Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01042 (bradykinin)
 15,585 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benazepril (CGS 14824A HCl) is a new prodrug type angiotensin converting enzyme (ACE) inhibitor. The active form is considered to be benazeprilat, a diacid hydrolyzed compound. Benazepril and benazeprilat inhibited the contraction induced by exposure with angiotensin I, not angiotensin II, in the isolated rabbit aorta. The ACE inhibiting activity of benazeprilat was 1000 times more potent than that of benazepril in this experiment. Benazepril as well as benazeprilat and captopril exerted little influence on norepinephrine, serotonin and high K(+)-induced contraction or bradykinin-induced relaxation in isolated blood vessel preparations, thus angiotensin II synthesis inhibition seemed to be the main cause for its vasodilation. Benazepril, unlike benazeprilat or captopril showed considerable influence on prostaglandin (PG)-induced responses at higher concentrations. The vasocontraction induced by PGF2 alpha was competitively antagonized at 10(-5)-10(-4) mol/l, while vascular responses induced by PGE1, PGE2 or PGI2 was inhibited at 3 x 10(-4) mol/l of benazepril. Although these influences on PGs might not contribute much to its vasodilatory mechanism, the action seemed interesting in relation to cough induction, a known side effect of ACE inhibitors in the market. Benazepril has two asymmetric carbon atoms, thus four optical isomers are possible, SS (benazepril), SR (CGP 14'829A), RS (CGP 42'454A), RR (CGP 42'456A). The SS configuration was the most potent for antagonizing angiotensin I-induced vasocontraction, which seemed to be the best fitted for the ACE molecule.
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PMID:Antihypertensive mechanism of action of the novel angiotensin converting enzyme inhibitor benazepril. Effect on isolated vascular preparations. 208 Sep 46

Exposure of cultured neonatal rat myocardial cells to metabolic inhibitors results in cellular ATP depletion. If prolonged, arachidonic acid is released from membrane phospholipid and irreversible cell injury may ensue. The present study was undertaken to identify the major products of arachidonic acid formed when myocardial cells are depleted of ATP by the metabolic inhibitors 2-deoxy-D-glucose (2-DG) and oligomycin (OG). Under basal conditions, myocardial cells metabolize [3H]arachidonic acid to 6-keto-[3H]prostaglandin (PG)F1 alpha, [3H]PGE2, [3H]PGF2 alpha, 12-[3H]hydroxy-6,8,11,14-eicosatetraenoic acid (12-[3H]HETE) and 11-[3H]HETE, indicating that these cells contain both cyclooxygenase and lipoxygenase pathways. After exposure of myocardial cells to 10 mM 2-DG and 0.1 micrograms/ml OG for 4 h, the basal release of 6-keto-PGF1 alpha and PGE2 is reduced by 3.4-fold and 2-fold, respectively. Supernatants obtained from cells prelabeled with [3H]arachidonic acid and treated with 2-DG and OG for 4 or 12 h did not contain detectable [3H]prostaglandins or [3H]HETEs, but only [3H]arachidonic acid when compared with untreated cells. After 4 and 12 h of treatment with 2-DG and OG, there was a 3.4- and 4.4-fold net release of endogenous arachidonic acid from treated compared with untreated cells. When stimulated with bradykinin, melittin (a phospholipase activator), or arachidonic acid, the synthesis of 6-keto-PGF1 alpha increased to a similar extent in both 2-DG- and OG-treated and -untreated cells. Hence, ATP-depleted myocardial cells do not convert arachidonic acid to oxygenated metabolites under basal conditions. The reduced arachidonic acid metabolism during ATP depletion is not due to direct inactivation of cyclooxygenase or membrane phospholipase. This impairment in arachidonic acid metabolism may represent an early event in myocardial cell injury.
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PMID:Reduced arachidonate metabolism in ATP-depleted myocardial cells occurs early in cell injury. 211 3

We altered renal prostaglandin production by isolated rat kidneys in several ways to see if this would influence the susceptibility of cells lining the medullary thick ascending limb to injury. Rats were fed a diet containing either safflower oil (high in linoleic acid) or fish oil (low in arachidonate precursors) as a source of fat. After 90 min of perfusion, the kidneys of rats fed safflower oil showed only 32.7 +/- 6.7% of medullary thick ascending limb cells near the inner medulla with severe damage, whereas the same zone in perfused kidneys of rats fed fish oil showed 96.6 +/- 1.3% severely damaged cells (P less than 0.01). The protection afforded by safflower oil was accompanied by a doubling of urinary excretion of PGE2 and 6-keto-PGF1 alpha, and was eliminated by indomethacin, which suppressed prostaglandin synthesis. Perfusion with bradykinin also greatly increased prostaglandin excretion and reduced severe medullary thick ascending limb damage in the deepest zone of the outer medulla from 51.3 +/- 6.6% in controls to 28.5 +/- 5.9% (P less than 0.02). The protection provided by bradykinin was also completely reversed by indomethacin. The results suggest that endogenous prostaglandins serve a protective function against hypoxic injury for cells of the medullary thick ascending limb.
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PMID:Influence of endogenous prostaglandins on mTAL injury. 213 30

The present study uses various kinin agonists and antagonists to examine the cellular mechanisms of bradykinin's actions on intracellular calcium, prostaglandins, and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured arterial smooth muscle cells (casmc) obtained from rat mesenteric arteries. Exposure to bradykinin produced a rapid release of calcium (peak less than or equal to 20 s) from intracellular stores and an increase in prostaglandin (PG) E2 and cAMP production in casmc. Compared with bradykinin, the bradykinin B1-agonist [des-Arg9]BK produced only a small increase in intracellular calcium. The bradykinin-mediated increase in intracellular calcium was competitively blocked by the B2 receptor antagonist [D-Arg-O-Hyp3-Thi5,8-D-Phe7]BK (B4307) but not the B1-antagonist ([des-Arg9-Leu8]BK). In addition, the similarity of the dose-response curves for the bradykinin-mediated increase in Ca2+, PGE2, and cAMP (half-maximal stimulation of 12, 11, and 13 nM, respectively) and the ability of the B2-antagonist (B4307) to block each of these effects of bradykinin suggest that all three effects are mediated by the same bradykinin (B2) receptor. Further studies revealed that increases in intracellular calcium are necessary for the bradykinin-mediated increase in PGE2 formation and the subsequent PGE2-dependent formation of cAMP. Taken together, these results suggest that bradykinin acts via a B2-receptor on arterial smooth muscle cells to release calcium from intracellular stores, leading to increases in PGE2 production and the PGE2-dependent activation of adenylate cyclase.
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PMID:Effects of kinins on cultured arterial smooth muscle. 215 31

Airway submucosal glands are by volume the most important source of macromolecules in airway secretions. These secretions, containing gel-forming mucins, antibacterial proteins, and antiproteases, comprise the major defensive barrier protecting the host against airborne pathogens. The identification of the mechanisms regulating secretion from the submucosal glands is key to understanding the genesis of this barrier and how it is altered by disease processes. Using a variety of methods, we and others have identified on the gland cells of several species receptors specific for ACh, norepinephrine, substance P, VIP, PGE1, PGE2, PGA1, PGD2, histamine and bradykinin. These receptors all participate in modulating the secretory activity of the airway submucosal glands. Studies of homogeneous cultures of bovine airway serous cells have yielded detailed information regarding the beta-adrenergic receptor on these cells. Using radioligand binding techniques, we found evidence for the presence of a single high affinity beta receptor of beta-2 subtype. Occupancy of this receptor by isoproterenol causes an elevation in the concentration of intracellular cAMP, which in turn stimulates the phosphorylation of a subset of cytoplasmic and membrane proteins. Based on the kinetics and pharmacology of these effects, it is likely that cAMP functions as a second messenger in the serous cell secretory pathway, probably acting through protein kinases. Current efforts are directed at identification of those phosphoproteins whose phosphorylation and dephosphorylation times are consistent with their possible roles in secretion.
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PMID:Receptors on airway gland cells. 215 62

We have recently shown that leukotriene B4 (LTB4), a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, sensitizes nociceptors to mechanical stimuli. The present study examined whether LTB4 also induces a thermal sensitization of cutaneous C-fiber high-threshold mechanonociceptors (C-HTMs). C-HTMs were characterized according to their responsiveness to noxious mechanical, thermal and chemical stimuli, including glacial acetic acid, bradykinin and capsaicin. C-HTMs were found to be either heat responsive (heat C-HTMs) or heat and chemically responsive (polymodal C-HTMs). Ninety-four percent of polymodal C-HTMs and 60% of C-HTMs were sensitized to thermal and mechanical stimuli by LTB4 (75 ng). All sensitized C-HTMs showed decreases in both thermal and mechanical thresholds. LTB4 lowered in both subclasses of C-HTMs average thermal threshold from 45 to 35 degrees C and produced an average decrease in the mechanical threshold of approximately 82-86%. For both heat and polymodal C-HTMs, the magnitude of LTB4-evoked decreases in thermal and mechanical thresholds was similar to that produced by 75 ng of PGE2. The possibility was discussed that LTB4 may contribute to the component of hyperalgesia that is resistant to non-steroidal anti-inflammatory agents.
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PMID:Leukotriene B4 induced decrease in mechanical and thermal thresholds of C-fiber mechanonociceptors in rat hairy skin. 215 21

