Effect of ramipril and furosemide treatment on interstitial remodeling in post-infarction heart failure rat hearts.
Extracellular matrix (ECM) remodeling and increased matrix metalloproteinase (MMP) expression and activity have been observed to be relevant in the development of heart failure (HF). We examined the effects of ramipril alone or with furosemide on ECM in a heart failure model. HF was induced by occlusion of the left coronary artery in spontaneously hypertensive rats (SHR). Rats were assigned to placebo (n=9), ramipril 1 mg/kg/day (n=11), furosemide 2 x 2 mg/kg/day (n=7) or both (1 mg/kg/day + 2 x 2 mg/kg/day n=8). LV-function, collagen content, MMP/TIMP (tissue inhibitor of matrix metalloproteinases) protein- and mRNA-expression were examined in non-infarcted LV tissue. MMP-2/TIMP-4 ratio was increased in HF. Ramipril reduced MMP-2 expression (active form), collagen type I mRNA expression and content and increased TIMP-4 levels associated with decreased left ventricular end diastolic pressure (LVEDP), mortality rate and increased LV pressure (LVP). Combination therapy with furosemide is less efficient with regard to collagen content and MMP-2 (active form) reduction but did not worsen beneficial effects of ramipril on LV function and mortality rate. Furosemide alone had no effect on MMP-2 (active form) expression, collagen content, LV function and mortality rate. Prevention of LV dilatation by ramipril was associated with decreased gelatinolytic activity and increased MMP-inhibition in heart failure SHR. Furthermore, ramipril reduced fibrosis by enhanced interstitial collagenase expression. Furosemide did not show the beneficial effects of ramipril on ECM remodeling but did not worsen LV function. Positive effects of furosemide treatment alone on LV remodeling and function were not observed.
Seeland
Ute
U
Med. Univ.-Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III -- Kardiologie und Angiologie, 66421 Homburg/Saar, Germany.
Kouchi
Ichiro
I
Zolk
Oliver
O
Itter
Gabi
G
Linz
Wolfgang
W
Böhm
Michael
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000502:physiology; D005665:Furosemide / Q000494:pharmacology*; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications; D009206:Myocardium / Q000473:pathology; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D020257:Ventricular Remodeling / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D016326:Extracellular Matrix Proteins; D005665:Furosemide; D008666:Metalloendopeptidases; D017257:Ramipril