PubMed Health⌕ Search

Biomedical subjects

Daniela Fraccarollo

Publications and source records attributed to Daniela Fraccarollo.

At least 19 recordsLinked to original sources
PubMed2006

The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.

OBJECTIVE: The chemokine fractalkine activates platelets and induces leukocyte adhesion to the endothelium. Expression of fractalkine and its receptor, CX3CR1, is elevated in coronary artery disease. We assessed the effects of fractalkine on vascular function in isolated rat aorta. METHODS AND RESULTS: CX3CR1 expression was demonstrated in rat aortic endothelial and smooth muscle cells by immunohistochemistry, Western blot, and polymerase chain reaction (PCR). Fractalkine (up to 1 microg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 microg/mL) for 5 minutes did not affect vascular reactivity. Pretreatment of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced nitric oxide (NO)-mediated relaxation after preconstriction with phenylephrine in a concentration-dependent manner. The concentration response to the NO donor DEA-NONOate was significantly shifted to the right. The radical scavenger tiron normalized the attenuated acetylcholine-induced relaxation after fractalkine incubation. Aortic superoxide formation was enhanced by fractalkine, which was inhibited by diphenyleneiodonium but not by inhibitors of xanthine oxidase or NO synthase. CONCLUSIONS: In addition to its role as a chemokine and adhesion molecule, fractalkine induces vascular dysfunction by stimulating vascular reactive oxygen species resulting in reduced NO bioavailability.

Acetylcholine↗
PubMed2006

Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects.

OBJECTIVES: Hypercholesterolemia contributes to coronary artery disease progression but little is known about its effect on left ventricular (LV) function after myocardial infarction (MI). The aim of this study was to investigate the effects of hypercholesterolemia and statin treatment in rabbits with experimental MI. METHODS AND RESULTS: New Zealand White rabbits on a normal or cholesterol-rich diet for 4 weeks, underwent permanent coronary artery ligation. Starting on the first day post-MI rabbits were treated with either placebo or simvastatin (5 mg/kg/day) for 9 weeks. Hypercholesterolemia itself did not affect LV function in sham-operated animals but further impaired LV systolic (dP/dtmax -42%) and diastolic (dP/dtmin -47%) function in MI rabbits on placebo. Simvastatin treatment not only prevented deterioration of LV function associated with hypercholesterolemia but improved LV function (dP/dtmax +130%; dP/dtmin +144%, P < 0.05). Simvastatin also attenuated the depression of LV function in normocholesterolemic MI rabbits (dP/dtmax +46%; dP/dtmin +53%, P < 0.05). Hypercholesterolemia in MI rabbits coincided with a significant increase in C-reactive protein levels (marker of inflammation) and Rac1-GTPase activity (marker of oxidative stress), and a reduction in cardiac sarcoplasmic-reticulum calcium ATPase-2 expression and endothelial nitric oxide synthase protein phosphorylation, all of which were normalised by simvastatin treatment. Elevated serum cholesterol levels were only partially reduced by simvastatin. CONCLUSIONS: Hypercholesterolemia further impaired the depressed LV function in rabbits post-MI. Statin treatment reversed this effect, and conferred additional protection, as in normocholesterolemic animals. Our study suggests that anti-inflammatory and anti-oxidative effects of simvastatin substantially contribute to its beneficial effects on cardiac function after MI.

Animals↗
PubMed2006

Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells.

