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)

Tissue factor apoprotein and relipidated tissue factor preparations extensively hydrolyze bradykinin, Lys-bradykinin, Met-Lys-bradykinin, substance P, [Asp1, Ile5]-angiotensin II, [Asp1, Ile5]-angiotensin I, and human fibrinopeptide A while acting more slowly on [Sar1, Ile5]-angiotensin II, [Me2Gly1, Ile5]-angiotensin II, bradykinin potentiating pentapeptide from B. jararaca, luteinizing hormone-releasing hormone, melanocyte stimulating hormone-release-inhibiting factor (Pro-Leu-Gly-NH2), and oxytocin. No hydrolysis of thyrotropin-releasing factor or bradykinin potentiating nonapeptide from B. jararaca is observed. Relipidated and apoprotein tissue factor act at identical rates under the conditions of the assay. Dansylation and chromatography of tissue factor-peptide incubation mixtures further indicate that relipidated and apoprotein tissue factor also hydrolyze peptides by identical mechanisms. No fewer than six bonds are hydrolyzed in bradykinin while the angiotensins and substance P are degraded to constituent amino acids. Only the N-terminal alanine is released from fibrinopeptide A. 2-Mercaptoethanol greatly inhibits the hydrolysis of bradykinin by relipidated tissue factor.
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PMID:The hydrolysis of biologically active peptides by bovine lung tissue factor (thromboplastin). 78 91

The dose-effect relationships of intraventricularly injected bradykinin, Gly-Arg-Met-Lys-bradykinin (GAML-bradykinin), synthetic substance P and angiotensin II on lever-lifting behavior of rabbits in a variable-interval (VI) 72-second schedule of sweetened water presentation were determined. All peptides used caused dose-dependent decreases in overall rates of VI responding during the experimental session in the following order of potency: angiotensin II greater than bradykinin = substance P greater than GAML-bradykinin. The angiotensin II dose-effect curve was less steep than those of the other peptides. The administration of nearly equimolar doses of the bradykinin potentiating peptides, BPP5a and BPP9a, slightly decreased overall VI response rates and caused a 10- to 20-fold potentiation of the rate-decreasing effect of bradykinin on VI responding. Both angiotensin II and bradykinin caused pauses in responding of dose-dependent duration at the beginning of the experimental session that were followed by normal VI responding. The effect of GAML-bradykinin on VI performance was similar to that of bradykinin and angiotensin II but had a delay of onset of 3 to 6 minutes. In contrast, substance P caused actual decreases in response output and pauses of variable duration interspersed between periods of regular VI responding. At the doses used, both bradykinin-potentiating peptides caused uniform decreases in VI responding throughout the experimental session. Gross behavioral changes caused by the peptides were also observed. After the intraventricular injection of bradykinin or GAML-bradykinin, rabbits showed decreased motility, ptosis, miosis and lowered ears; after angiotensin II, animals remained motionless but with wide open eyes, fully raised ears and no miosis. In turn, substance P caused restlessness and increased locomotion. These results together with reported evidence on other powerful central actions of bradykinin, angiotensin and substance P and on the existence of components of their releasing and destroying enzymatic systems in the brain suggest that linear peptides may play a role in the functioning of the central nervous system.
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PMID:Effect of intracerebroventricular bradykinin and related peptides on rabbit operant behavior. 109 6

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.
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PMID:Local potentiation of bradykinin-induced vasodilation by converting-enzyme inhibition in isolated coronary arteries. 128 32

Repeated sodium depletions produce a persistent, enhanced need-free salt intake in the rat, particularly in the female. The neurochemical mechanisms underlying the phenomenon are still unknown. The present studies evaluated the effect on the enhanced need-free salt intake of the female rat (1) of pharmacological interference with the natriorexigenic hormones angiotensin II and aldosterone and (2) of the central injection of the tachykinin peptides, which are endowed with antinatriorexic activity. The need-free salt intake of the female rat is not modified by treatment with the angiotensin-converting enzyme inhibitor captopril or by the aldosterone receptor antagonist RU-28318. On the other hand, the behavior is highly sensitive to the inhibitory effect of central tachykinins, suggesting the possibility that need-free salt intake might be linked to modification (down-regulation) of the inhibitory tachykininergic system.
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PMID:Central tachykinin injection potently suppresses the need-free salt intake of the female rat. 132 51

