Na(+)/H(+) exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats.
We investigated the effect of sodium/hydrogen exchange inhibition (NHE-1) on hypertrophy and heart failure after coronary artery ligation (CAL) in the rat. Animals were subjected to occlusion (or sham) of the left main coronary artery and immediately administered a control diet or one consisting of the NHE-1 inhibitor cariporide for 13-15 wk. Hearts were separated by small [</=30% of left ventricle (LV)] and large (>30% of LV) infarcts. CAL depressed change in left ventricular increase in pressure over time (LV +dP/dt) in small and large infarct groups by 18.8% (P < 0.05) and 34% (P < 0.01), respectively, whereas comparative values for the cariporide groups were 8.7% (not significant) and 23.1% (P < 0.01), respectively. LV end-diastolic pressure was increased by 1,225% in the control large infarct group but was significantly reduced to 447% with cariporide. Cariporide also significantly reduced the degree of LV dilation in animals with large infarcts. Hypertrophy, defined by tissue weights and cell size, was reduced by cariporide, and shortening of surviving myocytes was preserved. Infarct sizes were unaffected by cariporide, and the drug had no influence on either blood pressure or the depressed inotropic response of infarcted hearts to dobutamine. These results suggest an important role for NHE-1 in the progression of heart failure after myocardial infarction.
Kusumoto
K
K
Department of Pharmacology and Toxicology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
Haist
J V
JV
Karmazyn
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000494:pharmacology*; D002306:Cardiac Volume; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D006146:Guanidines / Q000097:blood / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D015994:Incidence; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000097:blood / Q000494:pharmacology*; D016019:Survival Analysis; D014693:Ventricular Fibrillation / Q000401:mortality; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D018342:Receptors, Adrenergic, beta-1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide