Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.13.12.5 (aequorin)
 1,451 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([CA2+]i). The present study was designed to determine the effects of the calcium antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with buffer containing 10(-8) M nisoldipine. From the left ventricular developed pressure, the time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i from 0.35 to 0.81 microM and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function (Fig. 1). Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM and in systolic [Ca2+]i to 0.77 microM and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.
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PMID:Ventricular function and calcium handling during ischemia. 128 12

The purpose of this study was to test the hypothesis that abnormal intracellular calcium handling characterizes myocardial stunning. Isolated, isovolumic, buffer-perfused ferret hearts were loaded with the bioluminescent calcium indicator aequorin for simultaneous measurement of individual calcium transients and left ventricular pressure. After 15 minutes of global ischemia and 20 minutes of reperfusion, left ventricular developed pressure was significantly reduced (75 +/- 7 versus 93 +/- 6 mm Hg, p < 0.05). During ischemia, [Ca2+]i levels were significantly elevated compared with preischemic levels, both during systole (1.38 +/- 0.31 versus 0.88 +/- 0.2 microM, p < 0.05) and end diastole (0.85 +/- 0.16 versus 0.38 +/- 0.13 microM, p < 0.05). Early during reperfusion, [Ca2+]i was also significantly elevated during systole (1.63 +/- 0.44 versus 0.88 +/- 0.20 microM, p < 0.05) and end diastole (0.75 +/- 0.15 versus 0.38 +/- 0.13 microM, p < 0.05). After 20 minutes of reperfusion, myocardial stunning occurred, but [Ca2+]i was not significantly different from preischemic levels. Thus, myocardial stunning does not result from decreased levels of activator calcium. The force-pCa relation generated by the stunned hearts was shifted downward compared with that generated by the control hearts, consistent with a decrease in maximum calcium-activated force (Fmax). At steady state during tetanus, the decrease in Fmax was confirmed, but there was no significant difference in the slope of the force-pCa relation of the stunned hearts versus controls. Thus, we conclude that stunned myocardium is characterized by decreased Fmax without desensitization of the myofilaments to [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. 142 31

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.
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PMID:Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic, coronary-perfused heart. 160 12

Intracellular free calcium concentration ([Ca2+]i) was measured in isolated ferret ventricular papillary muscles during and after long exposures to ischemia. All experiments were performed at 37 degrees C, and the muscles were stimulated at 1 Hz. Ischemia was simulated by changing from superfusion with oxygenated Tyrode's solution to superfusion with water-saturated gas (95% N2-5% CO2), thus simultaneously stopping oxygenation and restricting the extracellular space. [Ca2+]i was measured with aequorin, which was microinjected into superficial cells of the preparation. Exposure to ischemia caused a complex series of changes in [Ca2+]i. In the first few minutes the changes in [Ca2+]i were variable; however, after approximately 5 minutes all preparations exhibited a progressive increase in amplitude and duration of the stimulated rise in [Ca2+]i (the calcium transient). The amplitude of the calcium transients peaked after approximately 18 minutes of ischemia, when they were 339% of the control value. After this peak, the calcium transients progressively failed to occur in response to stimulation and declined in amplitude; simultaneously, spontaneous oscillations of [Ca2+]i appeared and increased in size and frequency. The oscillations in turn then gradually became less frequent until a large, prolonged (5-10 minute) increase in [Ca2+]i occurred, after which [Ca2+]i returned to a low level. There were no further oscillations after this event, which was seen on average after 37 minutes of ischemia. A slowly progressive contracture often began to develop at about this time. A gradual rise in resting [Ca2+]i occurred during the remainder of the exposure to ischemia. When muscles were reperfused after long exposures to ischemia, there was a very large and prolonged increase in [Ca2+]i, which was usually associated with a contracture and failure of recovery of developed tension. The large increase in [Ca2+]i could be reduced by the inclusion of 3 mM nickel chloride in the reperfusing solution. Comparison between reperfusion with O2 gas versus reperfusion with anoxic Tyrode's solution indicated that reoxygenation was more beneficial to the muscle than resumption of bulk flow. These results reveal the complex spectrum of changes in [Ca2+]i that occur during ischemia and on reperfusion. These changes in [Ca2+]i are likely to play an important role in the generation of ischemic arrhythmias and muscle damage.
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PMID:Changes in intracellular free calcium concentration during long exposures to simulated ischemia in isolated mammalian ventricular muscle. 160 68