OBJECTIVE: Standard drugs post-myocardial infarction (MI) such as angiotensin converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) increase levels of endothelial progenitor cells (EPC). However, potential underlying mechanisms have not yet been investigated. METHODS AND RESULTS: We studied the effects of ACE inhibition or statin treatment on EPC levels and on bone marrow molecular pathways involved in EPC mobilization after MI in rats. Three days post-infarction, acetylated LDL (acLDL)+/Ulex europeus-1 (UEA-1)+/VEGF receptor-2+/eNOS+ EPC levels and formation of endothelial colony forming units (CFU) were reduced to 60+/-12% (p < 0.05) and 68+/-7% (p < 0.05). In bone marrow, extracellular signal-regulated kinase (ERK) phosphorylation and matrix metalloproteinase (MMP)-9 activity were repressed. Endothelial nitric oxide synthase (eNOS) activity was unchanged, whereas reactive oxygen species (ROS) were increased two-fold in bone marrow. ACE or HMG-CoA reductase inhibition resulted in significant increases in EPC levels. ACE inhibition increased bone marrow ERK phosphorylation and MMP-9 activity. Statin therapy enhanced bone marrow VEGF protein levels, Akt phosphorylation, eNOS activity and normalized increased ROS levels. Augmented EPC levels in the early post-infarction phase by ACE inhibition or statin treatment were associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. Moreover, increased EPC levels in response to ACE inhibition or statin treatment were sustained 10 weeks post-infarction. CONCLUSIONS: Increased ROS and impaired MMP-9 activity in bone marrow likely contribute to reduced EPC mobilization in the early post-infarction phase. ACE inhibition or statin treatment increased EPC levels with distinct drug-specific effects on bone marrow molecular alterations.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.

OBJECTIVES: The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood. METHODS: We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats. RESULTS: Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed. CONCLUSIONS: Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Rosuvastatin reduces platelet activation in heart failure: role of NO bioavailability.

OBJECTIVES: Endothelial dysfunction and platelet activation are part of the cardiovascular phenotype in congestive heart failure (CHF). We investigated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition would beneficially modulate vascular NO bioavailability and platelet activation in experimental CHF. METHODS AND RESULTS: Chronic myocardial infarction was induced by coronary ligation in male Wistar rats. Animals were either treated with placebo or the HMG-CoA reductase inhibitor rosuvastatin. After 10 weeks, hemodynamic assessment was performed and endothelial function was determined in organ bath studies. NO bioavailability was assessed by in vivo platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Markers of platelet degranulation (surface expression of P-selectin and glycoprotein 53) were determined as well as the amount of circulating platelet-leukocyte aggregates. Endothelium-dependent, acetylcholine-induced vasorelaxation was significantly impaired in aortic rings from CHF rats and improved by rosuvastatin. In parallel, in vivo VASP phosphorylation reflecting NO bioavailability was significantly attenuated in platelets from CHF rats and normalized by rosuvastatin. Platelet activation, which was increased in CHF, was reduced by treatment with rosuvastatin. CONCLUSIONS: HMG-CoA reductase inhibition improved endothelial function, increased systemic NO bioavailability and inhibited exaggerated platelet activation in CHF rats. These mechanisms may contribute to the beneficial effects of statin treatment in CHF.

Animals↗
PubMed2004

Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent.

OBJECTIVE: The mitogen-activated protein (MAP) kinase system, especially the p38 MAP kinase, is activated in chronic heart failure (CHF). However, the role of vascular p38 MAP kinase in CHF has not been analyzed yet. METHODS AND RESULTS: In aortic rings from rats with CHF 10 weeks after myocardial infarction, acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax: 54+/-5%) compared to sham-operated animals (Rmax: 77+/-5%, p<0.01), while endothelium-independent relaxation elicited by sodium nitroprusside was not significantly changed. Aortic levels of phosphorylated p38 MAP kinase protein were significantly elevated in rats with CHF. In addition, phosphorylation of MAP kinase-activated protein kinase-2 (MAPKAPK-2), an index of p38 MAP kinase activity, was increased. Aortic superoxide anion generation was significantly enhanced in rats with CHF accompanied by elevation of the NAD(P)H oxidase subunit p47phox protein expression. Inhibition of p38 MAP kinase by treatment with the p38 MAP kinase inhibitor SB239063 (800 ppm in standard rat chow) reduced MAPKAPK-2 phosphorylation, preserved acetylcholine-induced relaxation (Rmax: 80+/-4%, p<0.01), and reduced vascular superoxide formation. SB239063 treatment did not affect blood pressure and left ventricular enddiastolic pressure. In aortic tissue from CHF animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril, p38 MAP kinase phosphorylation was significantly reduced. CONCLUSIONS: Vascular p38 MAP kinase is markedly activated in rats with CHF. Chronic p38 MAP kinase inhibition with SB239063 prevented endothelial vasomotor dysfunction through reduction of superoxide anion production.