We have recently shown that (a) [125I-Tyr8]bradykinin (BK) recognized bradykinin binding sites in guinea pig epithelium membranes with a Kd value of 1.6 nM and a Bmax of 156 fmol/mg protein, and (b) B2 agonists and some B2 antagonists, such as D-Arg-[Hyp3,D-Phe7,Leu8]BK, inhibited this specific binding with a Ki value of 32 nM. In the present study, we have radioiodinated the B2 antagonist Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK and have performed a full characterization of the binding properties of this tracer in the same membrane preparation. Equilibrium experiments performed in the absence or presence of an excess of BK (10(-5) M) showed that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK specifically labelled two different sites. One of these is the same as the site labelled by [125I-Tyr8]BK, and this indicates that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK interacts specifically with kinin B2 receptors. Equilibrium experiment performed in the presence of an excess of BK (10(-5) M) indicated that specific binding of 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK to the second site is also saturable and Scatchard analysis showed that the site is of high affinity with a Kd of 16.8 nM and a Bmax of 2.08 pmol/mg protein. Surprisingly, unlabelled B2 agonists such as bradykinin, [Tyr8]BK, [Leu8]BK, [Hyp3,Tyr8(OMe)]BK, D-Arg-[Hyp3]BK and kallidin were found to be inactive on this second site. A series of B2 receptor antagonists, Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK, D-Arg-[Hyp3,D-Phe7,Leu8]BK, D-Arg-[Hyp3,Leu5,8,D-Phe7]BK, D-Arg-[Hyp3,Gly6,D-Phe7,Leu8]BK and D-Arg-[Hyp3,Thi5,8,D-Phe7]BK inhibited 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK binding with Ki values of 25.0, 20.9, 15.8, 64.6 and 6606.9 nM respectively. On the other hand, [Thi5,8,D-Phe7]BK did not interfere with 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK but was found to be a potent inhibitor of [125I-Tyr8]BK binding (Ki = 53.7 nM). As expected, B1 receptor agonists, antagonists and peptides non-related to BK such as substance P, neurokinin A, neurokinin B, angiotensin II, bombesin, vasopressin and the calcitonin gene related peptide were unable to compete with 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK. The results show that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK is interacting with two distinct binding sites in the guinea pig epithelium: one is the well known bradykinin B2 receptor and the other is a new, non-characterized binding site that interacts exclusively with some bradykinin receptor antagonists.
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PMID:Characterization of a novel binding site for 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]bradykinin on epithelial membranes of guinea pig ileum. 132 66

Kinins are endogenously formed peptides that have diverse biological actions, including effects on the gastrointestinal tract. In the search of selective ligands, we studied the binding properties of a selective B2 radioiodinated antagonist (Tyr,D-Arg[Hyp3,D-Phe7,Leu8]BK) on epithelial membranes of guinea pig ileum. Equilibrium binding experiments showed that 125I-Tyr,D-Arg[Hyp3,D-Phe7,Leu8]BK specifically labels two different sites. One of these sites is the conventional B2 receptor. The new tracer recognized this site with a Kd of 34.7 nM and revealed a Bmax of 156 fmol/mg protein. In equilibrium binding experiments 125I-Tyr,D-Arg[Hyp3,D-Phe7,Leu8]BK also recognized a second specific site. Scatchard analysis showed that this second site was of high affinity (Kd of 16.8 nM) and very abundant (Bmax of 2.08 pmol/mg protein). Surprisingly, the natural B2 agonists bradykinin and kallidin were unable to inhibit the specific binding of 125I-Tyr,D-Arg[Hyp3,D-Phe7,Leu8]BK to the second site. A series of B2 antagonists failed to inhibit the specific binding of the new radiolabelled peptide. As expected, non related peptides such as angiotensin II, neurokinin A and B, substance P, vasopressin, calcitonin gene related peptide and bombesin were also inactive. These results show that the new tracer is interacting with two distinct binding sites in epithelial membranes of guinea pig ileum. One is the well known bradykinin B2 receptor and the other is a new, non characterized binding site that interacts exclusively with bradykinin receptor antagonists.
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PMID:125I-Tyr,D-Arg[Hyp3,D-Phe7,Leu8]BK, a radiolabelled B2 antagonist specifically interacts with two distinct binding sites on epithelial membranes of guinea pig ileum. 133 30