Changes of brain tissue calcium in the focal ischemia model of Wistar rat were investigated by three different methods; atomic absorption spectrophotometer, calcium stain with alizarin red S, and new histochemical method using aequorin, a calcium ion sensitive photoprotein. Tissue pH and tissue ATP were concomitantly investigated by histochemical method. Rat brain was frozen in situ at 15, 60 or 240 minutes after left middle cerebral artery was occluded. Coronal brain sections of 16 microns thickness was made and the brain slices applied for calcium stain and histochemical studies. The residual brain block was applied for atomic absorption spectrophotometric study. Tissue calcium content of left hemisphere increased from 1.34 +/- 0.09 (mean +/- SEM) (n = 7) to 1. 54 +/- 0.16 (n = 12), 2.07 +/- 0.12 (n = 9). 1.69 +/- 0.11 (n = 10) mumol/g wet weight after 15, 60 and 240 minutes respectively. Calcium stain with alizarin red S showed that the increase of calcium was observed in the peripheral part of the ischemic lesion where ATP was left in a spotty fashion, and calcium deposits disappeared with correspondence to exhaustion of ATP. Tissue calcium ion content studied by newly histochemical method, showed heterogeneous change. At an early stage of the ischemia, the increase of tissue calcium ion was shown only in the peripheral part of the ischemic lesion, and it gradually extended to the central part. Calcium ion increased in density in an area corresponding to that of the ATP decrease. Within the area of calcium ion increase, regional differences were noted; a greater increase at the border with the intact area and in the parts where ATP was heterogeneously preserved. In the non-ischemic area close to the ischemic area, where ATP was preserved with mild acidosis, calcium ion decreased more than in the surrounding area where ATP was preserved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Changes in cerebral energy and calcium metabolisms on focal cerebral ischemia]. 179 92

The bioluminescent of Ca(2+)-indicator, aequorin, was loaded into the left ventricular apex of blood-perfused hearts from 13 dogs for simultaneous recording of left ventricular pressure and intracellular calcium levels. During a 2 minute period of ischemia, systolic and diastolic pressures significantly decreased. In contrast, these pressure changes were associated with an increase in both systolic and diastolic calcium reaching a maximum diastolic value of 0.59 microM and a systolic value of 1.11 microM. This apparent dissociation between pressure and [Ca2+]i supports the hypothesis that changes in myofilament Ca2+ responsiveness are of major importance in modulating contractility during ischemia in large mammalian hearts.
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PMID:Excitation-contraction uncoupling during ischemia in the blood perfused dog heart. 188 75

In studies of ischemia and reperfusion, a major experimental problem has been the inability to measure intracellular ionized calcium ([Ca2+]i) in the intact heart. We have developed a new approach in which the bioluminescent calcium indicator aequorin is used to measure [Ca2+]i in the isolated, coronary-perfused ferret heart. Aequorin is loaded into subepicardial myocytes of the left ventricle, and the signals are recorded simultaneously along with isovolumic left ventricular (LV) pressure at a constant pacing rate. This system shows 1) no attenuation or change of time course of LV pressure development or coronary perfusion pressure after aequorin loading; 2) consistent responses to physiological interventions and drugs; 3) individual aequorin and pressure signals that do not require signal averaging for analysis; and 4) [Ca2+]i levels comparable with those reported in tissue or isolated myocyte cell preparations. During 5 minutes of hypoxia, diastolic [Ca2+]i and LV diastolic pressure increased while the systolic values of both [Ca2+]i and pressure decreased. The peak-to-peak systolic [Ca2+]i versus LV isovolumic pressure relation remained close to the control curve. In contrast, during 3 minutes of global ischemia, LV systolic and diastolic pressures fell rapidly, while [Ca2+]i increased substantially. The [Ca2+]i versus pressure relations for both systole and diastole shifted to the right, indicating desensitization of the contractile apparatus to [Ca2+]i. These results provide evidence that different primary mechanisms determine the systolic and diastolic responses to acute hypoxia versus ischemia. During hypoxia, changes in [Ca2+]i handling probably play a major role, while during ischemia, changes in the Ca2+ sensitivity of the myofilaments appear to be of primary importance in the modulation of contractile dysfunction.
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PMID:Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. 279 Dec 18

Isolated adult rat hearts in an isovolumic nonworking Langendorff preparation were loaded with the Ca2+ indicator aequorin to investigate the effects of ischemic reperfusion on free intracellular Ca2+ concentration ([Ca2+]i) homeostasis and left ventricular (LV) contractile function. In three groups (each n = 8) that underwent 10, 20, and 30 min of ischemia, recovery of developed pressure amounted to, respectively, 63% [77 +/- 3 (SE) mmHg], 48% (56 +/- 4 mmHg), and 34% (43 +/- 4 mmHg) of preischemic control (122 +/- 5 mmHg) after 60 min of reperfusion. Diastolic pressure remained elevated at 40 +/- 4, 55 +/- 3, and 65 +/- 6 mmHg, respectively (preischemic control, 12 mmHg). During early reperfusion (0-20 min), the light transient demonstrated a prolonged time to 90% decline from peak light (t90L), which was paralleled by a delayed relaxation on the LV pressure tracing in the 10- and 20-min ischemia groups. After 60 min of reperfusion, the prolongation of t90L persisted in all groups (10-min ischemia, 89 +/- 2 ms; 20 min, 95 +/- 3 ms; 30 min, 96 +/- 2 ms; control, 82 +/- 2 ms; P < 0.05). In contrast, the LV pressure tracing was abbreviated beyond the preischemic control, indicating altered myofibrillar Ca2+ responsiveness. Diastolic [Ca2+]i was elevated after 60 min of reperfusion (10-min ischemia, 0.40 +/- 0.06 microM; 20 min, 0.48 +/- 0.04 microM; 30 min, 0.51 +/- 0.06 microM; control, 0.32 +/- 0.01 microM) and had a significant positive correlation with LV diastolic pressure (r = 0.79; P < 0.001). A positive correlation was also found for the amplitude of the Ca2+ transient and LV developed pressure (r = 0.53; P < 0.05). These findings suggest that postischemic contractile dysfunction is related to altered Ca2+ modulation with impaired [Ca2+]i homeostasis following moderate to severe reperfusion injury in the rat.
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PMID:Contractile dysfunction and abnormal Ca2+ modulation during postischemic reperfusion in rat heart. 784 Feb 55

