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)

Angiotensin-converting enzyme (CE) occurs in three types of cell: endothelial, epithelial, and neuroepithelial. In all three, it appears to be bound to plasma membrane. With antisera to the human enzyme, CE is demonstrated in paraffin sections on the apical surface of epithelial cells in the proximal tubule of the kidney, the mucosa of the small intestine, the syncytial trophoblast of the placenta, and the choroid plexus. Epithelial CE is characteristically found on microvillous surfaces in contact with an effluent, well placed to act on substrate in flux. In the brain, CE occurs in nerve fibers and terminals, mainly mesiobasally and in basal ganglia. Mesiobasal CE coincides with other components of the renin-angiotensin system (RAS) in the choroid/ventricular fluid, the subfornical organ, and the magnocellular neurosecretory system of the hypothalamus. Extrapyramidal CE, however, may not be related to the RAS. In the substantia nigra and the globus pallidus, the enzyme has the same cellular distribution as two putative neuromodulators, substance P and enkephalin, the latter a known substrate of CE.
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PMID:Angiotensin-converting enzyme in epithelial and neuroepithelial cells. 631 Apr 27

Tonin, an esteroprotease isolated from rat submaxillary gland, is a serine protease with trypsin- and chymotrypsin-like activity. The substrate specificity of tonin shows that it differs from kallikreins and is definitely not a renin-like enzyme or an angiotensin-converting enzyme. Tonin can produce directly the vasoactive peptide angiotensin II, from angiotensin I, angiotensinogen and the synthetic tetradecapeptide substrate of renin by cleavage of a Phe-His bond. It has also been found to cleave some Phe and Arg bonds in various substrates such as beta-lipotropin (beta-LPH), adrenocorticotropin (ACTH), pro-opiomelanocortin (POMC) and substance P. Here we describe the complete amino acid sequence of rat submaxillary gland, tonin. Comparison of the sequence of 219 amino acids with other serine proteases, particularly kallikreins, gamma-subunit of nerve growth factor (NGF) and the recently described gamma-renin, reveals extensive similarities. More interestingly, it also reveals the substitution of an Asp residue always found in the serine protease active site triad (Asp, His, Ser) by a Leu residue. This unusual substitution does not seem to affect the proteolytic activity of the enzyme.
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PMID:Amino acid sequence of rat submaxillary tonin reveals similarities to serine proteases. 632 14

Neuropeptides can affect cardiovascular function in various ways. They can serve as cotransmitters in the autonomic nervous system; for example, vasoactive intestinal peptide (VIP) is released with acetylcholine and neuropeptide Y with norepinephrine from postganglionic neurons. Substance P and, presumably, other peptides can can affect cardiovascular function when released near blood vessels by antidromically conducted impulses in branches of stimulated sensory neurons. In the central nervous system, many different neuropeptides appear to function as transmitters or contransmittes in the neural pathways that regulate the cardiovascular system. In addition neuropeptides such as vasopressin and angiotensin II also circulate as hormones that are involved in cardiovascular control. Large doses of exogenous vasopressin are required to increase blood pressure in normal animals because the increase in total peripheral resistance produced by the hormones is accompanied by a decrease in cardiac output. However, studies with synthetic peptides that selectively antagonize the vasopressor action of vasopressin indicate that circulating vasopressin is important in maintaining blood pressure when animals are hypovolemic due to dehydration, haemorrhage or adrenocortical insufficiency. VIP dilates blood vessels and stimulates renin secretion by a direct action on the juxtaglomerular cells. Renin secretion is stimulated when the concentration of VIP in plasma exceeds 75 pmol/litre, and higher values are seen in a number of conditions. Neostigmine, a drug which increases the secretion of endogenous VIP, also increases renin secretion, and this increase is not blocked by renal denervation or propranolol. Thus, VIP may be a physiologically significant renin stimulating hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuropeptides in cardiovascular control. 640 Mar 63

