Infarct Size Limitation by a New Na-H Exchange Inhibitor, Hoe 642: Difference From Preconditioning in the Role of Protein Kinase C

Miura, Tetsuji; Ogawa, Takashi; Suzuki, Katsuo; Goto, Mahiko; Shimamoto, Kazuaki

doi:10.1016/s0735-1097(96)00522-0

Cited by 97 publications

(52 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This could be achieved by inhibiting I NHE or late I Na . Both approaches were cardioprotective in experimental models of ischemia/ reperfusion, since in this situation, an excessive increase of [Na + ] i contributes to progressive cytosolic and mitochondrial Ca 2+ -overload and thus, the induction of apoptosis through activation of the mitochondrial PTP [78,135,168,189]. Also in animal models of heart failure, both the inhibition of I NHE by cariporide and of late I Na by ranolazine reduced [Na + ] i and improved EC coupling and LV remodeling [6,34,38,62,163,202].…”

Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

View full text Add to dashboard Cite

Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

show abstract

Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

View full text Add to dashboard Cite

show abstract

“…In animal studies it exerted a powerful anti-infarct effect when present during an ischemic insult, but showed no benefit when present only after reperfusion. 39 In the EXPEDITION trial, 40 cariporide was tested in patients undergoing coronary bypass surgery. It was started prior to surgery and infusion continued for 24 h. Unfortunately, mortality caused by cerebrovascular events increased in the treatment group.…”

Section: Circulation Journal Vol73 July 2009mentioning

confidence: 99%

Why Do We Still Not Have Cardioprotective Drugs?

Downey

Cohen

2009

Circ J

125

View full text Add to dashboard Cite

Despite thousands of publications describing agents that limit infarct size in animals, all we have available today is reperfusion therapy. In this review, we examine why these drugs have not been translated into clinical practice.Many of the first interventions tested in clinical trials were very controversial in animal trials and their actual efficacy is still in question. Interventions based on the preconditioning mechanism have been very reproducible in animals, but clinical testing of them has just begun. Only approximately 25% of reperfused patients have infarcts large enough to put them at risk of heart failure and would require additional treatment. Inclusion of the 75% of patients with small infarcts in treatment groups has greatly diluted the significance of data in past clinical trials. Size of the risk zone has emerged as a reliable way to identify the vulnerable 25%. Recent small-scale clinical trials using risk stratification algorithms have shown clear infarct size limitation using ischemic and pharmacological postconditioning, confirming that the human heart responds like hearts of animal models. Most cardioprotectants have been studied in healthy animals, but recent studies indicate that aging and diabetes, common in coronary patients, do interfere with preconditioning-based interventions in animals. Clearly more study is needed to identify which interventions are adversely affected by comorbidities. (Circ J 2009; 73: 1171 -1177

show abstract

“…The amino acid sequence of NHE-1 has been demonstrated to be highly homologous in humans, rats and rabbits (495%, NoeÈ l & PouysseÂ gur, 1995), and for this reason T-162559 is thought to be capable of inhibiting rabbit NHE-1 and conferring on the rabbit heart tolerance against ischaemia and reperfusion. Cariporide and other NHE-1 inhibitors exert a similar cardioprotective eect in rabbits (Hendrikx et al, 1994;Miura et al, 1997;Munch-Ellingsen et al, 1998). In the rabbit model, T-162559 did not show a dose dependency between the two doses.…”

Section: Discussionmentioning

confidence: 84%

“…It protects the heart against ischaemia and reperfusion injury, limiting myocardial infarct size and suppressing ventricular ®brillation (Scholz et al, 1995;Aye et al, 1997;Miura et al, 1997). In addition, it has been reported that bolus intravenous administration of cariporide reduced the incidence of cardiac death and recurrent myocardial infraction in coronary artery bypass graft patients, based on the results of the GUARDIAN trial (TheÂ roux et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo pharmacology of a structurally novel Na⁺‐H⁺ exchange inhibitor, T‐162559

Kusumoto

Igata

Abe

et al. 2002

British J Pharmacology

View full text Add to dashboard Cite

3 T-162559 inhibited, in a concentration-dependent manner, the reduction in cardiac contractility, progression of cardiac contracture, and increase in lactate dehydrogenase release after global ischaemia and reperfusion in perfused rat hearts. The inhibitory eects of T-162559 were observed at a lower concentration range (10 ± 100 nmol l 71) than with cariporide and eniporide. T-162559 did not alter basal cardiac contractility or coronary¯ow after reperfusion, suggesting that it exerts direct cardioprotective eects on the heart. 4 Intravenous administration of T-162559 (0.03 and 0.1 mg kg 71) signi®cantly inhibited the progression of myocardial infarction induced by left coronary artery occlusion and reperfusion in rabbits; the infarct size normalized by area at risk was 74+6% in the vehicle group, and 47+5% and 51+7% in the T-162559-0.03 mg kg 71 and T-162559-0.1 mg kg 71 groups (both P50.05), respectively. 5 These results indicate that the new structural NHE-1 inhibitor T-162559 is more potent than cariporide and eniporide and possesses a cardioprotective eect against ischaemia and reperfusion injury in rat and rabbit models.

show abstract

Infarct Size Limitation by a New Na-H Exchange Inhibitor, Hoe 642: Difference From Preconditioning in the Role of Protein Kinase C

Cited by 97 publications

References 41 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Why Do We Still Not Have Cardioprotective Drugs?

In vitro and in vivo pharmacology of a structurally novel Na⁺‐H⁺ exchange inhibitor, T‐162559

Contact Info

Product

Resources

About

Infarct Size Limitation by a New Na-H Exchange Inhibitor, Hoe 642: Difference From Preconditioning in the Role of Protein Kinase C

Cited by 97 publications

References 41 publications

Excitation-contraction coupling and mitochondrial energetics

Excitation-contraction coupling and mitochondrial energetics

Why Do We Still Not Have Cardioprotective Drugs?

In vitro and in vivo pharmacology of a structurally novel Na+‐H+ exchange inhibitor, T‐162559

Contact Info

Product

Resources

About

In vitro and in vivo pharmacology of a structurally novel Na⁺‐H⁺ exchange inhibitor, T‐162559