Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have examined the ability of blood-derived monocytes and macrophages isolated from a patient with alveolar rhabdomyosarcoma and hypercalcaemia, to form 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) from 25-hydroxyvitamin D3 (25(OH)D3). Adherent monocyte-macrophage cells incubated with 25(OH)D3 over the initial 2 days in culture synthesized 1.9 pmol 24,25(OH)2D3/h/incubation (representing 0.63 pmol/h/10(6) cells), whereas macrophages synthesized 1.03 and 1.15 pmol 1 alpha,25(OH)2D3/h/incubation after 1 and 4 weeks in culture respectively. In a further experiment synthesis of 1 alpha,25(OH)2D3 by long-term cultured macrophages fell from 2.25 to 0.04 pmol/h/incubation following exposure to 10 nM 1 alpha,25(OH)2D3 for 7 days, whereas 24,25(OH)2D3 synthesis was induced (0.46 pmol/h/incubation). The vitamin D3 metabolites were identified by co-chromatography with authentic 24,25(OH)2D3 or 1 alpha,25(OH)2D3 in three different high-performance liquid chromatography systems. Serum 1 alpha,25(OH)2D3 in the patient was markedly suppressed at 5 pg/ml (normal 20-50 pg/ml) indicating that raised 1 alpha,25(OH)2D3 was not the cause of the hypercalcaemia, but rather, that raised calcium may have suppressed renal 1 alpha,25(OH)2D3 synthesis. Administration of APD (3-amino-1-hydroxypropylidine-1,1-bisphosphonate) corrected the hypercalcaemia in the patient suggesting that increased bone resorption was responsible for the raised calcium. The results of this study show for the first time that immature blood derived monocyte-macrophage cells can synthesize 24,25(OH)2D3 before they mature into macrophages able to synthesize 1 alpha,25(OH)2D3.
J Steroid Biochem Mol Biol 1991 Mar
PMID:Metabolism of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 by blood derived macrophages from a patient with alveolar rhabdomyosarcoma during short-term culture and 1 alpha,25-dihydroxyvitamin D3 after long-term culture. 200 22

The positive inotropic effect of A23187 has previously been indicated to be attributed to both the enhancement of the slow Ca inward current and the facilitation of Ca release from internal stores. The electromechanical effects of replacing external Ca by Sr on this dual action of A23187 were examined on guinea-pig papillary muscles driven at 0.2 Hz. Replacing most of external Ca by Sr (Sr 2.5 mM plus Ca 0.2 mM) (Sr-medium) increased the developed tension. This procedure simultaneously prolonged the time to peak developed tension (tPT) and the action potential duration at all repolarization phases (APD 10, APD 30 and ADP 80). In such preparations, A23187 (10(-6) M) caused a marked positive inotropic effect (938 +/- 180% of control) accompanied by a prolongation of APD at an early repolarization phase (APD 10), but did not affect tPT. Thereafter, returning superfusate to normal Ca medium (Ca 1.2 mM) in the presence of A23187 also caused a positive inotropic effect, but markedly shortened tPT. The electrical and mechanical responses to A23187 in Sr-medium were completely blocked by nifedipine (2 X 10(-6) M), Ca-channel-blocker, while the positive inotropic effect in normal Ca medium was not blocked by nifedipine. Ryanodine, an inhibitor of internal Ca release, did not affect the positive inotropic effect of A23187 in Sr-medium. These results suggest that in Sr-medium, an internal Ca pool of the myocardium, most likely sarcoplasmic reticulum, does not play a role in the activation of contraction.
J Mol Cell Cardiol 1987 Apr
PMID:Can strontium replace calcium as an activator of internal calcium release in cardiac muscles? Study on a dual action of A23187. 244 Oct 74

