Targeting the myocardial sodium-hydrogen exchange for treatment of heart failure.
Although the past number of years have seen a substantial improvement in the therapeutic approaches for the treatment of heart failure, mortality rates continue to be high. Moreover, the incidence of heart failure is expanding rapidly. Sodium-hydrogen exchange (NHE) is a key target for the treatment of heart failure. NHE is a major mechanism for intracellular pH regulation in most cell types, including the cardiac cell. Seven isoforms of NHE have been identified so far although cardiac cells possess primarily the ubiquitous NHE-1 subtype. NHE-1 is a major contributor to ischaemic and reperfusion injury and NHE-1 inhibitors exert marked cardioprotective effects, particularly when administered before ischaemia, findings which have now been extended to clinical trials. It is emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertropic factors such as angiotensin II, endothelin-1 and beta(1) adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure.
Morris
Karmazyn
K
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario N6A 5C1, Canada. mkarm@uwo.ca
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000188:drug therapy; D017136:Ion Transport / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy; D051381:Rats; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects
D002317:Cardiovascular Agents; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D012964:Sodium