eniporide and Myocardial-Ischemia

Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The National Heart, Lung, and Blood Institute convened a working group to discuss the reasons for the failure to translate potential therapies for protecting the heart from ischemia and reperfusion and to recommend new approaches to accomplish this goal. The Working Group concluded that cardioprotection in the setting of acute myocardial infarction, cardiac surgery, and cardiac arrest is at a crossroads. Present basic research approaches to identify cardioprotective therapies are inefficient and counterproductive. For 3 decades, significant resources have been invested in single-center studies that have often yielded inconclusive results. A new paradigm is needed to obviate many of the difficulties associated with translation of basic science findings. The Working Group urged a new focus on translational research that emphasizes efficacy and clinically relevant outcomes, and recommended the establishment of a system for rigorous preclinical testing of promising cardioprotective agents with clinical trial-like approaches (ie, blinded, randomized, multicenter, and adequately powered studies using standardized methods). A national preclinical research consortium would enable rational translation of important basic science findings into clinical use. The Working Group recommended that the National Institutes of Health proactively intervene to remedy current problems that impede translation of cardioprotective therapies. Their specific recommendations include the establishment of a preclinical consortium and the performance of 2 clinical studies that are likely to demonstrate effectiveness (phase III clinical trials of adenosine in acute myocardial infarction and cardiac surgery).

Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Coronary Artery Bypass; Drug Evaluation, Preclinical; Drug Utilization; Guanidines; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Prospective Studies; Sodium-Hydrogen Exchangers; Sulfones; Treatment Outcome

The myocardial Na+/H+ exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. However, there is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The mechanism for this most probably reflects the fact that activation of the exchanger is closely coupled to Na+ influx and therefore to elevation in intracellular Ca2+ concentrations through the Na+/Ca2+ exchange. The NHE is exquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects via phosphorylation-dependent processes. These generally represent various autocrine and paracrine as well as hormonal factors such as endothelin-1, angiotensin II and alpha1-adrenoceptor agonists, which probably act through receptor-signal transduction processes. Thus far, 6 NHE isoforms have been identified and designated as NHE1 through NHE6. All except NHE6, which is located intracellularly, are restricted to the sarcolemmal membrane. In the mammalian myocardium the NHE1 subtype is the predominant isoform, although NHE6 has also been identified in the heart. The predominance of NHE1 in the myocardium is of some importance since, as discussed in this review, pharmacological development of NHE inhibitors for cardiac therapeutics has concentrated specifically on those agents which are selective for NHE1. These agents, as well as the earlier nonspecific amiloride derivatives have now been extensively demonstrated to possess excellent cardioprotective properties, which appear to be superior to other strategies, including the extensively studied phenomenon of ischaemic preconditioning. Moreover, the salutary effects of NHE inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of the NHE in mediating injury is not species specific. The success of NHE inhibitors in experimental studies has led to clinical trials for the evaluation of these agents in high risk patients with coronary artery disease as well as in patients with acute myocardial infarction (MI). Recent evidence also suggests that NHE inhibition may be conducive to attenuating the remodelling process after MI, independently of infarct size reduction, and attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE offer substantial promise for clinical development for attenuation of both

Topics: Adenosine Triphosphate; Anti-Arrhythmia Agents; Cardiac Output, Low; Clinical Trials as Topic; Guanidines; Humans; Hydrogen-Ion Concentration; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Phosphorylation; Sodium-Hydrogen Exchangers; Sulfones

Blocking either the Na(+) channel or the Na(+)/H(+) exchanger (NHE) has been shown to reduce Na(+) and Ca(2+) overload during myocardial ischemia and reperfusion, respectively, and to improve post-ischemic contractile recovery. The effect of combined blockade of both Na(+) influx routes on ionic homeostasis is unknown and was tested in this study. [Na(+)](i), pH(i) and energy-related phosphates were measured using simultaneous (23)Na- and (31)P-NMR spectroscopy in isolated rat hearts. Eniporide (3 muM) and/or lidocaine (200 muM) were administered during 5 min prior to 40 min of global ischemia and 40 min of drug free reperfusion to block the NHE and the Na(+) channel, respectively. Lidocaine reduced the rise in [Na(+)](i) during the first 10 min of ischemia, followed by a rise with a rate similar to the one found in untreated hearts. Eniporide reduced the ischemic Na(+) influx during the entire ischemic period. Administration of both drugs resulted in a summation of the effects found in the lidocaine and eniporide groups. Contractile recovery and infarct size were significantly improved in hearts treated with both drugs, although not significantly different from hearts treated with either one of them.