The purpose of the present study was to determine whether Na(+)-H+ and Na(+)-Ca2+ exchanges modulate postischemic recovery of excitation-contraction coupling. Experiments were performed in 43 isolated isovolumic dog hearts perfused with blood (pH 7.40, 141 mmol/L Na+, 34 degrees C, paced at 2 Hz). A 3 x 3-mm region at the left ventricular (LV) apex was loaded with aequorin for monitoring [Ca2+]i simultaneously with LV pressure. No-flow ischemia for 2 to 3 minutes was followed by 20 minutes of aerobic reperfusion with (1) unmodified control blood (141 mmol/L Na+, pH 7.40), (2) acidemic blood (141 mmol/L Na+, pH 6.60, at 0 to 3 minutes of reperfusion), (3) hypernatremic blood (149 or 157 mmol/L Na+, pH 7.40, at 0 to 20 minutes of reperfusion), or (4) hyperosmotic blood (141 mmol/L Na+ + 30 mmol/L mannitol, pH 7.40, at 0 to 20 minutes of reperfusion). Reperfusion with unmodified control blood was immediately followed by an increase in [Ca2+]i and LV systolic and diastolic pressure that persisted for 2 to 3 minutes before returning to or below baseline. Ventricular arrhythmia occurred during this period (> 80%). This transient increase of [Ca2+]i was attenuated by acidemic or hypernatremic perfusate. With acidemic or hypernatremic reperfusion, recovery of LV developed pressure at 20 minutes was more complete than with unmodified control reperfusion: acidemic blood (n = 7), 93 +/- 3% (P < .01); hypernatremic blood (149 mmol/L Na+, n = 7), 89 +/- 2% (P < .02); hypernatremic blood (157 mmol/L Na+, n = 4), 91 +/- 2% (P < .01); and unmodified control blood (n = 17), 80 +/- 2%. With hyperosmotic reperfusion, recovery of LV developed pressure at 20 minutes was not improved (82 +/- 3%). From these results we conclude that (1) an increase in intracellular Ca2+ occurs transiently after no-flow ischemia and may cause arrhythmia and decreased Ca2+ responsiveness of the contractile elements, (2) acidemic and hypernatremic reperfusion ameliorates postischemic dysfunction by preventing the increase in intracellular Ca2+, suggesting that (3) Na(+)-H+ and Na(+)-Ca2+ exchange may play important modulatory roles during reperfusion.
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PMID:Acidemia and hypernatremia enhance postischemic recovery of excitation-contraction coupling. 818 86

Effects of the Ca2+ sensitizer N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride (Org-30029) on the myocardial contractile depression induced by acidosis and 2,3-butanedione monoxime (BDM) were investigated in aequorin-loaded canine ventricular myocardium. The peak Ca2+ transient-peak force relation during administration of Org-30029 (10(-4) to 10(-3) M) was shifted to the left and upward compared with the relation for elevation of the extracellular Ca2+ concentration ([Ca2+]o) (2.5-12.5 mM). Acidosis (pH 6.6) depressed the force with a small increase in the peak Ca2+ transient. BDM (3 mM) depressed the force with no change in the peak and duration of the Ca2+ transient, indicating that BDM may inhibit selectively the cross-bridge interaction. During acidosis or in the presence of BDM, elevation of [Ca2+]o increased the peak Ca2+ transient to the same extent as that in the control, but the force was inhibited. In contrast, Org-30029 increased the force to a level equivalent to the control with a slight change in the peak Ca2+ transient. In addition, during acidosis, Org-30029 (10(-3) M) increased the force in association with a slight decrease in the peak Ca2+ transient. Thus Org-30029 can reverse the myocardial contractile depression induced by a decrease in the Ca2+ sensitivity of myofilaments, as occurs in pathophysiological situations such as acidosis in cardiac ischemia. Org-30029 may exert the Ca(2+)-sensitizing effect by an increase in the affinity of troponin C for Ca2+ and by a direct action on the cross-bridge interaction.
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PMID:Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium. 894 98


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