Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of (aminoalkoxy)chromones has been prepared, members of which bind potently (16-100 nM) at the sigma binding site and bind weakly (greater than 1000 nM) at the dopamine D2 receptor and 33 other receptors, second messenger systems, and ion channels. At the sigma receptor, the preferred position of attachment for the aminoalkoxy side chain to the chromone ring followed the rank order: 7-position greater than 5-position greater than 6-position. Chromones that contained a 2-substituent that was not coplanar with the chromone ring system showed improved binding over compounds with coplanar substituents. The most potent compound at the sigma site, 7-[[7-(4-hydroxypiperidyl)heptyl]oxy]-2-phenylchromone (74), had receptor affinities (IC50) of 16 nM at the [3H]DTG site, 19 nM at the [3H]-(+)-3-PPP site, and 4000 nM (Ki) at the dopamine D2 receptor. The most selective compound examined, 6-[[6-(4-hydroxypiperidyl)hexyl]-oxy]-2-cyclopentylchromone (58), exhibited IC50s of 51 nM at the [3H]DTG site, 55 nM at the [3H]-(+)-3-PPP site, and 21,000 nM (Ki) at the dopamine D2 receptor. Compound 44 (6-[[6-(4-hydroxypiperidyl)hexyl]oxy]-3-methylflavone, NPC 16377) was systemically effective (ip and po) in two behavioral models predictive of antipsychotic compounds and systemically active in animal models of ischemia.
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PMID:(Aminoalkoxy)chromones. Selective sigma receptor ligands. 131 69

The novel compound 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) was evaluated for activity in a variety of tests associated with receptors for excitatory amino acids. NPC 12626 failed to inhibit the specific binding of RS-[3H] amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid or [3H] kainic acid to brain membranes in vitro but displaced both agonist and antagonist binding to N-methyl-D-aspartic acid (NMDA) receptors. Like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, NPC 12626 competitively blocked NMDA-induced enhancement of [3H]-1-thienylcyclohexyl)piperidine binding. In the voltage-clamped frog oocyte expression system, NPC 12626 was a competitive inhibitor of NMDA-evoked inward current with a pA2 of 6.24. After both i.c.v. or i.p. administration, NPC 12626 was a potent anticonvulsant in the pentylenetetrazol, maximal electroshock and NMDA seizure models. Furthermore, low doses (25 mg/kg) of NPC 12626 given i.v. were effective in preventing damage to the CA1 region of hippocampus in the gerbil model of global ischemia. Unlike the noncompetitive NMDA antagonist, phencyclidine, but like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid and pentobarbital, NPC 12626 only partially substituted for phencyclidine in a drug discrimination study. The results of the current study indicate that NPC 12626 is a novel, systemically active and competitive NMDA receptor antagonist.
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PMID:Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist. 254 56

Abdominal ischemia and reperfusion reflexly activate the cardiovascular system. In the present study, we evaluated the role of endogenously produced bradykinin (BK) in the stimulation of ischemically sensitive visceral afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of abdominal ischemia. Abdominal ischemia increased the portal venous plasma BK level from 49 +/- 10 to 188 +/- 66 pg/ml (P < 0.05). Injection of BK (1 microgram/kg ia) into the descending aorta significantly increased impulse activity (0.88 +/- 0.16 impulses/s) of 10 C fibers, whereas a kinin B1-receptor agonist, des-Arg9-BK (1 microgram/kg), did not alter the discharge rate. Inhibition of kininase II activity with captopril (4 mg/kg i.v.) potentiated impulse activity of 14 ischemically sensitive C fibers (0.44 +/- 0.09 vs. precaptopril, 0.33 +/- 0.08 impulses/s; P < 0.05). In addition, a kinin B2-receptor antagonist (NPC-17731; 40 micrograms/kg i.v.) attenuated activity of afferents during ischemia (0.39 +/- 0.08 vs. pre-NPC-17731, 0.72 +/- 0.13 impulses/s; P < 0.05) and eliminated the response of 10 C fibers to BK. Another kinin B2-receptor antagonist, Hoe-140 (30 micrograms/kg iv), had similar inhibitory effects on six other ischemically sensitive C fibers. In 15 separate cats treated with aspirin (50 mg/kg i.v.), Hoe-140 (30 micrograms/kg i.v.) attenuated impulse activity of only 3 of 16 ischemically sensitive C fibers. These data suggest that BK produced during abdominal ischemia contributes to the stimulation of ischemically sensitive visceral C fiber afferents through kinin B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous BK stimulates ischemically sensitive abdominal visceral C fiber afferents through kinin B2 receptors. 781 Jul 39

