Effects of 5-(N,N-Hexamethylene) Amiloride on Action Potentials, Intracellular Na, and pH of Guinea Pig Ventricular Muscle In Vitro

Lai, Zhong-Fang; Hotokebuchi, Nobuo; Cragoe, Edward J.; Nishi, Katsuhide

doi:10.1097/00005344-199402000-00013

Cited by 21 publications

(7 citation statements)

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“…Therefore, if amiloride is used in an experiment at a concentration of 100 to 1000 pM, inhibition of the Na+/H+ exchanger, voltage-dependent Na+ channel and Ca 21 channel can all be expected. Moreover, this agent has been observed to exert a depressant action on cardiac Na+ channels at 1000 pM in guinea pig ventricular muscle (16). These findings suggest that we can employ amiloride as a selective epithelial Na+ channel inhibitor at a concentration of less than 30 pM.…”

Section: Measurement Of Membrane Ion Transporter Activitiesmentioning

confidence: 79%

Non-selective Effects of Amiloride and Its Analogues on Ion Transport Systems and Their Cytotoxicities in Cardiac Myocytes

Murata¹,

Harada²,

Nakajima³

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-The effects of amiloride and its analogues (3',4'-dichlorobenzamil (DCB), 2',4'-dimethylbenzamil (DMB), 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and 5-(N-methyl-N-isobutyl)amiloride (MIBA)) on cardiac ion transporters (Na+/Ca2+ exchanger, Na+/H+ exchanger, Na+ pump and Ca 21 pump) and their cytotoxicities were tested in cardiac myocytes. All the tested compounds showed concentration-dependent inhibitory effects on the ion transporters studied in canine cardiac sarcolemmal vesicles. The concentrations (NM) of amiloride, DCB, DMB, EIPA and MIBA required to produce 50% inhibition were > 1000, 19, 10, 83 and 84, respectively, for the Na+/Ca2+ exchanger; 130, 73, 63, 16 and 14 for the Na+/H+ exchanger; > 1000, 72, > 300, > 300 and > 300 for the Na+ pump; and > 1000, 37, 93, 90 and 70 for the Ca 21 pump, respectively. Furthermore, these agents induced cell death in isolated rat cardiac myocytes and the 50% lethal concentrations (,uM) were > 1000, 9.2, 30, 16 and 17, respectively. These findings demonstrate that amiloride and its analogues have non-selective inhibitory effects on cardiac ion transporters and cytotoxicity in cardiomyocytes. When these drugs are employed as experimental tools to investigate the involvement of ion transporters in cell functions, the results must be interpreted with caution.

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Section: Measurement Of Membrane Ion Transporter Activitiesmentioning

confidence: 79%

Non-selective Effects of Amiloride and Its Analogues on Ion Transport Systems and Their Cytotoxicities in Cardiac Myocytes

Murata¹,

Harada²,

Nakajima³

et al. 1995

Japanese Journal of Pharmacology

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“…In fact, the classic Na + /H + exchange inhibitor amiloride was reported to improve postischemic functional recovery and attenuate intracellular Ca 2+ overload [22]. Amiloride or other nonselective amiloride derivatives, however, are known to act on Na + / Ca 2+ exchanger, the T-type Ca 2+ and tetrodotoxin-sensitive Na + channel as well, which afford detrimental effects for nephron or hypotension [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Na<sup>+</sup>/H<sup>+</sup> Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

