UNIPROT:P01185 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carbonyl terminal tripeptide sequence of bradykinin (Pro-Phe-Arg) is molecularly manipulated to obtain agents with potent antagonistic activity towards the smooth muscle contractile activity of bradykinin. Screening of various peptide derivatives revealed that heptyl amides or esters of H-D-Pro-Phe-Arg, and H-D-Phe-Phe-Arg possessed relatively stronger antibradykinin activity on the isolated smooth muscle preparation. The parent tripeptides, H-D-Pro-Phe-Arg-OH, and H-D-Phe-Phe-Arg-OH, and their amino acid components, i.e. D-Proline, D-Phenylalanine, L-Phenylalanine and Arginine, did not possess any antibradykinin activity in concentrations of up to 10(-4) M. When the heptyl derivatives of these peptides were incubated with either heparinized or citrated whole blood or plasma, the antibradykinin activity was not lost. Incubation of these peptide derivatives with either carboxypeptidase A or B did not result in any loss of the pharmacological effect. However, pancreatic protease extract produced a significant loss of the anti-oxytocic action on the isolated rat uterus preparation. H-D-Pro-Phe-Arg-NH-lauryl derivative also blocked the action of bradykinin and this effect sustained for a longer period of time comparative to the blockade with H-D-Pro-Phe-Arg-NH-heptyl derivative. In concentrations of 10(-7) M and 10(-8) M and 1 min incubation, which blocked the contractile action of bradykinin (1 nmole) on the isolated guinea pig ileum, these peptide derivatives did not block the action of acetylcholine, histamine, and serotonin. However, in concentrations of about 10(-6) M and higher with 5 min. incubation histamin is also blocked. On the isolated rat uterus preparation the contractile action of acetylcholine, angiotensin, oxytocin and vasopressin was blocked at concentrations of 10(-6) M. These findings warrant a differential pharmacological evaluation and in vivo testing of these peptide derivatives to investigate their therapeutic potential.
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PMID:Inhibition of the contractile action of bradykinin on isolated smooth muscle preparations by derivatives of low molecular weight peptides. 51 62

SK&F 101926 is a synthetic octapeptide which was designed to promote free water excretion by antagonizing the action of antidiuretic hormone. The clinical and pathologic changes in rats resulting from lethal doses of SK&F 101926 have suggested that death is associated with respiratory failure and/or cardiovascular collapse. To define the relationships between respiratory failure, cardiovascular collapse, and death, respiratory and cardiovascular parameters were monitored in anesthetized rats following the intravenous administration of SK&F 101926 at a dosage (3 mg/kg) which resulted in 70% mortality. Within 5 min after receiving this dosage, mean arterial blood pressure was reduced to values between 30 and 40 mm Hg in all rats. This degree of hypotension was well tolerated by some rats and, consequently, was not considered to be the cause of death. Deaths occurred between 9 and 58 min after dosing and were preceded by respiratory depression involving marked reductions in respiratory rate and the lack of compensatory increases in tidal volume. At the time of respiratory arrest, heart rates remained above 200 beats/min, mean arterial blood pressure remained between 30 and 40 mm Hg, and there were no consistent changes in dynamic lung compliance or total pulmonary resistance. Pretreatment of rats with a mast cell stabilizing agent (disodium cromoglycate), a mast cell degranulating agent (compound 48/80), or a histamine/5-hydroxytryptamine blocking agent (cyproheptadine) prevented the reductions in respiratory rate and death caused by SK&F 101926. These pretreatments also reduced the effect of SK&F 101926 on blood pressure, but were not able to completely prevent the hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Respiratory and cardiovascular changes associated with toxic doses of a peptide antagonist of vasopressin in the rat. 160 Dec 32

SK&F 101926, a synthetic peptide, is a potent antagonist of vasopressin at both the V2 and the V1 receptors. Following intravenous administration of SK&F 101926 (5 mg/kg), mean arterial pressure (MAP) immediately fell 75 mm Hg. Heart rate increased approximately 50 beats/min. Cutaneous flushing and cyanosis appeared approximately 2 to 5 min after the SK&F 101926 administration. Three of the five rats died within 40 min with no improvement in either color or MAP. The two surviving animals slowly recovered from these symptoms. The hypotension and flushing recorded in these studies resembled the effects during hypotensive shock. SK&F 101926 degranulated rat peritoneal mast cells in vitro as measured by the liberation of histamine. Analogs of SK&F 101926 were identified having reduced activity to release histamine from mast cells in vitro. The activity of these analogs to release histamine in vivo was also tested, as reflected by rat paw edema. A positive correlation was found between the potency to produce edema in vivo and the potency to release mast cell histamine in vitro (r = 0.94, p less than 0.05). In addition, compounds that released mast cell histamine and induced rat paw edema also produced hypotension and death when administered intravenously, while analogs which produced minimal histamine release in vitro produced minimal or no cardiovascular changes or lethality in vivo at the same dosages (5 mg/kg). Finally, cyproheptadine (10 mg/kg), an antagonist at both the serotonin and the histamine receptors, blunted the effects of SK&F 101926 on MAP and blocked the lethality. Pretreatment with a combination of histamine (H1 and H2) antagonists provided little protection against the SK&F 101926-induced toxicity. These data indicate that the cardiovascular toxicity of SK&F 101926 (and related peptides) is mediated via the release of autocoids from mast cells. Serotonin appears to play a major role in mediating the cardiovascular toxicity of SK&F 101926.
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PMID:Hypotension induced by vasopressin antagonists in rats: role of mast cell degranulation. 168 65