Topics: Animals; Blood Pressure; Guanidines; Heart; Heart Rate; Hydrogen-Ion Concentration; Lidocaine; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Phosphates; Rats; Rats, Wistar; Sodium; Sodium Channel Blockers; Sodium Channels; Sodium-Hydrogen Exchangers; Sulfones

Cold cardioplegia protects against reperfusion damage. Blocking Na+/H+ exchange may be as protective as cardioplegia by improving the left ventricular pressure (LVP)-[Ca2+] relationship after cold ischemia. In guinea pig isolated hearts subjected to cold ischemia (4 h, 17 degrees C) and reperfusion, the cardioprotective effects of a Krebs-Ringer (KR) solution, a cardioplegia solution, a KR solution containing the Na+/H+ exchange inhibitor eniporide (1 microM), and a cardioplegia solution containing eniporide were compared. Treatments were given before and initially after cold ischemia. Systolic and diastolic [Ca2+] were calculated from indo-1 fluorescence transients recorded at the LV free wall. During ischemia, diastolic [Ca2+] increased in each group but more so in the KR group. Peak systolic and diastolic [Ca2+] on initial reperfusion were highest after KR and smallest after cardioplegia + eniporide. After reperfusion, systolic-diastolic LVP (% of baseline) and infarct size (%), respectively, were KR, 47 +/- 3%, 37 +/- 4%; cardioplegia, 71 +/- 5%*, 20 +/- 2.2%*; KR + eniporide, 73 +/- 5%*, 11 +/- 3%* dagger; and cardioplegia + eniporide 77 +/- 3%*, 10 +/- 1.4%* dagger (*P

Topics: Animals; Calcium; Cytosol; Guanidines; Guinea Pigs; Heart Arrest, Induced; Heart Rate; Heart Ventricles; Hypothermia, Induced; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion Injury; Sodium-Hydrogen Exchangers; Sulfones; Ventricular Pressure

1. We investigated the inhibitory effects of a non-acylguanidine Na(+)-H(+) exchange (NHE) inhibitor, T-162559 ((5E,7S)-[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylideneamino] guanidine dimethanesulphonate), on NHE-1, and its cardioprotective effect against ischaemia and reperfusion injury in rats and rabbits. 2. T-162559 inhibited human platelet NHE-1 in a concentration-dependent manner, with an IC(50) value of 13+/-3 nmol l(-1), making it 16 and three times more potent than cariporide IC(50): 209+/-75 nmol l(-1), P<0.01) and eniporide (IC(50): 40+/-11 nmol l(-1), P=0.066), respectively. T-162559 also inhibited rat NHE-1 with an IC(50) value of 14+/-2 nmol l(-1), which was five and three times lower than that of cariporide (IC(50): 75+/-7 nmol l(-1), P<0.01) and eniporide (IC(50): 44+/-2 nmol l(-1), P<0.01), respectively. 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 effects of T-162559 were observed at a lower concentration range (10 - 100 nmol l(-1)) than with cariporide and eniporide. T-162559 did not alter basal cardiac contractility or coronary flow after reperfusion, suggesting that it exerts direct cardioprotective effects on the heart. 4. Intravenous administration of T-162559 (0.03 and 0.1 mg kg(-1)) significantly 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(-1) and T-162559-0.1 mg kg(-1) groups (both P<0.05), 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 effect against ischaemia and reperfusion injury in rat and rabbit models.

Topics: Animals; Blood Platelets; Cardiotonic Agents; Dose-Response Relationship, Drug; Guanidines; Humans; In Vitro Techniques; Injections, Intravenous; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Quinolines; Rabbits; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Sulfones

Whereas inhibition of the Na(+)/H(+) exchanger (NHE) has been demonstrated to reduce myocardial infarct size in response to ischemia-reperfusion injury, the ability of NHE inhibition to preserve endothelial cell function has not been examined. This study examined whether NHE inhibition could preserve endothelial cell function after 90 min of regional ischemia and 180 min of reperfusion and compared this inhibition with ischemic preconditioning (IPC). In a canine model either IPC, produced by one 5-min coronary artery occlusion (1 x 5'), or the specific NHE-1 inhibitor eniporide (EMD-96785, 3.0 mg/kg) was administered 15 min before a 90-min coronary artery occlusion followed by 3 h of reperfusion. Infarct size (IS) was determined by 2,3,5-triphenyl tetrazolium chloride staining and expressed as a percentage of the area-at-risk (IS/AAR). Endothelial cell function was assessed by measurement of coronary blood flow in response to intracoronary acetylcholine infusion at the end of reperfusion. Whereas neither control nor IPC-treated animals exhibited a significant reduction in IS/AAR or preservation of endothelial cell function, animals treated with the NHE inhibitor eniporide showed a marked reduction in IS/AAR and a significantly preserved endothelial cell function (P < 0.05). Thus NHE-1 inhibition is more efficacious than IPC at reducing IS/AAR and at preserving endothelial cell function in dogs.

Topics: Acetylcholine; Animals; Coronary Circulation; Coronary Vessels; Dogs; Endothelium, Vascular; Guanidines; Heart Ventricles; Hemodynamics; Ischemic Preconditioning, Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Organ Size; Reperfusion Injury; Sodium-Hydrogen Exchangers; Sulfones

Topics: Amiloride; Animals; Guanidines; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Sodium; Sodium-Hydrogen Exchangers; Sulfones