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.
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PMID:NPC 16377, a potent and selective sigma-ligand. II. Behavioral and neuroprotective profile. 809 65

Neutrophil accumulation and activation within the myocardium during ischemia and reperfusion has been shown to play a prominent role in the development of myocardial stunning and infarction. To determine if a simple inhibitor of neutrophil adhesion could reduce myocardial infarct size, we administered NPC 15669 (a new antiinflammatory agent that inhibits neutrophil adhesion) to 12 pigs (6 controls, 6 NPC-treated) in a porcine model of ischemia and reperfusion injury. Each animal received a continuous infusion of either NPC (10 mg/kg intravenous bolus followed by 6 mg.kg-1 x h-1 intravenous infusion) or an equal volume of normal saline solution during 1 hour of left anterior descending artery occlusion and 2 hours of reperfusion. There were no significant differences in the pre-ischemia, mid-ischemia, or postischemia rate-pressure product between control and experimental groups. The regions at risk were similar in both groups. However, the mean myocardial infarct size was reduced by 51% with administration of NPC 15669 (30.7% +/- 6.8%) compared with controls (62.3% +/- 5.4%; p < 0.01). These data indicate that NPC 15669, an inhibitor of neutrophil adhesion, substantially reduces myocardial infarct size after transient left anterior descending artery occlusion and that adhesion of the white cell to vascular endothelium may be an important element of the pathogenesis of myocardial infarction.
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PMID:Inhibition of neutrophil adhesion reduces myocardial infarct size. 823 1

2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742), the most potent isomer of the mixture 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626), was evaluated for activity in tests associated with receptors for excitatory amino acids. In receptor binding assays, NPC 17742 was selective for the N-methyl-D-aspartate (NMDA) receptor with a potency comparable to that of D(-, -3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Like (+/-)cis-4-phosphono-methyl-2-piperidine carboxylic acid (CGS 19755) and (+/-)(E)-2-amino-4-methyl-5-phosphono-3-penteneoic acid (CGP 37849), NPC 17742 competitively inhibited NMDA-induced enhancement of 1-[(2-thienyl)cyclohexyl]piperidine binding to the NMDA receptor ionophore and partially inhibited [3H]glycine binding to strychnine-insensitive sites. In contrast, NPC 17742 and CGP 37849 inhibited Mg(++)-stimulated 1-[(2-thienyl)cyclohexyl]piperidine binding in a noncompetitive fashion. In voltage-clamped Xenopus oocytes expressing excitatory amino acid receptors, NPC 17742 (pKB = 6.91) was equipotent with CGP 37849 (pKB = 7.17) in inhibiting NMDA-induced inward currents. Likewise, NPC 17742 (ED50 = 2.68 mg/kg) was equipotent with CGP 37849 and CGS 19755 in blocking NMDA-induced convulsions, but was less potent than these two compounds in the maximal electroshock test. Unlike CGP 37849 or CGS 19755, NPC 17742 potently antagonized seizures induced by pentylenetetrazol. In a model of global ischemia, low doses of NPC 17742 given either before or after ischemic result were effective in blocking damage to hippocampal CA1 neurons. The pharmacologic responses to NPC 17742 occurred at doses 30- to 300-fold lower than the acute lethal dose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological profile of NPC 17742 [2R,4R,5S-(2-amino-4,5-(1, 2-cyclohexyl)-7-phosphonoheptanoic acid)], a potent, selective and competitive N-methyl-D-aspartate receptor antagonist. 842 28

Plasma antithrombin-III (AT-III), protein S, and protein C were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on their plasma levels were elucidated. Forty-nine open-chest swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. During MS an increase in the plasma AT-III (from 98.5 +/- 3.38% to 138.1 +/- 3.6%) during the early occlusion phase, without any further changes was observed. The profile of total protein S was not changed during MS. Protein C increased at the end of occlusion (from 45.3 +/- 1.8% to 55.7 +/- 1.4%) reaching a peak (64.5 +/- 1.4%) at the beginning of reperfusion. When compared with controls, no significant differences were found in the antithrombotics profile during MS after pretreatment with Mac-1 inhibitor. For the AMI, the AT-III decreased during occlusion (from 98.5 +/- 3.4% to 61.0 +/- 3.6%). The protein S decreased during occlusion with the lowest level at 1 h of reperfusion (from 71.8 +/- 2.2% to 46.7 +/- 1.0%), followed by an increase during late reperfusion (59.2 +/- 1.5%). Contrarily, protein C increased during occlusion and early reperfusion (from 44.7 +/- 2.6% to 79.4 +/- 2.4%), but declined to 49.6 +/- 2.5% thereafter. In both Mg and diltiazem-treated swine, protein C was higher at the end of occlusion and during the entire reperfusion period compared with controls. Mg and diltiazem therapy was associated with the slight elevation of plasma AT-III. The patterns for protein S level during ischemia-reperfusion were similar with the controls. Protein S was higher at the end of occlusion and through the entire reperfusion in the NPC 15669-treated animals when compared with the controls. Mac-1 inhibition was associated with the elevated protein C during late reperfusion. Ability of Mg, diltiazem, and Mac-1 inhibitor to favorably modulate the plasma level of antithrombotics have direct clinical implications for the use of these agents in patients with acute coronary artery syndromes.
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PMID:Serial changes of natural antithrombotics during myocardial ischemia-reperfusion in swine. Effects of magnesium, diltiazem, and a novel Mac-1 inhibitor. 889 53

Myocardial ischemia-reperfusion alters regional and systemic platelet function. The aim of our study was to elucidate the role of the Mac-1 receptor in changes of platelet function by using the leumedin, NPC-15669, an inhibitor of Mac-1 upregulation. In an open-chest swine model (n = 15), the treatment group (n = 6) received NPC-15669 (10 mg/kg loading dose over 12 min at the rate of 5 ml/min at the onset of left-anterior descending coronary artery occlusion, followed by constant infusion at 6 mg kg-1 h-1 during 90 min of reperfusion). Regional platelet aggregation (response to 5 microM ADP) increased after 15 min occlusion (126% of baseline) and at 90 min of reperfusion (156% of baseline). This increase in platelet aggregability was inhibited by NPC-15669 (83% of baseline after 15 min occlusion and 98% of baseline at 90 min reperfusion, both p < 0.001 compared to control). Systemic platelet function was not affected by NPC-15669 after 15 min occlusion (102% of baseline vs. 96% of baseline for control, p = NS). At 90 min of reperfusion platelet function was increased in controls (131% of baseline) and not affected by NPC-15669 (126% of baseline, p = NS). Myocardial neutrophil accumulation did not differ between the control and treatment groups. Inhibition of Mac-1 upregulation by NPC-15669 attenuates the increased regional platelet aggregability resulting from myocardial ischemia-reperfusion, with a less marked effect on the systemic response. The data suggest that Mac-1 may modulate regional platelet responses induced by ischemia-reperfusion. The increased aggregability of platelets during ischemia and reperfusion and its attenuation by inhibition of Mac-1 may be relevant for future strategies to reduce coronary arterial occlusion by platelet thrombi.
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PMID:Pretreatment with an inhibitor of mac-1 alters regional and systemic platelet function during ischemia-reperfusion in swine. 890 72

Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.
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PMID:Mac-1 inhibitor affects certain hemostatic parameters during myocardial stunning in swine. 890 73

Ischemically sensitive visceral sympathetic nerve fibers, which are thought to represent the afferent limb of a strong cardiovascular pressor reflex, can be stimulated by exogenously applied bradykinin (BK). During ischemia, BK also is known to be produced locally and to serve as an endogenous stimulus for activation of ischemically sensitive nerve endings. It is unclear, however, whether ischemically induced BK production is sufficient to elicit a reflex cardiovascular response. Accordingly, femoral arterial and venous catheters were positioned in anesthetized cats, and the superior mesenteric and celiac arteries were isolated for placement of snare occluders. After dual occlusion of these arteries (20 min), one of two chemically dissimilar specific kinin B2 (BK2) receptor antagonists, HOE-140 (30-40 micrograms/kg iv, n = 8) or NPC-17731 (30-40 micrograms/kg iv, n = 11), was administered and dual occlusion was repeated. The reflex rise of mean arterial blood pressure (BP) of 16 +/- 3.7% was significantly (P < 0.05) reduced by HOE-140 to 8.4 +/- 2.0%. NPC-17731 similarly attenuated the reflex BP increment from 13 +/- 1.2 to 6.2 +/- 1.6% (P < 0.05). In a separate set of control animals the first and second periods of ischemia induced reflex BP increments that did not differ significantly (16 +/- 2.7 and 16 +/- 5.7%, respectively). Qualitatively similar decrements of the BP response were produced by the BK2 receptor antagonists in two additional groups in which blood flow to the superior mesenteric and celiac arteries was diverted to a venous reservoir to eliminate the initial transient (mechanically induced) rise in BP associated with artery ligation that is known not to be associated with the reflex response. These results indicate that the stimulation of BK2 receptors on visceral afferent nerves by BK is responsible, at least in part, for the reflex cardiovascular response during visceral ischemia.
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PMID:Bradykinin BK2 receptors contribute to reflex cardiovascular responses during brief abdominal ischemia. 945 81


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