Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: DrugBank:EXPT00514 (Amiloride)
1,513 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of amiloride on mechanical, electrical and mitochondrial function as well as ultrastructural integrity, in isolated rat hearts subjected to 30 min low-flow ischemia and 30 min reperfusion. In control hearts, ischemia produced a rapid loss of contractility and a concomitant elevation in resting tension which were associated with a 100% incidence in arrhythmic activity. Reperfusion produced a 22 and 54% recovery in force and rate of force (dF/dt) development, respectively. In control hearts the incidence of arrhythmias was 100% within 5 min of reperfusion which then declined to 50% by 30 min. Ultrastructural defects in these hearts were restricted primarily to mitochondrial damage. Amiloride significantly attenuated the elevation in resting tension at the end of ischemia. Postischemic recovery was significantly increased to 38 and 86% for force and dF/dt, respectively and the incidence of arrhythmias was reduced to 30%. No ultrastructural defects were ever observed in amiloride-treated reperfused hearts. Both interfibrillar and subsarcolemmal mitochondria exhibited depressed respiratory function and adenine nucleotide translocase activity. Although virtually all parameters tended to be elevated in mitochondria isolated from amiloride-treated hearts, a significant increase was seen in only one case. Our results therefore demonstrate an ability of amiloride to enhance postischemic contractile recovery and reduce the incidence of arrhythmias, particularly during reperfusion, an effect associated with virtual total prevention of ultrastructural defects. Although the salutary effect was not significantly correlated to improved mitochondrial function, this dissociation may have been due to removal of damaged mitochondria during the isolation process, in view of diminished mitochondrial damage as viewed by transmission electron microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effects of amiloride on the ischemic reperfused rat heart. Relation to mitochondrial function. 160 Oct 55

The present study was designed to examine whether activation of Na+/H+ exchange and subsequent massive Ca2+ influx via Na+/Ca2+ exchange are involved in the pathogenesis of myocardial reperfusion injury. We tested the effects of 1 mM amiloride, which is known to inhibit both Na+/H+ and Na+/Ca2+ exchange, and 3 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), which is known to act as a specific inhibitor against Na+/H+ exchange, on the incidence of ventricular arrhythmias, isovolumic left ventricular function and creatine kinase (CK) release during reperfusion after 15 or 30 min of global ischemia in the isolated and perfused guinea pig heart. Treatment of a normally perfused heart with amiloride decreased heart rate significantly and tended to increase coronary flow and left ventricular developed pressure (LVDP), whereas treatment with EIPA decreased all of these 3 measurements significantly. Treatment with amiloride or EIPA for 15 min before ischemia, and during reperfusion after 15 min of ischemia, under electrical pacing at 240 rpm to eliminate a negative chronotropic effect abolished ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion associated with highly significant inhibition of increases in left ventricular end-diastolic pressure (LVEDP) and CK release. Amiloride or EIPA pretreatment also inhibited the incidence of VF and increases in LVEDP and CK release significantly during reperfusion after 30 min of ischemia. However, amiloride was more effective in preventing these events than EIPA. The treatment with amiloride or EIPA only during reperfusion after 15 or 30 min of ischemia also decreased the incidence of VF and inhibited the increases in LVEDP and CK release significantly, though less effectively than the pretreatment modality. These results suggest that EIPA prevents ventricular arrhythmias, contracture and myocardial cellular injury during reperfusion after 15 min of ischemia by inhibiting Na+/H+ exchange, while amiloride exerts more powerful protection against these events than EIPA during reperfusion after 30 min of ischemia by inhibiting both Na+/H+ and Na+/Ca2+ exchange.
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PMID:Effects of amiloride and an analogue on ventricular arrhythmias, contracture and cellular injury during reperfusion in isolated and perfused guinea pig heart. 194 91