Human placenta is surprisingly rich in post-proline dipeptidyl peptidase activity. Among various cell fractions, microsomes have the highest specific activity. A homogeneous enzyme preparation is obtained in a six-step purification procedure. The final preparation appears homogeneous upon dodecyl sulfate electrophoresis, but analytical isoelectric focussing reveals various active bands with isoelectric points in the range of pH 3-4. The enzyme is a glycoprotein containing about 30% carbohydrate. Treatment with neuraminidase lowers the isoelectric points but does not reduce the heterogeneity of the band pattern. The subunit molecular weight is 120000 as estimated by dodecyl sulfate electrophoresis, whereas Mr of the native enzyme is greater than 200000, as can be concluded from gel filtration experiments. The purified dipeptidyl peptidase cleaves various synthetic and natural peptides, including substance P, kentsin, casomorphin and a synthetic renin inhibitor. In general, the specificity of the placenta peptidase is similar to that of post-proline dipeptidyl peptidase from other sources. Phenylalanylprolyl-beta-naphthylamide (Km = 0.02 mM, V = 92 U/mg) is the best substrate among various synthetic peptide derivatives. Only peptides with a free N-terminal amino group and proline, hydroxyproline, or alanine in position 2 of the N-terminal sequence are cleaved. However, X-Pro-Pro-. . . structures, e.g. as in bradykinin, are not attacked. 1 mM bis-(4-nitrophenyl)phosphate or 1 mM diisopropylfluorophosphate completely inactivate the peptidase within 30 min at 30 degrees C (pH 8). The peptidase is also completely inhibited by 1 mM Zn2+ and by other heavy metals.
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PMID:Isolation and characterization of dipeptidyl peptidase IV from human placenta. 675 24

A porcine kidney microsomal metalloendopeptidase has been enriched 3900-fold. Gel filtration on a calibrated Toyo-Soda G-3000 SW column indicated an appropriate molecular weight for the endopeptidase of 88,000 +/- 2000. The purified enzyme is inhibited by a number of synthetic inhibitors of thermolysin. The endopeptidase hydrolyzes the succinyl (Suc)-containing fluorogenic peptide substrate Suc-Ala-Ala-Phe-(7-amino-4-methylcoumarin) at the Ala-Phe position with a Km of 2.9 X 10(-4) M. The endopeptidase also hydrolyzes a variety of peptides including corticotropin, substance P, angiotensin I and II, neurotensin, somatostatin, bradykinin, and the renin tetradecapeptide substrate. The endopeptidase hydrolyzes both [Leu]- and [Met]enkephalin at the Gly-Phe bond.
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PMID:Purification of a membrane-bound metalloendopeptidase from porcine kidney that degrades peptide hormones. 703 58

Sensitivity in the low-femtomole range with mass resolution greater than 20,000 is demonstrated for several polypeptides analyzed by a mass spectrometer that pairs matrix-assisted laser desorption/ionization (MALDI) and Fourier-transform mass spectrometry (FTMS). The compounds investigated were substance P, renin substrate, melittin, the B-chain of bovine insulin, and bovine insulin. Standard solutions of the polypeptides were prepared with 30% acetonitrile+water, and micropipettes were used to transfer small amounts (1-20 fmol) to a sample probe. The samples were embedded in a large excess of matrix material (2,5-dihydroxybenzoic acid) and ionized by a pulse from an excimer laser. The FTMS instrument used for these experiments has the MALDI source in a separate chamber outside the magnetic field. Ions are extracted from the source and transported by an RF-only quadrupole ion guide to an FTMS analyzer cell mounted in the homogeneous region of a 6.5 T superconducting magnet. The high sensitivity of MALDI-FTMS is due, in part, to the high transfer efficiency of the ion guide, even for ions with a wide range of kinetic energies. The ion guide is easy to use because there are only two adjustments (RF amplitude and DC offset voltage), and unlike electrostatic ion transport means, alignment of it with the axis of the magnetic field is not critical. The mass resolution and sensitivity of MALDI-FTMS is compared with that of MALDI done with time-of-flight, magnetic sector, and quadrupole ion-trap mass spectrometers.
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PMID:Detection limits for matrix-assisted laser desorption of polypeptides with an external ion source Fourier-transform mass spectrometer. 752 7