Nakai¹,

Horimoto²,

Mieno³

et al. 2002

Eur Surg Res

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Background: Inhibition of Na⁺/H⁺ exchange has been shown to provide functional protection during ischemia and reperfusion in mature heart. This study was undertaken to elucidate the effect of Na⁺/H⁺ exchange inhibitor HOE642 in the aged rabbit heart. Methods: Isolated rabbit hearts were subjected to 1 h of left descending coronary artery (LAD) ischemia and 1 h of reperfusion. To determine the effects of HOE642 on ischemia/reperfusion injury, seven aged or mature hearts received the Na⁺/H⁺ exchange inhibitor HOE642 (1 µM) for 15 min before the ischemia and for 30 min after reperfusion. Seven aged (more than 135 weeks) or mature (15–20 weeks) rabbit hearts served as a control (untreated) with no interventions. Left ventricular pressures, monophasic action potentials and coronary flows were measured throughout the experiment and infarct size was detected at the end of experiment. Results: (1) In the mature hearts, HOE642 improved postischemic functional recovery (63.1 ± 5.0% vs. 84.4 ± 5.4%, mature untreated vs. mature HOE, p < 0.05) and reduced infarct size as compared to untreated hearts (42.0 ± 2.5% vs. 24.8 ± 2.3%, mature untreated vs. mature HOE, p < 0.05). (2) Although infarct size in aged untreated hearts was significantly decreased as compared to mature untreated hearts (42.0 ± 2.5% vs. 19.3 ± 1.6%, mature untreated vs. aged untreated, p < 0.05), there are no significant differences regarding postischemic functional recovery between mature and aged untreated hearts (63.1 ± 5.0% vs. 59.5 ± 5.9%, mature untreated vs. aged untreated, p = n.s.). (3) In the aged hearts, HOE642 improved postischemic functional recovery as compared to untreated hearts (59.5 ± 5.9% vs. 85.9 ± 8.1%, aged untreated vs. aged HOE, p < 0.05). Conclusion: Na⁺/H⁺ exchange inhibitor HOE642 is effective against ischemia-reperfusion injury in senescent as well as mature hearts.

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“…The amiloride-sensitive Na ϩ -H ϩ exchanger has been noted in human T cells and a leukemic T cell line stimulated with IL-2 or anti-CD3 Ab (36,37) and has been reported in epithelial (38) and cardiac cells (39). Thus, the effects of amiloride on T cell proliferation may be explained by suppression on the Na ϩ -H ϩ exchange.…”

Section: Figurementioning

confidence: 94%

An Amiloride-Sensitive and Voltage-Dependent Na+ Channel in an HLA-DR-Restricted Human T Cell Clone

Lai

Chen

Nishimura

et al. 2000

The Journal of Immunology

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We investigated changes in voltage-gated Na+ currents and effects of extracellular Na+ on proliferation in HLA-DR-restricted human CD4+ αβ T cells after stimulation with a non-self antigenic peptide, M12p54–68. In the absence of antigenic peptide, neither single (n = 80) nor APC-contacted (n = 71) T cells showed voltage-gated inward currents recording with whole-cell patch-clamp techniques, even with Ca2+ and Na+ ions present in the perfusion solution. However, with the same recording conditions, 31% (26 of 84) of APC-contacted T cells stimulated with the antigenic peptide showed voltage-dependent inward currents that were elicited from −60 mV. The inward currents were not inhibited in extracellular Ca2+-free conditions or in the presence of 1 mM NiCl2. However, they were completely inhibited in extracellular Na+-free conditions, which were made by replacing Na+ with iso-osmotic N-methyl-d-glucamine or choline. The Na+ currents were insensitive to tetrodotoxin, a classical blocker of Na+ channels, but were dose-dependently inhibited by amiloride, a potassium-sparing pyrazine diuretic. Furthermore, the Ag-specific proliferative response of T cells was completely inhibited in Na+-free Tyrode’s solution and was suppressed by amiloride in a dose-dependent manner. Our findings suggest that activation of amiloride-sensitive and voltage-gated Na+ channels would be an important step to allow an adequate influx of Na+ and maintain a sustained high Ca2+ level during T cell activation.

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Effects of 5-(N,N-Hexamethylene) Amiloride on Action Potentials, Intracellular Na, and pH of Guinea Pig Ventricular Muscle In Vitro

Cited by 21 publications

References 0 publications

Non-selective Effects of Amiloride and Its Analogues on Ion Transport Systems and Their Cytotoxicities in Cardiac Myocytes

Non-selective Effects of Amiloride and Its Analogues on Ion Transport Systems and Their Cytotoxicities in Cardiac Myocytes

Na<sup>+</sup>/H<sup>+</sup> Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

An Amiloride-Sensitive and Voltage-Dependent Na+ Channel in an HLA-DR-Restricted Human T Cell Clone

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