Effects of Na+-H+ exchange blocker amiloride on left ventricular remodeling after anterior myocardial infarction in rats

Hasegawa, Shuuichi; Nakano, Masayuki; Taniguchi, Yasuhiro; Imai, Shoichi; Murata, Katsuyuki; Suzuki, Tadashi

doi:10.1007/bf00879877

Cited by 31 publications

(11 citation statements)

References 19 publications

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“…The main focus of most of the studies was the development of hypertrophy and contractile function. In all these studies it was found that chronic inhibition of NHE-1 attenuates development of cardiac hypertrophy and improved contractile performance, which was associated, in most of the studies, with less signs of HF [20,59,62,[71][72][73][76][77][78][79]. Also it was found that the survival rate improved and that fibrotic structural changes and presence of apoptosis were decreased [20][21][71][72]79].…”

Section: Chronic Inhibition Of Nhe-1 During Development Of Hypertrophmentioning

confidence: 96%

“…Therefore, prevention of development of hypertrophy might be a beneficial treatment. Recent evidence suggests that NHE-1 is important in cardiac growth [47,[58][59][60][61] and that its activity is augmented by hypertrophic factors such as α 1 -adrenergic and β 1 -adrenergic activation [62,63], endothelin-I [64] and angiotensin-II [65,66]. This led to the hypothesis that NHE-1 may be a downstream mediator of these factors and that inhibition would prevent or reduce cellular hypertrophy and HF process (Fig.…”

Section: Chronic Inhibition Of Nhe-1 During Development Of Hypertrophmentioning

confidence: 98%

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Chronic Inhibition of Na+/H+-Exchanger in the Heart

Baartscheer

2006

CVP

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The incidence and prevalence of heart failure (HF) has increased over the last decades. The main reasons for this increase are the ageing population and an increase in survival rate after myocardial infarction and other cardiovascular diseases. Although, pharmacotherapy has significantly improved survival, the prognosis of HF is still rather poor. Total mortality is high and approximately half of the deaths are sudden and unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors generally given with diuretic and digoxin are the standard treatment for patients with HF. Despite the established benefits of ACE-inhibitors there is a need for new pharmacological tools for the treatment of HF. Recent experimental evidence has shown that activity of the Na(+)/H(+)-exchanger in the heart (NHE-1) is increased in HF. Because NHE-1 exchanges intracellular H(+) for extracellular Na(+) in a one by one stoichiometry, the intracellular ionic changes resulting from increased activity, will be a increased pH(i) and intracellular sodium ([Na(+)](i)). Activation of NHE-1 results only in a small increase in pH(i), under physiological conditions where bicarbonate-dependent mechanisms are active. However, a considerable increase in [Na(+)](i) was always present. The elevation of [Na(+)](i) might be responsible for the increase of intracellular calcium ([Ca(2+)](i)) levels mediated by the Na(+)/Ca(2+)-exchanger (NCX). Increases in [Na(+)](i), pH(i) and [Ca(2+)](i), features of cardiac myocytes isolated from failing hearts, are recognized as a cell growth signal And thus may play a role in the hypertrophic response, cellular remodeling and finally the development of HF. Acute application of cariporide, an inhibitor of NHE-1, on failing myocytes not only normalized [Na(+)](i) but also cytoplasmic and sarcoplasmic reticulum calcium handling and the propensity to develop delayed after depolarizations (DAD's). In several animal models of HF it has been shown the chronic inhibition of NHE-1 attenuates the development of hypertrophy and whole heart remodeling. Recently, in a volume and pressure overload model of HF in rabbits it has been demonstrated that chronic treatment also prevents the development of HF and cellular ionic and electrophysiological remodeling. Therefore, chronic treatment with an inhibitor of NHE-1 might prove beneficial in patients at risk of developing HF, especially when given at an early stage.