The mediators of the hyperdynamic circulation of liver cirrhosis are not well characterized. Substance P is a potent vasodilatory peptide produced by the enteric nervous system and partly cleared by the liver. In this work we have investigated the plasma levels of substance P and their relationship to the hemodynamic, neurohormonal, and renal function changes occurring in patients with cirrhosis. Seven healthy subjects (control group), 7 cirrhotic patients without ascites (group I), and 24 cirrhotic patients with ascites (group II) were studied. Cardiac output (CO), femoral blood flow (FBF), blood volume (BV), femoral arteriovenous difference of oxygen content (Ca-v O2), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma norepinephrine (NE) were determined. Five patients underwent trans-jugular intrahepatic porto-systemic stent shunt (TIPSS) because of refractory ascites. Immunoreactive substance P (irSP) was measured by radioimmunoassay after plasma extraction. irSP was higher in ascitic patients than in healthy controls (P < .01) and directly correlated with PRA, PAC, plasma NE, and Pugh's score and was inversely correlated with urinary sodium excretion, glomerular filtration rate, and Ca-v O2. No differences were observed between portal and peripheral vein irSP concentration. TIPSS placement induced a decrease in portal pressure and an increase in CO but circulating irSP remained unchanged. Our data show that circulating irSP is increased in decompensated cirrhotic patients and may be involved in the pathogenesis of the hemodynamic changes of cirrhosis. Alleviation of portal hypertension did not result in decreased plasma levels of this vasodilatory substance.
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PMID:Plasma levels of substance P in liver cirrhosis: relationship to the activation of vasopressor systems and urinary sodium excretion. 752 11

The aim of this study was to investigate the effects of systemically or intracerebrally administered RA-octil, a derivative of the angiotensin converting enzyme (CE)-inhibitor ramipril, on memory and reinforcement and to compare its effectiveness with that of the neurokinin substance P (SP). In the first experiment systemic post-trial application of RA-octil and SP in the rat enhanced habituation, a learning task which does not require motivational treatments. Unlike SP, injection of RA-octil did not have reinforcing effects as measured with a conditioned place preference task. In the second experiment, a facilitation of inhibitory avoidance learning was obtained by injection of RA-octil or SP unilaterally into the basal forebrain immediately after the learning trial. In contrast, a 5 h delayed injection of RA-octil had no effects on learning. The results demonstrate memory-enhancing effects of RA-octil after systemic application as well as after injection into the basal forebrain. Furthermore, the mnemogenic effects of SP after central and peripheral administration were confirmed. Since RA-octil, although being structurally closely related to CE-inhibitors, does not affect plasma CE, yet exhibits mnemogenic effects, it is possible that "cognition-enhancing" actions of CE-inhibitors are dissociable from their action within the renin-angiotensin system.
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PMID:Mnemogenic effects of injecting RA-octil, a CE-inhibitor derivate, systemically or into the basal forebrain. 753 64

Afferent renal nerves (ARN) have been implicated in the development of one-kidney renal wrap (1K-WRAP) hypertension. The role of renal nerves in desoxycorticosterone acetate-salt (DOCA) hypertension, a low-renin model of hypertension, is controversial. The present study was designed to determine if spinal substance P (SP) and/or calcitonin gene-related peptide (CGRP) in ARN affects the development of 1K-WRAP or DOCA hypertension in adult rats. Selective long-term partial depletion of spinal SP and CGRP within small primary afferent nerve fibers including unmyelinated ARN was achieved by intrathecal administration of capsaicin. After capsaicin treatment, 1K-WRAP hypertension was induced by removing the right kidney and wrapping the left kidney with a figure-8 ligature. In a second group of rats, DOCA hypertension was induced by subcutaneous application of desoxycorticosterone pellets after unilateral nephrectomy. Systolic arterial pressure was monitored for 8 weeks by tail cuff plethysmography after which direct blood pressure measurement was performed followed by immunohistochemistry. Intrathecal capsaicin administration had no significant effect on SP-ir and CGRP-ir of ARN soma located within thoracic dorsal root ganglia whereas immunoreactivity against these peptides was reduced by one third to one half in the dorsal horn, indicating effective long-term spinal depletion of these neuropeptides. Intrathecal capsaicin enhanced the development of 1K-WRAP hypertension, since arterial pressure was greater in the treated group. In contrast, DOCA hypertension was unaffected by capsaicin pretreatment. Considering the neurotoxic action of capsaicin for SP-ir and CGRP-ir unmyelinated primary afferent neurons, we hypothesize that spinal SP, CGRP and/or related peptides existing in ARN and other capsaicin-sensitive unmyelinated primary afferent neurons in the lower thoracic spinal cord may ameliorate 1K-WRAP hypertension, but not DOCA hypertension.
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PMID:Intrathecal capsaicin enhances one-kidney renal wrap hypertension in the rat. 753 2

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics and efficacy of renin inhibitors. 758 99


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