo-oxygenase pathway. In addition, B1 receptors, when upregulated following LPS treatment, can interact in a synergistic manner with several inflammatory mediators such as PGI2, PGE2, CGRP, PAF and 5-HT. Such results indicate that induction of the B1 receptor might have a significant pathophysiological role in modulating chronic inflammatory diseases.
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PMID:Upregulation of B1 receptor mediating des-Arg9-BK-induced rat paw oedema by systemic treatment with bacterial endotoxin. 885 92

A dry, tickly and often bothersome cough is the most common adverse effect of ACE inhibitors. Recent studies indicate that cough may develop in around 10% of the patients treated with ACE inhibitors. In half of these patients, the ACE inhibitor has to be discontinued. Cough has emerged as a class effect occurring with all ACE inhibitors with no clear difference between the single substances. While ACE inhibition is safe in the vast majority of patients with obstructive airways disease, asthmatic symptoms or exacerbation of asthma as well as a rise in bronchial reactivity have been occasionally reported. ACE inhibition increases the cough reflex. The mechanisms underlying ACE inhibitor-induced cough are probably linked to suppression of kininase II activity, which may be followed by an accumulation of kinins, substance P and prostaglandins. Physicians should be aware that a dry cough is the most common adverse effect of ACE inhibitors and that this symptom may occur not necessarily shortly after institution of therapy but months or even a year later. Replacement by another ACE inhibitor should not be tried, since the cough will almost always recur on rechallenge with the same or another ACE inhibitor. After withdrawal of the ACE inhibitor, which is the treatment of choice, cough will resolve usually within a few days.
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PMID:ACE inhibitor-induced cough and bronchospasm. Incidence, mechanisms and management. 906 25

1. Substance P (SP) and capsaicin induced a mechanical hyperalgesia when injected into rat knee joints. 2. The NK1 receptor antagonists CP 99994 (10-100 nmol) and RP 67580 (0.1-1 nmol) blocked the development of, and also reversed, SP-induced hyperalgesia. Capsaicin (10 nmol)-induced hyperalgesia was blocked by capsazepine (0.5-5 nmol). 3. Capsaicin-induced hyperalgesia was prevented and reversed by the NK1 receptor antagonists CP 99994 (100 nmol) and RP 67580 (1 nmol). 4. The bradykinin B2 receptor antagonist icatibant (5 pmol) blocked the development of both SP and capsaicin-induced hyperalgesia. Icatibant (100 pmol kg-1, i.v.) also reversed an established SP and capsaicin-induced hyperalgesia. 5. Both low dose SP (1 nmol) and capsaicin (1 nmol)-induced hyperalgesia were potentiated by the kininase II inhibitor captopril (100 micrograms). 6. The B1 receptor antagonists desArg9Leu8-bradykinin (BK) (0.5-5 nmol) and desArg10[Hoe 140] (5-50 pmol) only blocked the development of SP-induced hyperalgesia for 30 min after administration. desArg9Leu8-BK (10 nmol kg-1 i.v.) did not reverse an established SP-induced hyperalgesia. 7. Capsaicin-induced hyperalgesia was blocked by desArg9Leu8-BK (0.5 nmol) and this antagonist also reversed an established capsaicin-induced hyperalgesia. 8. Interleukin-1 receptor antagonist (IL-1ra 0.1 microgram) reduced the development of SP-induced hyperalgesia up to 4 h after administration, but did not reverse an established hyperalgesia. IL-1ra (0.1 microgram) also blocked the development of and reversed an established capsaicin-induced hyperalgesia. 9. Indomethacin pretreatment (1 mg kg-1, s.c.) did not reduce the development of either SP- or capsaicin-induced hyperalgesia but following indomethacin-pretreatment desArg9Leu8-BK (10 nmol kg-1, i.v.) failed to reverse a capsaicin-induced hyperalgesia. 10. In conclusion, both SP and capsaicin can induce behavioural hyperalgesia when injected into the knee joint of rats. In addition, blockade of NK1, bradykinin B1, B2 and IL-1 beta receptors can substantially modulate this hyperalgesia.
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PMID:Substance P and capsaicin-induced mechanical hyperalgesia in the rat knee joint; the involvement of bradykinin B1 and B2 receptors. 886 63