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Section: Chronic Inhibition Of Nhe-1 During Development Of Hypertrophmentioning

confidence: 96%

Section: Chronic Inhibition Of Nhe-1 During Development Of Hypertrophmentioning

confidence: 98%

Chronic Inhibition of Na+/H+-Exchanger in the Heart

Baartscheer

2006

CVP

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“…No obvious effect was observed (table 1). One mg/kg/day of amiloride, a nonselective inhibitor of the Na + /H + exchanger, has been reported to reduce the heart weight to body weight ratio at 28 days in a rat permanent occlusion model [20], which suggests that the Na + /H + exchanger could be involved in ventricular remodeling. Because we used a rat myocardial ischemia and reperfusion model, the infarct size was less than that of the permanent occlusion model.…”

Section: Discussionmentioning

confidence: 99%

Effects of SM-20550, a New Na<sup>+</sup>/H<sup>+</sup> Exchange Inhibitor, on Survival and Infarct Size in Rat Myocardial Infarction

Yamada¹,

Sasabe²,

Matsui³

et al. 2002

Pharmacology

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The effect of a novel potent Na⁺/H⁺ exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], on survival after myocardial infarction was studied. Anesthetized rats underwent occlusion of the coronary artery (30 min) followed by reperfusion (14 days). SM-20550 was administered intravenously before ischemia (1-day treatment group) or before ischemia and on the 2 days following (3-day treatment group). The infarct size was significantly reduced on the 14th day after surgery by approximately 17 and 20% in 1- and 3-day treatment groups, respectively. The survival rate on day 14 was significantly enhanced in both treatment groups (96%) compared with the vehicle-treated control group (70%). These results suggest that SM-20550 improved survival after myocardial infarction, at least due to its antinecrotic effect.

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“…For example, early studies have shown that orally administered amiloride, a nonspecific NHE inhibitor, reduces fiber diameter in rat coronary ligation [86] and murine dilated cardiomyopathy models [87]. Dietary administration of the NHE1 specific inhibitor cariporide completely abrogates the increased length of surviving myocytes after one week after coronary artery occlusion and ameliorates contractile dysfunction in the absence of afterload reduction, thereby implicating a direct effect of the drug on myocardial remodeling [88].…”

Section: Experimental Evidence For Nhe Involvement In Cardiomyocyte Hmentioning

confidence: 99%

The Na+/H+ Exchanger: A Target for Cardiac Therapeutic Intervention

Karmazyn¹,

Sawyer²,

Fliegel

2005

CDTCHD

105

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The Na(+)/H(+) exchanger (NHE) is a ubiquitous protein present in mammalian cells. In higher eukaryotes this integral membrane protein removes one intracellular H(+) for one extracellular Na(+) protecting cells from intracellular acidification. NHE is of essential importance in the myocardium. It prevents intracellular acidosis that inhibits contractility. NHE also plays a key role in damage to the mammalian myocardium that occurs during ischemia and reperfusion and is involved in hypertrophy of the myocardium. NHE is composed of a membrane bound domain of approximately 500 amino acids plus a hydrophilic regulatory cytoplasmic domain of approximately 315 amino acids. The NHE1 isoform is the only significant plasma membrane isoform present in the myocardium. The activity of NHE1 is elevated in animal models of myocardial infarcts and in left ventricular hypertrophy. During ischemia and reperfusion of the myocardium, NHE activity catalyzes increased uptake of intracellular sodium. This in turn is exchanged for extracellular calcium by the Na(+)/Ca(2+) exchanger resulting in calcium overload and damage to the myocardium. Numerous inhibitors of NHE have been developed to attempt to break this cycle of calcium overload. In animal models excellent success has been obtained in this regard. However in humans, clinical trials have resulted in only modest success and recently, significant detrimental side effects were note of one NHE inhibitor. The mechanisms by which these inhibitors affect NHE activity are presently being investigated and regions of the protein important in NHE activity and inhibitor efficacy are related but not identical. Future studies may develop superior inhibitors that may circumvent recently reported side effects. Recently, NHE inhibition has been shown to be remarkably effective in preventing hypertrophy in some animal models. Whether this proves to be a practical treatment for hypertrophy in humans has yet to be determined.

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Effects of Na+-H+ exchange blocker amiloride on left ventricular remodeling after anterior myocardial infarction in rats

Cited by 31 publications

References 19 publications

Chronic Inhibition of Na+/H+-Exchanger in the Heart

Chronic Inhibition of Na+/H+-Exchanger in the Heart

Effects of SM-20550, a New Na<sup>+</sup>/H<sup>+</sup> Exchange Inhibitor, on Survival and Infarct Size in Rat Myocardial Infarction

The Na+/H+ Exchanger: A Target for Cardiac Therapeutic Intervention

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