1. The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D-Tyr(Et)VAVP (SK&F 101926; 25 micrograms kg-1) and the selective V2 antidiuretic agonist, desamino-8-D-arginine vasopressin (dDAVP; 3 micrograms kg-1) was studied in ketamine-anaesthetized rhesus monkeys. 2. The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2-4 weeks). A similar desensitization to dDAVP-associated flushing was observed on repeated administration. 3. Treatment with dDAVP also resulted in reduced SK&F 101926-associated flushing. 4. The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP. 5. The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia. 6. Indomethacin (5 mg kg-1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926. 7. Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia. 8. It was concluded that the flushing response to vasopressin-like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.
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PMID:Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey. 317 11

1. In vivo the effects of endothelin-1 (ET-1) are limited by its rapid removal from the circulation and possibly by its metabolism by enzymes such as neutral endopeptidase 24.11, deamidase or carboxypeptidase A. Here, using as a model the isolated perfused mesenteric arterial bed of the rat, we have examined the involvements of these enzymatic activities in the vascular responses to ET-1. 2. Samples of Krebs buffer which had been recirculated through the mesenteric arterial bed for 30 min rapidly destroyed the activity of ET-1 as assessed either by bioassay on rings of rat thoracic aorta or by high performance liquid chromatography (h.p.l.c.). For instance, after 15 min incubation with the recirculated-Krebs solution (recirc-K) the contraction induced by 3 x 10(-9) M ET-1 was reduced by more than 90%. Contractions induced by sarafotoxin 6b (3 x 10(-9) M) were similarly suppressed by preincubation with recirc-K whereas those to Arg-vasopressin (3 x 10(-9) M) were unaffected. 3. The degradation of ET-1 by recirc-K was prevented by 1,10-phenanthroline (10(-3) M), abolished by heating the recirc-K solution to 90 degrees C for 15 min, and reduced by EGTA (5 x 10(-3) M) or ET-1(16-21) (10(-5) M). For instance, in the presence of ET-1(16-21) (n = 6) the contraction induced by ET-1 was reduced by only 40% after 15 min incubation with recirc-K buffer. Leupeptin (3 x 10-4 M), dichloroisocoumarin(5 x 10-5 M), phenylmethyl-sulphonyl fluoride (10-3 M), a combination of bacitracin (300 mg ml-1),bestatin (10-5 M), captopril (10-5 M), phosphoramidon (10-4 M) and thiorphan (10-4 M) or Polypep (aproprietary protein digest) did not inhibit the degradation of ET-1 by recirc-K.4. In experiments examining directly the vascular responses of the isolated perfused mesentery of the rat, the addition of cumulative concentrations of ET-1 to the recirculating Krebs solution caused small concentration-dependent increases in perfusion pressure. The inclusion of ET-1(16-2l), ET-1(17-21), or ET-1(18-21) (10-5M) greatly potentiated these responses, but not those to Arg-vasopressin or methoxamine.The effects of 1,10-phenanthroline or EGTA could not be examined in this system because these agents both depressed non-specifically the vasoconstrictor responses of the mesenteric vascular bed.5. Thus, the rat mesentery releases an enzyme that very rapidly destroys ET-1 or the very closely related peptide, sarafotoxin 6b but not Arg-vasopressin. This enzyme is most probably a metallopeptidase because of its sensitivity to inhibition by 1,10-phenanthroline or EGTA. It is particularly interesting that a simple vascular bed such as the mesentery produces such a powerful endothelin metabolising enzyme. It is tempting, therefore, to speculate that the endothelin degrading enzyme active at neutral pH that- we have found is important in the metabolism of ET-1 throughout the vasculature.
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PMID:Rapid degradation of endothelin-1 by an enzyme released by the rat isolated perfused mesentery. 777 48