Acetylcholine↗
PubMed2004

Endothelial dysfunction in congestive heart failure: ACE inhibition vs. angiotensin II antagonism.

BACKGROUND: Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure (CHF). The present study systematically investigated the effect of angiotensin II (AT(1))- receptor blockade on vascular superoxide (O(2)(-)) production and endothelial dysfunction. METHODS AND RESULTS: Vasodilator responses and O(2)(-) production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham-operated animals (Sham). Rats were either treated with placebo (P), with the AT(1)-receptor antagonist Irbesartan (50 mg kg(-1) day(-1)) or with the ACE inhibitor Trandolapril (0.3 mg kg(-1) day(-1)). In CHF-P, endothelium-dependent, acetylcholine-induced relaxation was significantly attenuated compared with Sham-P. Chronic treatment with Trandolapril or Irbesartan significantly improved endothelium-dependent relaxation. Aortic O(2)(-) formation was markedly increased in CHF, and was not significantly affected by Trandolapril treatment, while it was reduced by Irbesartan. eNOS expression was reduced in CHF and normalised by both treatments. CONCLUSION: Endothelial vasomotor function in CHF rats was normalised by long-term treatment with an ACE inhibitor or an AT(1)-antagonist. Reduced aortic eNOS expression was normalised by both treatments, whereas aortic superoxide formation was only reduced by the AT(1)-antagonist Irbesartan.

Analysis of Variance↗
PubMed2004

Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction.

The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.

Animals↗
PubMed2003

Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction.

OBJECTIVES: We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin-converting enzyme (ACE) inhibition on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). BACKGROUND: Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure. METHODS: Starting 10 days after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the ACE inhibitor trandolapril (0.3 mg/kg/day), or a combination of both for nine weeks. RESULTS: Both monotherapies attenuated the rise in LV end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVEDP and LVEDV, significantly improved LV function and reduced plasma norepinephrine levels. The time constant of LV pressure isovolumic decay (tau) was prolonged in placebo MI rats, significantly shortened by eplerenone, and normalized by eplerenone/trandolapril. Increased collagen type I gene expression and collagen content in the noninfarcted LV myocardium from MI placebo rats was attenuated by trandolapril, but almost completely prevented by eplerenone and eplerenone/trandolapril. The addition of eplerenone to ACE inhibition prevented sarcoplasmic-reticulum calcium ATPase downregulation and the increases in LV gene expression of beta-MHC and atrial natriuretic factor more effectively than either monotherapy. Furthermore, combination treatment attenuated the increase in myocardial angiotensin II type 1 receptor expression and increased phosphorylated endothelial nitric oxide synthase protein levels. CONCLUSIONS: The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion.

Chemokines released by the endothelium have proaggregatory properties on platelets. Fractalkine, a recently discovered membrane-bound chemokine with a transmembrane domain, is expressed in vascular injury; however, the effects of fractalkine on platelets have not yet been investigated. Blood was taken from healthy Wistar-Kyoto rats and the expression of the fractalkine receptor on platelets was demonstrated. The modulation of surface expression of P-selectin was assessed by flow cytometry. P-selectin expression was significantly enhanced by in vitro stimulation with recombinant rat fractalkine compared with baseline levels. Selectively inhibiting the function of recombinant fractalkine by an antagonizing antibody or the disruption of the G-protein-coupled intracellular signaling cascade of the fractalkine receptor by pertussis toxin (PTX) completely prevented fractalkine-mediated platelet activation. Preincubation with apyrase significantly attenuated the fractalkine-induced degranulation. In a flow chamber model of platelet adhesion, stimulation with fractalkine significantly enhanced platelet adhesion to collagen and fibrinogen. Similar to P-selectin expression, enhanced adhesion could be prevented by the antagonizing antibody or preincubation of platelets with PTX. Fractalkine, which is overexpressed in atherosclerosis and vascular injury, contributes to platelet activation and adhesion and hence is likely to play a pathophysiologically important role for increased thrombogenesis in vascular diseases.

