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)

1 Behavioural and biochemical effects of substance P (SP, 1 to 10 mug) administered in a small volume to discrete areas of the rat's brain were studied by means of a refined microinjection technique.2 SP injected unilaterally into the zona reticulata of the substantia nigra elicited dose-dependent contraversive circling and an increase in dopamine turnover in the ipsilateral striatum. SP applied to the zona compacta or zona lateralis, or to the medial lemniscus, evoked ipsiversive turning with a fall in dopamine turnover and a rise in 5-hydroxytryptamine (5-HT) turnover in the corresponding striatum.3 In both cases the onset of turning was immediate, reached a peak at about 5 min and lasted for 10 min. Both types of behaviour were blocked by haloperidol and exaggerated by nialamide.4 Unilateral injections of SP given into the crus cerebri, zona incerta, caudate nucleus, putamen or globus pallidus did not modify the animal's behaviour.5 In rats pretreated with apomorphine or amphetamine, SP induced contraversive circling which was followed by locomotion in the opposite direction.6 Turning responses to a second dose of SP were diminished at 3 h and reproducible at 24 h after the first injection.7 Bacitracin (50 ng) injected into the zona reticulata caused ipsiversive turning. Larger intranigral doses of bacitracin (10 mug), as with intracisternal SP (10 mug), evoked ;barrel rotation'.8 No changes in the free concentrations of aspartate, glutamate, gamma-aminobutyric acid, glycine or alanine were detected in any brain region following an intracisternal injection of 10 mug SP, although glutamine levels were elevated throughout the brain 30 to 60 min later.
 ...
PMID:Effects of substance P injected into the substantia nigra. 42 15

We determined changes in prolyl endopeptidase activity in developing rat brain. A new and highly sensitive fluorogenic substrate, 7-(succinyl-Gly-Pro)-4-methylcoumarinamide, was used for determination of the enzyme activity. The enzyme activity per brain increased until 2 weeks of age, and then decreased during maturation. The enzyme was purified about 7800-fold from the brain of the rat at 2 or 3 weeks of age. The enzyme has a pH optimum of 5.8 to 6.5, and an approximate molecular weight of 70,000. The enzyme activity was completely inhibited by low concentrations of diisopropylfluorophosphate and partially inhibited by high concentrations of phenylmethanesulphonylfluoride, which are potent serine protease inhibitors. Moreover, thiolblocking agents and some heavy metals also have a strong effect on the activity. Bacitracin was found to be a potent inhibitor, with an IC50 value of 2.5 x 10(-6) M at 0.5 mM of the substrate. The enzyme was proved to hydrolyze the NH2-terminal tetrapeptide. Arg1-Pro2-Lys3-Pro4, from substance P to produce the heptapeptide, Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-CONH2. The Km value of the hydrolysis of substance P was 1.0 mM. This enzyme may be related to the regulation of substance P in the brain, and to the development of neurones by forming the tetrapeptide because the tetrapeptide has almost the same effect as substance P on the neurite extension of neuroblastoma.
 ...
PMID:Changes in prolyl endopeptidase during maturation of rat brain and hydrolysis of substance P by the purified enzyme. 616 Dec 26

The pharmacology of the early and delayed phases of the neurogenic oedema responses to electrical stimulation of the saphenous nerve was studied in anesthetized rats using a quantitative Evans blue dye leakage technique. The immediate response to 5 min nerve stimulation was not reduced by aprotinin or mepyramine in combination with methysergide. However the response measured 10 min later and also that to 15 min nerve stimulation were reduced by these agents indicating that kinins and mast cell amines might be released after some delay, but they did not contribute significantly to the early phase of the response. Results with indomethacin indicated that prostaglandins were not involved in the later phase of the response. Bacitracin which has been reported to potentiate the sialogogic effect of substance P, the most likely candidate for primary mediator of neurogenic oedema, was without effect on the early phase of the response. Morphine, which has been suggested to inhibit stimulus-evoked substance P release from primary afferent terminals, reduced the early phase of the neurogenic oedema response but it also reduced blood pressure. Both effects were abolished by naloxone and thus it is likely that the reduction in the neurogenic oedema response was due to the depressor action of morphine. In confirmation of previous findings, capsaicin pretreatment of both adult rats and rats as neonates resulted in marked reduction of the neurogenic oedema response without effect on the vascular permeability response to substance P.
 ...
PMID:Pharmacology of the neurogenic oedema response to electrical stimulation of the saphenous nerve in the rat. 723 72