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis (HPA) and principal coordinator of the stress response. As in stress, intracerebroventricular administration of CRH suppresses the immune system indirectly, via glucocorticoid and/or sympathetic system-mediated mechanisms. Also, during inflammatory stress, the cytokines TNF alpha, IL-1, and IL-6 stimulate hypothalamic CRH and/or vasopressin secretion as a way of preventing the inflammatory reaction from overreacting. Recently, CRH receptors were described in peripheral sites of the immune system, and CRH was found to promote several immune functions in vitro. We demonstrated a direct role of CRH in the inflammatory immune process in vivo, by first studying the effect of systemic CRH immunoneutralization in an experimental model of carrageenin-induced aseptic inflammation in Spague-Dawley rats. We extended these observations to other forms of experimental inflammation, including streptococcal cell wall polysaccharide- and adjuvant-induced arthritides and peptide R16 (epitope of the interphotoreceptor retinoid-binding protein)-induced uveitis in Lewis rats. We also studied human disease states, including rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative colitis. Inflamed tissues contained large amounts of IR CRH, reaching levels similar to those observed in the hypophyseal portal system. We also demonstrated the presence of CRH mRNA and CRH receptors in inflammatory cells and identified the mast cells as a major immune target for CRH. In addition to production by immune cells, the peripheral nervous system, including the postganglionic sympathetic neurons and the sensory fibers type C, appears to contribute to IR CRH production in inflammatory sites. The production of CRH from the postganglionic sympathetic neurons may be responsible for the stress-induced activation of allergic/autoimmune phenomena, such as asthma and eczema, via mast cell degranulation. Antalarmin, a novel nonpeptide CRH receptor antagonist, displaced 125I-labeled ovine CRH binding in rat pituitary, frontal cortex, and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmin significantly inhibited CRH-stimulated ACTH release and carrageenin-induced subcutaneous inflammation in rats. Thus, antalarmin and other related compounds that antagonize CRH at the level of its own receptor have therapeutic potential in some forms of inflammation directly mediated by type 1 CRH receptors and promise to enhance our understanding of the many roles of CRH in immune/inflammatory reactions.
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PMID:Corticotropin-releasing hormone and inflammation. 962 33

The effects of cold-restraint stress, repeated over 3 days, and treatment of rats with vasoactive intestinal peptide (VIP) on the contractile responses of isolated aorta to vasoconstrictors, and on aortic adventitial mast cells were investigated. Stress significantly reduced the contractile response of rat aorta smooth muscle to norepinephrine (NE), angiotensin II (Ang II) and vasopressin (VP). Decreased sensitivity to NE, Ang II and VP may result from decreased receptor density, and affinity or reduced effector efficacy. Stress induced degranulation, decreased the number and changed the granular content of mast cells; all degranulated mast cells were stained with alcian blue, and the percentage of safranin staining cells was decreased. Given prior to stress, VIP reversed the reduced contractile responses and sensitivity of aorta to NE and Ang II but had no effect on VP subsensitivity. VIP also inhibited stress-induced degranulation of mast cells, and after VIP only alcian blue-stained mast cells were seen. When VIP was given to non-stressed rats, the contractile response of the aorta to NE, but not Ang II or VP, was increased compared with control. Mast cell count was decreased in the adventitia of non-stressed VIP treated rats. The results indicate that stress decreases the heparin content of mast cells and VIP has an additive effect. In conclusion, VIP modulates both stress-induced mast cell activity and reduced sensitivity of aorta smooth muscle to NE and Ang II. It can be suggested that VIP may moderate some effects of stress on vascular pathophysiology.
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PMID:The effect of stress and in vivo vasoactive intestinal peptide (VIP) treatment on the response of isolated rat aorta to norepinephrine, angiotensin II and vasopressin, and adventitial mast cells. 1134 95