With the use of microelectrodes, intracellular pH (pHi), surface pH (pHs), and intracellular Na+ activity (aiNa) were measured in isolated guinea pig papillary muscles during normal superfusion and during a reversible condition of simulated ischemia. Acid loading by NH+4 prepulse or by CO2-HCO3- addition during superfusion with pH 7.4 solutions caused internal acidification followed by a recovery of pHi, which could be inhibited by amiloride. pHi recovery was associated with an amiloride-sensitive peak rise of aiNa and membrane hyperpolarization, indicative of Na(+)-H+ exchange. Peak increase of aiNa was absent if the pH of the superfusion solution was concomitantly lowered. Imposed ischemia after control superfusion caused membrane depolarization and acidification of pHi and pHs. The change of pHs consistently was larger than that of pHi. aiNa decreased from 5.5 to 4.6 mM after 10-min ischemia. Enlarging the pHi (and pHs) decrease in ischemia by prior reduction of the tissue buffer capacity (CO2-HCO3(-)-free superfusion) was unable to induce a rise of aiNa during the subsequent ischemic period. Amiloride had no significant effect on aiNa during ischemia. It is concluded that the important acidification of pHs reduces the rate of pHi regulatory Na(+)-H+ exchange and thereby contributes to a longer maintenance of the Na+ electrochemical gradient in ischemic cardiac muscle.
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PMID:Acidification and intracellular sodium ion activity during stimulated myocardial ischemia. 216 81

Amiloride has previously been shown to facilitate receptor binding of atrial natriuretic factor (ANF) to membranes of adrenal cortex and to enhance ANF induced inhibition of steroid secretion in vitro. This interaction of amiloride and ANF also holds true for the cardiovascular system. In precontracted rabbit aortic strips the relaxing effect induced by the combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was overadditional. The production of cyclic guanosine monophosphate (cGMP), which parallels ANF induced relaxations of vascular strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of ANF (10(-8) mol/l). In spontaneously hypertensive rats ANF-induced decreases in blood pressure were potentiated by amiloride. Post ischemia reperfusion arrhythmias in isolated rat hearts were reduced by ANF. Amiloride increased this effect. The binding experiments revealed an interaction of amiloride and ANF on the receptor level. Binding of labeled ANF to aortic tissue was concentration-dependently increased by amiloride. Addition of ATP had the opposite effect. Therefore it can be suggested that amiloride and ATP interfere with a mechanism regulating the sensitivity of the vascular ANF-receptor for its ligand regarding binding and signal transforming presumably by a kinase mediated phosphorylation/dephosphorylation process.
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PMID:Potentiation of the effects of atrial natriuretic factor on the cardiovascular system by amiloride. 255 51

Amiloride (40 micrograms/ml) was studied in the isolated rat heart subjected to low-flow ischemia followed by reperfusion. Reperfusion after 30 min of ischemia produced recoveries of force, rate of force development (+dF/dt), and rate of relaxation (-dF/dt) of 42, 82, and 71%, respectively, in control hearts. Amiloride did not enhance the maximum degree of recovery, although, when present during ischemia, it markedly shortened the time required for peak recovery. Reperfusion after 60 min of ischemia resulted in 18, 43, and 34% recovery of force, +dF/dt, and -dF/dt, respectively. Amiloride significantly enhanced recovery to a maximum of 39, 88, and 78% for force, +dF/dt, and -dF/dt, respectively. The improved contractile recovery was accompanied with substantial reductions in the release of creatine kinase (CK) and 6-ketoprostaglandin F1 alpha. Coronary perfusion pressure and resting tension were generally unaffected by amiloride, although there was a moderate tendency to attenuate these parameters after reperfusion. The salutary effects of amiloride were dependent on the drug's presence during ischemia with maximum protection when it was administered during both ischemia and reperfusion and no benefit when added at the time of reperfusion. Because of amiloride's well-documented property in inhibiting Na+-H+ exchange, it is possible that this process plays an important role in modulating the cardiac response to reperfusion.
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PMID:Amiloride enhances postischemic ventricular recovery: possible role of Na+-H+ exchange. 284 57