The specific binding of bradykinin (BK) was investigated using membrane fractions from mesangial cells in primary culture, a cloned cell line, and in intact adherent cells with three different radiolabelled BK analogues: 125I-[Tyr0]BK, 125I-[Tyr5]BK and 125I-[Tyr8]BK. The best radioligand was 125I-[Tyr0]BK, and assay conditions were determined to ensure maximal stable binding. Binding appeared to be reversible and not to be inhibited by a wide variety of protease inhibitors including converting enzyme inhibitor and phosphoramidon. The maximum density of binding sites (Bmax) was about 88 +/- 18 fmol/mg protein, which is equivalent to about 6000 sites/cell, and the dissociation constant averaged 2 nM. No significant difference in Bmax was observed between membranes from cells in primary culture and those from cloned cells. Of the BK analogues tested, unmodified BK exhibited the highest inhibition constant (close to 10(-10) M). No displacement of 125I-[Tyr0]BK was observed in the presence of the B1 agonist des-Arg9-BK or several unrelated peptides, including atrial natriuretic factor and angiotensin I and II, whereas 50% inhibition of binding was achieved with the B2 antagonist [D-Arg,Hyp3,D-Phe7]BK (10(-9)M). Addition of BK for 3 min to the incubation medium of cloned mesangial cells induced a dose- and time-dependent increase in PGE2 unlike des-Arg9-BK, which showed no such effect. The secretion was strongly inhibited by prior incubation with the B2 antagonist [D-Arg,Hyp3,D-Phe7]BK. The pharmacological profile of the binding site determined with various BK agonists and antagonists, and the stimulating effect of binding site activation on prostaglandin release strongly suggest that B2-kinin-like receptors are present in rat mesangial cells.
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PMID:Characterization of a B2-bradykinin receptor in rat renal mesangial cells. 217 85

Pravadoline is a new chemical entity with analgesic activity in humans. This report describes the pharmacology of pravadoline and compares the activity of pravadoline with that of two major classes of analgesics, the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Like the NSAIDs, pravadoline inhibited the synthesis of prostaglandins (PGs) in mouse brain both in vitro (IC50, 4.9 microM) and ex vivo (ED50, 20 mg/kg p.o.) and displayed antinociceptive activity in rodents subjected to a variety of chemical, thermal and mechanical nociceptive stimuli. Administration of pravadoline prevented the writhing response induced by i.p. administration of acetylcholine (ED50, 41 mg/kg p.o.) or PGE2 (ED50, 24 mg/kg p.o.) and prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees C (minimum effective dose, 100 mg/kg s.c.). In the rat, treatment with pravadoline prevented acetic acid-induced writhing (ED50, 15 mg/kg p.o.), brewer's yeast-induced hyperalgesia (Randall-Selitto test) (minimum effective dose, 1 mg/kg p.o.), the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50, 41 mg/kg p.o.) and bradykinin-induced head and forepaw flexion (ED50, 78 mg/kg, p.o.). The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg s.c.) and pravadoline did not bind to opioid receptors at concentrations up to 10 microM. However, like the opioid analgesics, pravadoline diminished the electrically induced twitch response of mouse vas deferens preparations, but, in contrast to opioids, this action of pravadoline was not attenuated by naloxone. The possibility is discussed that this effect of pravadoline upon isolated tissues may contribute to its antinociceptive activity. In contrast to NSAIDs, pravadoline was more potent ex vivo as an inhibitor of the formation of PGs in brain vs. stomach. In addition, pravadoline failed to produce gastrointestinal lesions when administered p.o. to rats or mice, and did not possess significant anti-inflammatory activity at antinociceptive doses. Also unlike NSAIDs, pravadoline inhibited rat gastrointestinal transit when administered at doses similar to those which were antinociceptive. The overall pharmacologic profile of pravadoline suggests that the compound may be capable of managing more diverse or more severe pain than is achieved by anti-inflammatory analgesics, without producing side effects commonly associated with either the opioid or the nonopioid analgesics.
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PMID:Pharmacology of pravadoline: a new analgesic agent. 224 40