Effects of the lectin concanavalin A on cardiotonic response to A23187 and isoprenaline were examined in guinea-pig papillary muscles driven at 0.2 Hz. Concanavalin A (Con A) alone did not affect the cardiac action potential and contractility at concentrations up to 3.6 x 10(-4) g/ml. The contraction increased by isoprenaline, beta-adrenoceptor agonist, was not significantly affected by Con A in this concentration range. However, the positive inotropic effect of A23187 (10(-6) M) was markedly inhibited by this lectin. The maximum inhibitory action was observed at 1.8 x 10(-4) g/ml, while below 3.6 x 10(-5) g/ml, Con A failed to inhibit the inotropic effect of A23187. The inhibitory effect of Con A (3.6 x 10(-4) g/ml) was observed only on the late component of biphasic contraction induced by A23187, and then A23187-induced prolongation of the action potential duration at an early repolarization phase (APD 10) also disappeared. Similar inhibitory action was caused by nifedipine (10(-6) M), but in contrast to Con A, nifedipine markedly inhibited the action potential plateau and the contraction by itself. In the presence of Con A, the residual inotropic effect of A23187 on the early component of contraction was blocked by ryanodine (2 x 10(-6) M). The present inhibitory effect of Con A was completely blocked by the pre-treatment with either alpha-methyl-D-mannoside (10 mM) or endoglycosidase F (1 mU/ml). Succinyl Con A (3.6 x 10(-4) g/ml) and wheat germ agglutinin (2.4 x 10(-4) g/ml) did not significantly affect the positive inotropic effect of A23187. In voltage clamp experiments, the slow inward current was markedly augmented by A23187. This augmentation was nearly completely inhibited by Con A. These results suggest that Con A prevents the process of activation of Ca channels by A23187 through the binding of this lectin to specific carbohydrate residues presumably resulting in cross-linking of glycoproteins on membrane surface. Con A-sensitive carbohydrate residue is assumed to be involved in the modulation of Ca channel activation by A23187.
J Mol Cell Cardiol 1989 Jun
PMID:Effects of concanavalin A on cardiotonic responses to A23187 and isoprenaline. 250 52

In this study, we have used an alpha 1-adrenergic receptor photoaffinity ligand, 2-[4-(4-azido-3-iodo-benzoyl)-piperazin-1-yl]-4-amino-6, 7-dimethoxyquinazoline (125I-APD), to label covalently the alpha 1-adrenergic receptor in a smooth muscle cell line. Our results indicate that in the absence of light, (125I)APD binds reversibly to a site in the DDT1 MF-2 cell membranes having pharmacological characteristics of an alpha 1-adrenergic receptor. Following incorporation of (125I)APD into partially purified membranes a single labeled band of protein with a Mr of 81 000 was visualized by autoradiography following sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Incorporation of (125I)-APD into this band was affected by adrenergic agonists and antagonists in a manner consistent with an alpha 1-adrenergic interaction. Prazosin (alpha 1-selective) blocked incorporation of the label into the Mr = 81 000 protein while yohimbine (alpha 2-selective) did not. Of the adrenergic agonists, (-)-epinephrine and (-)-norepinephrine but not (-)-isoproterenol blocked labeling of the Mr = 81 000 protein. We conclude that the ligand binding site of the DDT1 MF-2 cell alpha 1-adrenergic receptor resides in a Mr = 81 000 protein.
Mol Cell Biochem 1985 May
PMID:Photoaffinity labeling of the DDT1 MF-2 cell alpha 1-adrenergic receptor. 286 76

