Biomedical subjects

Daniela Fraccarollo

Publications and source records attributed to Daniela Fraccarollo.

21 records · Page 2Linked to original sources

PubMed2002

Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy.

OBJECTIVES: We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). METHODS: Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. RESULTS: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition. CONCLUSION: Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.

Actins↗

PubMed2002

Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling.

OBJECTIVES: Endothelin A (ETA) receptor blockade started early after myocardial infarction (MI) promotes adverse left ventricular (LV) dilatation. We tested the hypothesis that inhibition of ETA receptors during the early phase of healing affects collagen synthesis and accumulation, and induces expansion of infarcted myocardium. METHODS: Starting 3 h after coronary ligation, female Wistar rats were treated with the selective ETA receptor antagonist LU 135252 (30 mg/kg body wt/day) or placebo. A period of 7 days after MI, hemodynamic, morphometric and biochemical studies were performed. RESULTS: ET(A) receptor blockade enhanced infarct expansion index and decreased LV systolic function. Infarct scar of LU 135252-treated rats displayed decreased gene expression of fibrillar type I/III collagens and of transforming growth factor-beta(1) (TGF-beta(1)). Collagen content in the infarct scar and border regions was lower after ETA inhibition. In addition, Western blot analysis revealed, after ETA receptor blockade, enhanced matrix metalloproteinases MMP-13, and MMP-2 expression in the infarcted LV myocardium. CONCLUSIONS: These data demonstrate that endothelin stimulates collagen accumulation at the site of infarction. Decreased collagen and TGF-beta(1) gene expression, associated with enhanced infarct expansion and MMP up-regulation likely contributes to ETA receptor blockade-mediated deleterious effects on ventricular remodeling after infarction.

Animals↗

PubMed2002

Angiotensin-converting enzyme inhibition and endothelin antagonism for endothelial dysfunction in heart failure: mono-or combination therapy.

The effect of angiotensin-converting enzyme (ACE) inhibition and endothelin A (ET ) receptor antagonism alone and in combination on endothelial vasomotor dysfunction in chronic heart failure (CHF) was compared. Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats with experimental CHF 12 weeks after extensive myocardial infarction compared with sham-operated animals. Rats were treated with placebo, with the ET receptor antagonist LU 135252 (30 mg/kg/d), with the ACE inhibitor trandolapril (0.3 mg/kg/d), or with a combination of LU 135252 and trandolapril. Infarct size was similar among the groups. In the placebo group, the concentration-response curve of the endothelium-dependent, acetylcholine-induced relaxation was significantly shifted to the right and the maximum relaxation was attenuated (R 53 +/- 3%) compared with the sham placebo group (R 72 +/- 3%). Treatment with LU 135252 as well as trandolapril significantly improved acetylcholine-induced maximum relaxation (LU 135252 66 +/- 4%, trandolapril 67 +/- 4%, p < 0.05 versus CHF placebo). In addition to R (LU 135252/trandolapril 70 +/- 4%), combination therapy also improved the pathologic rightward shift (p < 0.05). Increased O production in CHF was significantly reduced in all treatment groups. The increased relaxation elicited by exogenous superoxide dismutase in CHF was reduced to normal values by monotherapy and further attenuated by combination treatment. Although monotherapy with the ACE inhibitor trandolapril and the ET receptor antagonist LU 135252 improved endothelial dysfunction in experimental CHF, combination therapy was more effective.

Angiotensin-Converting Enzyme Inhibitors↗