In domestic fowl, angiotensin II (ANG II) produces a unique vasodepressor response in vivo and endothelium-dependent relaxation of aortic rings in vitro that appear to be a direct effect on vascular smooth muscle mediated through vascular angiotensin receptors. To explore the possible role of the endothelium in ANG II-induced vasodilation, ANG II binding to aortic membrane fractions and intact endothelium and prostaglandin (PG) production were examined in fowl aortas. 125I-[Ile5]ANG II binding by endothelium-intact aortic membrane fractions was consistently higher than binding by identically prepared endothelium-deleted membrane fractions at virtually all concentrations of ligand (10 pM-0.20 microM). Incubation of intact aortic rings with 125I-[Ile5]ANG II (0.50 nM) resulted in specific endothelial binding that increased linearly with time from 5.5 +/- 1.7 (SE) fmol/mg protein at 5 min to 13.7 +/- 1.8 at 30 min. Endothelial ANG II binding increased linearly with the dose of ligand, from 2.7 +/- 0.3 fmol/mg protein at 0.1 nM to 21.0 +/- 2.2 at 1.0 nM. Specific ANG II binding to aortic endothelium was competitively displaced 73 +/- 11% by unlabeled ANG II (0.1 microM) but not by bradykinin (0.1 microM). Incubation of intact aortic rings with [14C]arachidonic acid resulted in the formation of radioactive metabolites that comigrated in thin-layer chromatography with authentic PGE2 but not with 6-keto-PGF1 alpha. PGE2 production by aortic rings (44.4 +/- 4.5 ng.mg dry tissue-1.h-1) was not stimulated by addition of ANG II. These results suggest that specific receptors for ANG II exist in fowl aortic endothelium and that PGs are not involved in ANG II-induced vasodilation of the fowl aorta.
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PMID:Angiotensin II binding sites in aortic endothelium of domestic fowl. 231 22

1. Properties of sensory receptors with slowly conducting nerve fibers (less than 10 m/s) were studied using a rat skin-saphenous nerve in vitro preparation where receptive fields of identified single units can be isolated and superfused at the corium side with defined chemical solutions. 2. With mechanical search stimuli, 150 slowly adapting units were identified, 88% C-fibers, and the remainder, A delta-fibers. The majority of these units (65%) were categorized as mechano-heat sensitive ("polymodal") with controlled radiant heat stimulation. The remaining units were classified as low- or high-threshold mechanoreceptors according to their von Frey thresholds. 3. Bradykinin (BK), in concentrations of 10(-8) to 10(-4) M, was repeatedly applied for 1 min at 10-min intervals. Fifty-six percent of the polymodal C-fibers responded to BK (up to 10(-5) M), in contrast to 17% of the heat-insensitive units (P less than 0.01). No correlation between BK sensitivity and conduction velocity or von Frey threshold was found. 4. The BK "threshold concentrations" to excite C- and A delta-fibers were about equally distributed over a range from 10(-8) to 10(-5) M. 5. There was a large interindividual variability in pattern and magnitude of the response to BK. Intraindividually, a marked tachyphylaxis upon repeated BK stimulation was observed. 6. In fibers with a slow development of tachyphylaxis, the effects of conditioning application of different chemicals on BK responsiveness were studied. Norepinephrine in 10(-7) M concentration did not produce a significant effect, whereas 10(-5) M and 10(-4) M seemed to increase the BK responses. 7. Prostaglandin E2 (10(-6) M) caused a weak sensitization to BK on average (n.s.), but serotonin (10(-6) M) was clearly effective (P less than 0.05). 8. The strongest sensitization to BK (P = 0.01) resulted from conditioning heat stimulation, which also uncovered a responsiveness in some units initially insensitive to BK. 9. In some experiments the calcium concentration in the superfusate of receptive fields was lowered to 0.3 mM, which induced ongoing activity in C-fibers and markedly increased the BK responses in two polymodal units tested. Increasing the calcium concentration to 3.0 mM reversed these effects. 10. After completing the BK test protocol, polymodal C-fibers were exposed to other chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemosensitivity of fine afferents from rat skin in vitro. 234 84


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