Peptic ulcer is a common disorder of gastrointestinal system and its pathogenesis is multifactorial, where smoking and nicotine have significant adverse effects. Smoking and chronic nicotine treatment stimulate basal acid output which is more pronounced in the smokers having duodenal ulcer. This increased gastric acid secretion is mediated through the stimulation of H2-receptor by histamine released after mast cell degranulation and due to the increase of the functional parietal cell volume or secretory capacity in smokers. Smoking and nicotine stimulate pepsinogen secretion also by increasing chief cell number or with an enhancement of their secretory capacity. Long-term nicotine treatment in rats also significantly decreases total mucus neck cell population and neck-cell mucus volume. Smoking also increases bile salt reflux rate and gastric bile salt concentration thereby increasing duodenogastric reflux that raises the risk of gastric ulcer in smokers. Smoking and nicotine not only induce ulceration, but they also potentiate ulceration caused by H. pylori, alcohol, nonsteroidal anti-inflammatory drugs or cold restrain stress. Polymorphonuclear neutrophils (PMN) play an important role in ulcerogenesis through oxidative damage of the mucosa by increasing the generation of reactive oxygen intermediates (ROI), which is potentiated by nicotine and smoking. Nicotine by a cAMP-protein kinase A signaling system elevates the endogenous vasopressin level, which plays an aggressive role in the development of gastroduodenal lesions. Smoking increases production of platelet activating factor (PAF) and endothelin, which are potent gastric ulcerogens. Cigarette smoking and nicotine reduce the level of circulating epidermal growth factor (EGF) and decrease the secretion of EGF from the salivary gland, which are necessary for gastric mucosal cell renewal. Nicotine also decreases prostaglandin generation in the gastric mucosa of smokers, thereby making the mucosa susceptible to ulceration. ROI generation and ROI-mediated gastric mucosal cell apoptosis are also considered to be important mechanism for aggravation of ulcer by cigarette smoke or nicotine. Both smoking and nicotine reduce angiogenesis in the gastric mucosa through inhibition of nitric oxide synthesis thereby arresting cell renewal process. Smoking or smoke extract impairs both spontaneous and drug-induced healing of ulcer. Smoke extract also inhibits gastric mucosal cell proliferation by reducing ornithine decarboxylase activity, which synthesises growth-promoting polyamines. It is concluded that gastric mucosal integrity is maintained by an interplay of some aggressive and defensive factors controlling apoptotic cell death and cell proliferation and smoking potentiates ulcer by disturbing this balance.
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PMID:Smoking and the pathogenesis of gastroduodenal ulcer--recent mechanistic update. 1461 84

An unusual crustacean cardioactive peptide (CCAP) from the pericardial organs of the shore crab Carcinus maenas has been purified to homogeneity by a two-step reversed-phase HPLC procedure. Manual microsequencing using the 4-(N,N-dimethylamino)azobenzene 4'-isothiocyanate/phenylisothiocyanate double-coupling technique and automated gas-phase sequencing of the oxidized peptide revealed that CCAP is a nonapeptide (M(r) 957) of the sequence Pro-Phe-[unk]Cys-Asn-Ala-Phe-Thr-Gly-Cys-NH(2). We have confirmed the sequence by chemical synthesis of the C-terminally amidated and nonamidated forms of the peptide. The presence of the amide group was indicated by lack of susceptibility to carboxypeptidase A and Y treatment and was confirmed by the observation that the native CCAP comigrated with the amidated synthetic peptide on HPLC. Native and synthetic CCAP displayed high accelerating activity on a semi-isolated crab heart preparation, whereas the nonamidated synthetic peptide was of much lower potency. The effect of CCAP was both inoand chronotropic. The two pericardial organs of one animal yielded 30-40 pmol of extractable CCAP. Its sequence does not resemble that of any known neuropeptide. However, a "mirror-image" similarity to vasopressin is conspicuous.
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PMID:Unusual cardioactive peptide (CCAP) from pericardial organs of the shore crab Carcinus maenas. 1659 3

Because degranulation of brain mast cells activates adrenocortical secretion (41, 42), we examined whether activation of such cells increases renin and vasopressin (antidiuretic hormone: ADH) secretion. For this, we administered compound 48/80 (C48/80), which liberates histamine from mast cells, to pentobarbital-anesthetized dogs. An infusion of 37.5 microg/kg C48/80 into the cerebral third ventricle evoked increases in plasma renin activity (PRA), and in plasma epinephrine (Epi) and ADH concentrations. Ketotifen (mast cell-stabilizing drug; given orally for 1 wk before the experiment) significantly reduced the C48/80-induced increases in PRA, Epi, and ADH. Resection of the bilateral splanchnic nerves (SPX) below the diaphragm completely prevented the C48/80-induced increases in PRA and Epi, but potentiated the C48/80-induced increase in ADH and elevated the plasma Epi level before and after C48/80 challenge. No significant changes in mean arterial blood pressure, heart rate, concentrations of plasma electrolytes (Na+, K+, and Cl-), or plasma osmolality were observed after C48/80 challenge in dogs with or without SPX. Pyrilamine maleate (H1 histaminergic-receptor antagonist) significantly reduced the C48/80-induced increase in PRA when given intracerebroventricularly, but not when given intravenously. In contrast, metiamide (H2 histaminergic-receptor antagonist) given intracerebroventricularly significantly potentiated the C48/80-induced PRA increase. A small dose of histamine (5 microg/kg) administered intracerebroventricularly increased PRA twofold and ADH fourfold (vs. their basal level). These results suggest that in dogs, endogenous histamine liberated from brain mast cells may increase renin and Epi secretion (via the sympathetic outflow) and ADH secretion (via the central nervous system).
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PMID:Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs. 1818 67

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