The effects of A23187 on electromechanical activity of guinea-pig papillary muscles were examined by microelectrode techniques. A23187 (10(-6) M) caused a marked positive inotropic effect (868% of control) on preparations driven at 0.2 Hz. This inotropic effect was accompanied by a significant prolongation of the action potential duration at an early repolarization phase (APD 10), but not at a late repolarization phase (APD 30 and APD 80). Other parameters of action potential were unaffected. In the presence of nifedipine (10(-6) M), Ca2+ channel blocker, A23187 still increased the contractile force (495% of control) but had no effect on APD 10. On the other hand, APD 30 and APD 80 were significantly shortened. In the presence of ryanodine (2 X 10(-6) M), an inhibitor of internal Ca2+ release, A23187 was also able to cause the positive inotropic effect (389% of control). This inotropic effect was accompanied by a prolonged APD 10. These electrical and mechanical effects of A23187 were completely blocked by the combined treatment with nifedipine and ryanodine, suggesting that A23187 has a dual action. In papillary muscles depolarized by 26 mM [K+]0, A23187 augmented the slow action potential. In voltage clamp experiments using a single sucrose-gap method, A23187 caused a marked increase in the slow inward current and the outward current. The effects of A23187 were not antagonized by a beta-adrenoceptor and a histamine (H2) receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1986 Sep
PMID:Electromechanical effects of A23187 on guinea-pig ventricular muscle: a dual action of A23187. 309 29

The effects of cocaine on the duration of the cardiac action potential were investigated in isolated guinea-pig ventricular myocytes at 37 degrees C. Following a 10-min exposure of cells to 3 microM cocaine, APD90 increased significantly by +22 +/- 5% (n = 6). In contrast, following a ten minute exposure to 30 or 100 microM cocaine, APD90 was reduced by -24 +/- 6% (n = 5) and -53 +/- 2% (n = 8), respectively. The ionic basis for cocaine's effects on the APD was investigated using the whole cell voltage-clamp technique at 37 degrees C. Cocaine produced a concentration-dependent reduction in the amplitude of IK tail currents with an estimated IC50 of 4 microM. The kinetics and voltage dependence of the cocaine-sensitive current indicate that cocaine selectively blocks a current identical to the E-4031 sensitive current IKr. No significant reduction of the slow component of IK (IKs) was observed during exposure to 30 or 100 microM cocaine. High (30 and 100 microM) concentrations of cocaine also produced a significant reduction of both the L-type calcium current and the TTX-sensitive plateau current. Pre-treatment of cells with 10 microM TTX also converted the APD-shortening effect of 30 microM cocaine to one of APD-prolonging. This implies that cocaine block of a TTX-sensitive window current contributes to the APD-shortening effects produced by high concentrations of cocaine. We conclude that: (1) cocaine produces a biphasic concentration-dependent effect on repolarization in guinea-pig ventricular myocytes; and (2) this biphasic effect on repolarization results from differences in the sensitivity of inward and outward currents to the blocking effects of cocaine.
J Mol Cell Cardiol 1996 Apr
PMID:Analysis of the ionic basis for cocaine's biphasic effect on action potential duration in guinea-pig ventricular myocytes. 873 95

We studied the effect of the Na+/H+ exchanger inhibitor methylisobutyl amiloride (MIA, 1 microM) on action potential characteristics and arrhythmias induced by: (a) reperfusion following regional ischemia in rat hearts and (b) realkalization after lactate acidosis in rabbit hearts. We also determined the effect of MIA on the incidence of transient inward currents (ITIs) induced by acidosis-realkalization in rabbit cardiocytes. Ligation of the LAD coronary artery for 10 min depolarized the resting potential from -78 +/- 1.9 mV to -66.9 +/- 1.0 mV and depressed the action potential but did not induce overt arrhythmias. Delayed afterdepolarizations were observed during ischemia in 50% of untreated hearts whereas reperfusion produced severe ventricular tachyarrhythmias in all of them. MIA reduced the incidence of arrhythmias to 27% and their duration to less than 1 min. MIA increased action potential duration by 38 +/- 4.1%. BaCl2 produced a similar APD lengthening and had an antifibrillatory effect. Acidic reperfusion induced bradycardia and reduced severity of arrhythmias. In rabbit hearts, MIA increased the action potential duration by 61 +/- 4.3% and abolished arrhythmias on realkalization. Eleven out of 18 cells developed transient inward currents during acidosis-realkalization and seven of them underwent irreversible injury. MIA prevented the appearance of ITIs, had no effect on ICa,L but decreased the outward component of IK1 by 50%. Our results suggest that the protective effect of MIA is in part due to changes in cellular electrical activity that modulate Na+ and Ca2+ entry via different pathways.
J Mol Cell Cardiol 1996 May
PMID:Modulation of the electrophysiological effects of ischemia reperfusion by methylisobutyl amiloride. 876 49