We tested the hypothesis that Na+/H+ exchange contributes to reperfusion stunning and arrhythmias. The effects of amiloride, an established inhibitor of Na+/H+ exchange, were compared with those of a new inhibitor (HOE 694). Working hearts, subjected to 20-min global ischemia and reperfused for 30 min, were pretreated (for 5 min before ischemia) or reperfused (initial 2 min) with HOE 694 or amiloride. Pretreatment with 10(-7) M HOE increased recovery of aortic output (AO) after 30-min reperfusion: As a percentage of the preischemic controls, values were 38.5 +/- 3.6% (n = 7) for controls versus 50.6 +/- 3.9% (n = 5) for the treated group (p < 0.05). Pretreatment with HOE (10(-6) M) increased AO recoveries from 38.2 +/- 2.0% (n = 5) to 52.9 +/- 2.7% (n = 5) (p < 0.05). Amiloride (10(-5) M) pretreatment improved AO recoveries from 41.6 +/- 2.7% (n = 6) to 55.8 +/- 4.0% (n = 6) (p < 0.05). Thus, pretreatment by both HOE 694 and amiloride decreased reperfusion stunning. Adding HOE (10(-7) M) only in the reperfusion period increased AO recoveries from 36.4 +/- 1.2% (n = 6) to 62.4 +/- 3.2% (n = 11) (p < 0.002). Amiloride (10(-5) or 10(-3) M) added only during reperfusion did not improve recovery of AO. HOE 694, active in much lower concentrations than amiloride, was the only compound active against stunning when added only during reperfusion. In addition, both compounds inhibited reperfusion arrhythmias when added at reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role for the Na+/H+ exchanger in reperfusion stunning in isolated perfused rat heart. 750 8

Intracellular acidification may be the initial stimulus for a cascade of events contributing to intracellular calcium overload. Ischaemia results in the accumulation of lactate and other proton donors causing intracellular acidification. During reperfusion the activity of the Na+/H+ exchanger recovers, allowing extrusion of protons at the expense of increases in intracellular sodium. The rise in intracellular sodium decreases the gradient required for sodium calcium exchange, resulting in accumulation of intracellular calcium. These data are in keeping with the pathophysiological model that the Na+/H+ exchanger is an important part of a cascade leading from intracellular acidosis to intracellular sodium loading followed by calcium overload. From this model we predicted that amiloride would be antiarrhythmic. In 1988, we reported that low concentration of amiloride (0.1-0.3 microM) suppresses the induction of sustained ventricular tachyarrhythmias in dogs late following infarction. Amiloride suppressed inducible ventricular tachycardia in approximately 50% of the animals. In an extension of this work we assessed the efficacy of amiloride in suppressing inducible ventricular tachycardia in humans who presented with symptomatic ventricular tachycardia. In that study, amiloride manifested antiarrhythmic activity, but not to the degree that was observed in our dog model. Six of 31 patients (19%) had complete suppression of induced ventricular tachycardia. In an extension of this work, we assessed in our in vivo dog model which of the pharmacological effects of amiloride were associated with antiarrhythmic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical and in vivo antiarrhythmic potential of sodium-hydrogen exchange inhibitors. 773 94

