Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia.
The cardiac sarcolemmal Na+/H+ exchanger extrudes intracellular H+ in exchange for Na+, in an electroneutral process. Of the 6 mammalian exchanger isoforms identified to date, the Na+/H+ exchanger (NHE)-1 is believed to be the molecular homolog of the sarcolemmal Na+/H+ exchanger. The exchanger is activated primarily by a reduction in intracellular pH (intracellular acidosis), although such activation is subject to modulation by a variety of endogenous mediators (e.g., catecholamines, thrombin, endothelin) through receptor-mediated mechanisms. A large body of preclinical evidence now suggests that inhibition of the sarcolemmal Na+/H+ exchanger attenuates many of the unfavorable consequences of acute myocardial ischemia and reperfusion. Much of this evidence has been obtained with recently developed potent, selective inhibitors of the exchanger, such as HOE-642 (cariporide) and its structurally related congener HOE-694, in studies using both in vitro and in vivo models of ischemia and reperfusion in a variety of species. The data from these studies indicate that Na+/H+ exchange inhibition leads to a decreased susceptibility to severe ventricular arrhythmia, attenuates contractile dysfunction, and limits tissue necrosis (i.e., decreases infarct size) during myocardial ischemia and reperfusion. Such protection is likely to arise, at least in part, from attenuation of "Ca2+ overload," which has been linked causally with all of these pothologic phenomena. The consistent and marked cardioprotective benefit that has been observed with cariporide and related compounds in preclinical studies suggests that Na+/H+ exchange inhibition may represent a novel and effective approach to the treatment of acute myocardial ischemia in humans.
Avkiran
M
M
Cardiovascular Research, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006146:Guanidines / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism; D009336:Necrosis; D010101:Oxygen Consumption / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000209:etiology
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; C093373:cariporide