S-T segment changes have been cited as evidence for preconditioning in the human heart during repeated angioplasty inflations. Opening of preformed collaterals, however, could explain these observations. We have measured the profile of S-T segment and monophasic action potential (MAP) changes in a species with low collateralization. Open-chested pigs were subjected to two cycles of 8-min LAD occlusion and 8-min reperfusion prior to 60-min ischemia and 2-h reperfusion. Two epicardial ECGs and MAP were continuously recorded from the ischemic zone and one ECG from the normal zone. Flow was measured using Xenon washout. Infarct (IS) and risk zone (RZ) sizes were assessed after reperfusion in a subset of six pigs and confirmed profound protection with preconditioning (IS/RZ = 14 +/- 9% v 42 +/- 3% in controls, P < 0.05). S-T segment elevation was smaller early in the 2nd or 3rd (0-3 min) ischemic cycles than in the 1st. In contrast, in the 1st ischemic cycle, MAP duration after 3 min was reduced to 90 +/- 2% control and this was further reduced in the 2nd and 3rd ischemic episodes to 74 +/- 4% and 77 +/- 3% respectively. Thus, preconditioning increased APD shortening while simultaneously decreasing S-T segment elevation during the early minutes of ischemia. It therefore seems unlikely that the ability of preconditioning to limit S-T segment changes is related to limitations in APD shortening. All electrophysiological differences were lost later during ischemia. Collateral flow during the three ischemic cycles was 4.8 +/- 3.7, 5.8 +/- 2.3 and 5.6 +/- 2.9% (n = 5/grp, ns) respectively. Thus, in the absence of a significant increase in collateral flow. S-T segment and MAP changes provide an index of preconditioning but only during the first few minutes of occlusion. S-T segment changes observed during PTCA may therefore reflect genuine preconditioning in man although the contribution of ischemia-induced increases in collateral flow cannot be ignored.
J Mol Cell Cardiol 1996 Jun
PMID:Electrophysiological characteristics of repetitive ischemic preconditioning in the pig heart. 878 75

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the dual coronary perfusion model to assess pharmacological activity since, even in rat, a species with extremely low collateral flow, there is evidence of cross-flow between the left and right ventricles.
J Mol Cell Cardiol 1995 Dec
PMID:Further investigations into the mechanism of antifibrillatory action of the specific IK1 blocker, RP58866, assessed using the rat dual coronary perfusion model. 882 80

The effects of acute and chronic glutathione depletion (single i.p. injection of 3 mmol/kg L-buthionine-S,R-sulphoximine and 2 mmol/kg for 4 days) on heart action potential (AP) characteristics, electronmicroscopy, cytochemistry and biochemistry and vascular contractility and nitric oxide-mediated relaxation were studied in rats and guinea pigs. In guinea pig cardiac preparations both acute and chronic glutathione depletion caused a significant decrease of maximum rate of rise of depolarization phase and duration of action potential AP(APD) at 25, 50, and 90% of repolarization but did not modify the other AP parameters. The contractile responses of helically cut aortic strips to norepinephrine were not altered by chronic glutathione depletion but the relaxing responses of precontracted preparations to acetylcholine were significantly reduced both in rats and guinea pigs. Morphologically there were indications of permeability changes, intracellular and interstitial edema and myofilament damage in the myocardium. There was also a decrease in cytochromoxydase and succinyl dehydrogenase activities both in rats and guinea pigs. The present data suggest that glutathione depletion may influence the Na+ and K+ channel activities, causes morphological and biochemical changes in cardiac preparations and may interfere with nitric oxide generation or its action in aortic strips.
Mol Cell Biochem 1998 Aug
PMID:Changes in cardiac electrophysiology, morphology, tissue biochemistry and vascular reactions in glutathione depleted animals. 974 25


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