The angiotensin I-converting enzyme (kininase II, ECA) is a membrane bound enzyme anchored to the cell membrane through a single transmembrane domain located near its carboxyterminal extremity. Secretion of ACE by the cell occurs most likely as a result of a posttranslational cleavage of the membrane anchor and intracellular region. The ACE molecule is organized into two large highly homologous domains, each bearing consensus sequences for zinc binding in metallopeptidases. Site directed mutagenesis allowed to establish that both domains bear in fact a functional active site, able to convert angiotensin I into angiotensin II and to hydrolyze bradykinin or substance P. The two active sites of ACE, however, do not display the same sensitivity to anion activation (the C terminal active site being more chloride activatable) and also differs in kinetic parameters for peptide hydrolysis. The C terminal active site can hydrolyze faster angiotensin I and substance P and the N terminal active site is able to perform a peculiar endoproteolytic cleavage of an in vitro substrate of ACE, the luteinizing hormone releasing hormone. Both active sites bind with a high affinity, competitive inhibitors but the Kd of the reaction can vary up to 10 between the two active sites. All together, these observations suggest that ACE contains two active sites, whose structure is not exactly identical. They may have a different substrate specificity, however this remains speculative at the present time. Concerning the regulation of ACE gene expression in man, population studies indicated that the large interindividual variability in plasma ACE levels is genetically determined. An insertion/deletion polymorphism located in an intron of ACE gene is associated with differences in the level of ACE in plasma and cells. The physiological and clinical implications of these observations is discussed.
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PMID:[Angiotensin converting enzyme (kininase II). Molecular and physiological aspects]. 133 89

The central cardiovascular and dipsogenic effects of angiotensin II involve interactions with norepinephrine, dopamine, and serotonin. Our findings that angiotensin II receptors and substance P immunoreactivity show a parallel distribution in the dorsal medulla and that angiotensin II releases substance P from perfused rat medulla slices revealed the potential for a functional relation between these peptidergic systems as well. Additional evidence suggests that the heptapeptide angiotensin-(1-7) exerts its biological activities via selective angiotensin receptor subtypes. Thus, we compared the effects of these two peptides on release of substance P and monoamines in perfused slices of medulla and hypothalamus from 77 male Sprague-Dawley rats. Transmitter levels were determined in 6-minute collections of perfusate before (basal), during (experimental), and after (recovery) perfusion with either angiotensin-(1-7), angiotensin II, or Krebs' solution alone (control). Substance P was measured by radioimmunoassay and monoamines and their metabolites by high-performance liquid chromatography with electrochemical detection. In the medulla, 2 microM angiotensin II but not angiotensin-(1-7) significantly increased efflux of substance P (221 +/- 87% of basal) and norepinephrine (130 +/- 17% of basal) during the experimental period. The effect of angiotensin II on substance P was sustained into the recovery period. Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were not detected in this brain region. In the hypothalamus, both angiotensin-(1-7) and angiotensin II increased substance P (169 +/- 30% and 141 +/- 35% of basal, respectively); the effect of angiotensin II was sustained throughout the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential actions of angiotensin II and angiotensin-(1-7) on transmitter release. 134 28

Superior cervical ganglia from 7 human cadavers (3-7 h post mortem) were immunostained for tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and 14 different neuropeptides. The results show that ganglionic cells contain TH, DBH, neuropeptide Y (NPY), somatostatin, vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP). These substances were present predominantly within large ganglionic cells. Inside the ganglion, the number and topographical distribution of various types of immunoreactive cells differed from one another. NPY and CGRP immunoreactivities were found in some TH-positive cells, but that co-localization never exceeded the 30% of the TH cells. Leu-enkephalin showed a weak immunoreactivity, which was restricted to fibers or varicosities. Neuropeptides like substance P, dynorphin A and B, cholecystokinin, galanin, corticotropin-releasing factor, thyrotropin-releasing hormone, angiotensin II and neurotensin showed no immunoreactivity in the human superior cervical ganglion.
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PMID:Neuropeptides in the human superior cervical ganglion. 135 73

Neurotransmitters involved in the central regulation of the autonomic function have, to some extent, been elucidated. Substance P, adrenaline and glutamate neurons originating from the rostral ventrolateral medulla oblongata (VLM) produce a tonic excitation of sympathetic preganglionic neurons. The A1 noradrenaline neurons in the caudal VLM inhibit sympathetic activity by inhibiting neurons in the rostral VLM. In the dorsal medulla, the baroreceptor afferents with substance P converge to the adrenaline-neuropeptide Y (NPY) interneurons located in the dorsal strip of the nucleus tractus solitarius (NTS). These interneurons suppress neuronal activity of the A2 noradrenaline neurons, a vasopressor system, by interacting with alpha 2-adrenergic and NPY receptors. The area postrema, a circumventricular organ devoid of the blood-brain barrier, has access to regulatory information of blood-borne angiotensin II and atrial natriuretic peptide at specific receptors on the neuronal elements. The information is then transmitted to the NTS and dorsal motor nucleus of the vagus. Studies focusing on the physiological and pharmacological profiles of neurotransmitters are expected to enhance our knowledge of the central regulation of the autonomic function.
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PMID:[Central autonomic mechanism and neurotransmitters]. 135 64


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