1. The aim of this study was a pharmacological characterization of the multiple NANC inhibitory transmission systems producing relaxation of the circular muscle of guinea-pig proximal colon. In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (0.3 microM) and MEN 10627 (1 microM), respectively, electrical field stimulation (EFS) produced a frequency-dependent (0.1-3 Hz) relaxation. During a cumulative frequency-response curve, the maximal relaxant effect was produced at 3 Hz and approached the maximal relaxation to 1 microM isoprenaline. In the presence of both apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM), EFS failed to evoke relaxation up to 1 Hz; at 1-10 Hz, a slowly developing relaxation ensured which approached 50% of the Emax to isoprenaline. The EFS-evoked NANC relaxation, either in the presence or absence of apamin and L-NOARG, was unaffected by in vitro capsaicin pretreatment (10 microM for 15 min). 2. Three protocols of EFS were developed for further pharmacological analysis: (a) EFS at 1 Hz for 5 s in the presence of L-NOARG, producing a transient fast apamin-sensitive relaxation; (b) EFS at 1 Hz for 5 s in the presence of apamin, producing a transient fast L-NOARG-sensitive relaxation; and (c) EFS at 10 Hz for 5 s in the presence of both apamin and L-NOARG, producing a transient but slowly developing and more sustained relaxation. 3. The neutral endopeptidase inhibitor, thiorphan (1-10 microM), enhanced and prolonged the apamin- and L-NOARG-resistant NANC relaxation produced by EFS at 10 Hz, without affecting that evoked at 1 Hz in the presence of apamin or L-NOARG. The angiotensin converting enzyme inhibitor, captopril (1-10 microM) was without effect. 4. The cAMP analogue inhibitor of protein kinase A, Rp-cAMPs (100-300 microM) significantly reduced and shortened the NANC relaxation produced by 10 Hz EFS in the presence of L-NOARG without affecting that produced by 1 Hz EFS in the presence of apamin or L-NOARG. 5. The inhibitor of sarcoplasmic reticulum Ca-ATPase, cyclopiazonic acid (CPA, 3-10 microM for 60 min) abolished the 1 Hz EFS-induced relaxation in the presence of L-NOARG, and greatly inhibited that produced by 10 Hz EFS in the presence of both apamin and L-NOARG. The relaxation produced by 1 Hz EFS in the presence of apamin was inhibited by about 32% at 10 microM only. 6. Nifedipine (1 microM) did not affect the EFS-induced NANC relaxations. In the presence of nifedipine, tetraethylammonium (TEA, 1 mM) enhanced the 1 Hz EFS-induced relaxation in the presence of L-NOARG (158% of control) and that produced by 10 Hz EFS in the presence of apamin and L-NOARG (215% of control) while that evoked by 1 Hz EFS in the presence of apamin was slightly affected (109% of control). 7. In the presence of atropine, guanethidine, SR 140333 and MEN 10627, bath application of human vasoactive intestinal polypeptide (VIP, 0.1 nM-10 nM) produced a concentration-dependent, slowly developing relaxation of colonic strips. The relaxation to VIP was unaffected by apamin (0.3 microM), L-NOARG (100 microM), nifedipine (1 microM) or nifedipine plus TEA (1 mM); it was inhibited by CPA (10 microM) and Rp-cAMPs (100 microM) and was potentiated by thiorphan (10 microM). 8. The putative VIP receptor antagonist, VIP(10-28) (10 microM) did not affect the VIP-induced relaxation nor the NANC relaxation to 10 Hz EFS in the presence of apamin and L-NOARG. 9. The present findings provide evidence that three distinct NANC inhibitory mechanisms mediate relaxation of the circular muscle of the guinea-pig proximal colon. The first system provides a fast relaxation in response to low frequency of stimulation and may involve the action of a transmitter(s) (possibly ATP) which mobilizes intracellular Ca2+ from sarcoplasmic reticulum leading to the activation of apamin-sensitive K+ channels. The second system likewise provides a fast relaxation of the colon in
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PMID:Characterization of the apamin- and L-nitroarginine-resistant NANC inhibitory transmission to the circular muscle of guinea-pig colon. 888 60

In anesthetized, mechanically ventilated guinea pigs, infusion of captopril (1 mg/kg/h), an angiotensin converting enzyme inhibitor, significantly enhanced bronchoconstriction induced by intravenous injection of bradykinin (BK; 0.1-30 nmol/kg). Pretreatment of guinea pigs with capsaicin (100 mu g/kg) slightly suppressed the bronchoconstriction by BK alone and almost all of the enhancement of BK-induced bronchoconstriction by captopril was suppressed. Intravenous injection of substance P (SP; 0.1-100 nmol/kg), neurokinin A (NKA; 0.1-30 nmol/kg) and neurokinin B (NKB; 0.1-30 nmol/kg) also induced dose-dependent bronchoconstriction but captopril treatment enhanced only the bronchoconstriction induced by SP. BK degradation in bronchoalveolar lavage fluid (BALF) in vitro was significantly suppressed by captopril (p < 0.05). Captopril infusion to guinea pigs significantly increased the levels of BK, SP, and NKA in BALF after BK injection (p < 0.05). FK224, an NK1 and NK2 receptor antagonist and SR 48968, an NK2 receptor antagonist, significantly suppressed the bronchoconstriction induced by BK alone (p < 0.01 and p < 0.05, respectively) as well as the enhancement by captopril (p < 0.01). It can be concluded that the enhancement of BK-induced bronchoconstriction by captopril was attributable to inhibition of the degradation of BK itself and thereby enhanced release of NKA and partly of SP from sensory nerves by BK.
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PMID:Role of tachykinins in enhancement of bradykinin-induced bronchoconstriction by captopril. 890 88


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