To determine the role of various Na+ transport systems in the edema fluid accumulation after ischemia and reperfusion in the lung, we evaluated the effect of amiloride (a Na+ channel blocker), ouabain (a Na(+)-K(+)-adenosinetriphosphatase blocker), and phloridzin (a Na(+)-glucose cotransport blocker) in isolated rat lungs. Ischemia and reperfusion (I/R) significantly increased the edema accumulation, with the wet-to-dry weight ratios increasing to 10.14 +/- 0.58 from 6.03 +/- 0.05 in control lungs (P < 0.04). Amiloride significantly augmented the amount of edema fluid (wet-to-dry weight ratio 12.26 +/- 0.77), and ouabain further increased the amount of edema (wet-to-dry weight ratio 18.58 +/- 1.00). Phloridzin did not significantly affect edema formation associated with I/R. Isoproterenol decreased the amount of edema formation in the presence and absence of amiloride. This occurred because the endothelial permeability as assessed by filtration coefficient was restored to normal values and less edema formed. The present study indicates that Na+ channels and Na(+)-K(+)-adenosinetriphosphatase, components of the active Na+ absorption transport system, are very important in opposing edema fluid accumulation in rat lungs subjected to I/R injury and operate as an edema safety factor. However, if the endothelial damage associated with I/R is allowed to persist, then the transport processes, even if operative, are insufficient to prevent continuous edema accumulation.
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PMID:Vascular permeability and epithelial transport effects on lung edema formation in ischemia and reperfusion. 783 12

The roles of the Na+/H+ exchange system in the development and cessation of reperfusion induced ventricular arrhythmias were studied in the isolated perfused rat heart. The hearts were perfused in the working heart mode with modified Krebs Henseleit bicarbonate (KHB) buffer and whole heart ischemia was induced by a one-way ball valve with 330 beat/min pacing. Ischemia was continued for 15 min followed by 20 min of aerobic reperfusion (control). Amiloride (1.0 mM), an inhibitor of the Na+/H+ exchange system, was added to the KHB buffer only during reperfusion (group B) or only during ischemic periods (group C). Electrocardiographic and hemodynamic parameters were monitored throughout the perfusion. Coronary effluent was collected through pulmonary artery cannulation and PO2, PCO2, HCO3- and pH were measured by blood-gas analyzer. The incidence of reperfusion induced ventricular arrhythmias was 100%, 100% and 0% in control, group B and group C, respectively. The mean onset time of termination of reperfusion arrhythmias was significantly shorter in group B than in control. PCO2 increased from 39.0 +/- 0.9 to 89.3 +/- 6.0 mmHg at the end of ischemia in control and from 40.6 +/- 0.4 to 60.5 +/- 5.8 in group C, the difference between groups was statistically significant. HCO3- level decreased from 21.8 +/- 0.1 to 18.3 +/- 0.5 mmol/l in control, however, this decrease was significantly inhibited in group C (from 22.0 +/- 0.5 to 20.3 +/- 0.2). The increase in PCO2 and the decrease in HCO3- in group B were similar over time to those observed in control.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Na+/H+ exchanger and reperfusion-induced ventricular arrhythmias in isolated perfused heart: possible role of amiloride. 838 97

Although many causal factors have been proposed for the ischemia-reperfusion injury, the exact mechanisms for interdependent derangements of mechanical, electrical and metabolic events remains unclear. For this purpose, the Langendorff-perfused rat hearts were subjected to regional brief ischemia followed by reperfusion to study the protective effects of amiloride, an inhibitor of Na(+)-H+ exchange. Amiloride (0.1 mM) attenuated the rise in tissue Na+ and Ca2+, both duration and incidence of arrhythmias (p < 0.05 vs. control), sarcolemmal injury (assessed by Na-K ATPase) and lipid peroxidation (assessed by malonedialdehyde formation) during reperfusion. Treatment of hearts with monensin, a sodium inophore, reversed the protective effects of amiloride. Reduction in transsarcolemmal Na+ and pH gradients during ischemia exhibited protective effects similar to those seen with amiloride. These results suggest that cardiac dysfunction, sarcolemmal injury and triggered arrhythmias during ischemia-reperfusion are due to the occurrence of intracellular Ca2+ overload caused by the activation of Na(+)-H+ exchange and Na(+)-Ca2+ exchange systems in the myocardium.
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PMID:Effects of amiloride on the mechanical, electrical and biochemical aspects of ischemia-reperfusion injury. 838 83


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