The distribution of tachykinin receptors in guinea-pig airways was studied using newly developed selective radioligands, [125I][Lys5,Tyr(I2)7,MeLeu9,Nle10]neurokinin A-(4-10) for NK2 receptors and [125I]Bolton-Hunter-[Sar9,Met(O2)11]substance P for NK1 receptors. Optimum incubation times were 60 and 45 min for tachykinin NK2 and NK1 sites, respectively, in slide-mounted sections of guinea-pig lung. Bacitracin (40 micrograms/ml) greatly reduced specific binding of [125I][Lys5,Tyr(I2)7,MeLeu9,Nle10]neurokinin A-(4-10), whereas phosphoramidon (1 and 10 microM) and bacitracin (40 micrograms/ml) significantly increased the specific binding of [125I]Bolton-Hunter-[Sar9,Met(O2)11]substance P. Dense specific binding of [125I]Bolton-Hunter-[Sar9,Met(O2)11]substance P occurred over bronchial smooth muscle of large and small airways, with moderate binding on bronchial epithelium and over pulmonary arterial smooth muscle. Moderate specific binding of [125I][Lys5,Tyr(I2)7, MeLeu9,Nle10]neurokinin A-(4-10) was associated with bronchial smooth muscle of mainly large airways but not with other histological regions. This is the first autoradiographic report of (a low density of) tachykinin NK2 binding sites on airway smooth muscle and supports the potent actions of NK2 receptor ligands as contractile agents in guinea-pig isolated bronchi.
 ...
PMID:Autoradiographic localization of tachykinin NK2 and NK1 receptors in the guinea-pig lung, using selective radioligands. 889 98

We identified a number of clinically used drugs and biologically active endogenous peptides able to significantly decrease the rate of human plasmatic aminopeptidase (AP) leucine-enkephalin (LEU) degradation. Bacitracin, bestatin, fluvoxamine, and each of 4 peptides tested significantly increased, in a dose-dependent manner (10-10 M), LEU degradation half-life (t1/2) in each of 5 plasma samples studied. Each sample was obtained by pooling equal volume of 6 randomly selected, individual plasmas (4 male and 2 female healthy, drug-free volunteers). Thirty subjects (20 females and 10 males) participated in this study. With the exception of fluvoxamine, this inhibitory effect was lacking in various other commonly used drugs with widely different chemical structures and pharmacological profiles, eg, antidepressants (SSRIs, imipramine-like tricyclics, MAOIs), acute antimigraine agents (triptan class drugs), the nonselective beta-adrenergic antagonist propranolol, and serotonin receptor agonists and antagonists. Agents (concentration 10 M used as illustration), listed in decreasing order of LEU-AP inhibitory activity: substance P > angiotensin III > methionine-enkephalin > angiotensin II > fluvoxamine > bestatin gave t1/2 values (+/- SD) of 39.3 +/- 1.1, 29.4 +/- 0.8, 28.3 +/- 0.8, 27.4 +/- 0.7, 24.5 +/- 1.5, and 23.6 +/- 0.9 minutes, respectively. Control, bacitracin, and fluphenazine (known LEU-AP inhibitors were used for comparison) values of 11.8 +/- 1.0, 31.3 +/- 0.7, and 19.6 +/- 1.0 minutes, respectively. As expected, these drugs significantly decreased the initial velocity of peptide degradation; Iv values (+/- SD) of: 0.17 +/- 0.1 (0.02 +/- 0.01), 0.23 +/- 0.2 (0.02 +/- 0.01), 0.25 +/- 0.2 (0.02 +/- 0.01), 0.26 +/- 0.2 (0.03 +/- 0.01), 0.31 +/- 0.1 (0.03 +/- 0.01), and 0.33 +/- 0.1 (0.03 +/- 0.01), respectively; control, bacitracin, and fluphenazine: 1.10 +/- 0.3 (0.12 +/- 0.03), 0.20 +/- 0.1 (0.02 +/- 0.01), and 0.82 +/- 0.2 (0.08 +/- 0.02) pg LEU/min (pg LEU/mg protein/min), respectively. Results emphasize the selective nature of chemical structures required to significantly inhibit AP activity and provided information that could help the rational design of agents with high specificity in a biologic milieu containing multiple peptidases. In this case, targeted modulation of the bioavailability of LEU and other endogenous AP-degraded hormonal and nonhormonal peptides could be useful in the treatment of the pathophysiology associated with various disease conditions. Whether their development could find useful pharmacological applications remains to be explored.
 ...
PMID:Inhibition of human plasma leucine5-enkephalin aminopeptidase hydrolysis by various endogenous peptides and a select number of clinically used drugs. 1554 85