Analysis of Variance↗
PubMed2003

Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.

OBJECTIVES: To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects. METHODS: Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks. RESULTS: Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups. CONCLUSIONS: In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure.

OBJECTIVE: Innate immune response proteins such as inflammatory cytokines, inducible nitric oxide synthase, and toll like receptors are implicated in myocardial depression and left ventricular (LV) remodeling after myocardial infarction (MI). Although all these innate immunity proteins share the downstream activation of the transcription factor NF-kappaB (nuclear factor kappa B) and activator protein 1 (AP-1), the involvement of NF-kappaB and AP-1 in LV remodeling has not been demonstrated so far. METHODS AND RESULTS: Nuclear translocation of NF-kappaB and AP-1 was studied by electrophoretic mobility shift assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase of LV remodeling. In the non-infarcted myocardium of MI rats, NF-kappaB and AP-1 were significantly activated (2.5-fold) as compared to sham-operated animals. Immunohistochemistry demonstrated NF-kappaB activation mainly in cardiac myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor trandolapril led to a further 2-fold increase in the activation of NF-kappaB and AP-1 when compared to placebo-treated animals with the same MI size (P<0.001). Human failing hearts explanted at the time of heart transplantation exhibited marked nuclear translocation of NF-kappaB in cardiac myocytes when compared to control hearts. NF-kappaB as well as AP-1 were both significantly activated in congestive heart failure due to ischemic or dilated cardiomyopathy. CONCLUSION: In experimental and human heart failure, both NF-kappaB and AP-1 are chronically activated in cardiac myocytes. These findings suggest an important involvement of NF-kappaB and AP-1 in the cardiac remodeling process.

Adult↗
PubMed2003

Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition.

An increased risk of thrombembolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and platelet activation. After experimental myocardial infarction, male Wistar rats were treated with placebo, the ACE inhibitor trandolapril, the selective aldosterone receptor antagonist eplerenone or the combination of both, for 10 weeks. Platelet-bound fibrinogen and surface-expressed P-selectin were not modulated in rats without CHF compared with sham-operated animals, but were significantly increased in CHF rats (LVEDP>15 mmHg). In CHF rats, ACE inhibition significantly reduced platelet P-selectin expression while bound fibrinogen was not modulated. Eplerenone reduced P-selectin expression to a comparable extent, while platelet-bound fibrinogen was normalised. Combination therapy with eplerenone and trandolapril completely abolished both the increased P-selectin expression as well as fibrinogen binding. Phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at both Ser(157) and Ser(239), which reflects the activity of platelet inhibitors including nitric oxide, was significantly reduced in platelets from placebo-treated CHF rats, and was completely normalised by combination treatment, but only marginally increased by either mono-therapy. The results show that platelet activation was evident only in CHF rats. Monotherapy with ACE inhibition or eplerenone partially reduced this increased platelet activation, which was completely rescued to basal levels by combination therapy. Increased nitric oxide bioavailability can only partially explain the reduced platelet activation by eplerenone and ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction: an experimental serial cardiac magnetic resonance imaging study.

OBJECTIVES: We sought to assess the influence of long-term hydroxymethylglutaryl coenzyme A reductase inhibition (statin) therapy on left ventricular (LV) remodeling after myocardial infarction (MI) by use of serial cardiac magnetic resonance imaging (CMRI) studies. BACKGROUND: Statin therapy has been shown to reduce cardiac hypertrophy in vitro and in vivo, but the influence on LV post-MI remodeling is largely unknown. METHODS: The CMRI measurements were taken four and 12 weeks after left coronary artery ligation in a 7.05-tesla Biospec. The MI size, LV mass and volumes, cardiac output (CO), and ejection fraction were determined. Rats were treated for 12 weeks with either placebo (P), cerivastatin (C; 0.6 mg/kg body weight per day) as a dietary supplement, or cerivastatin plus the nitric oxide synthase (NOS) inhibitor N-methyl-L-arginine methyl ester (L-NAME, 76 mg/100 ml) and hydralazine (8 mg/100 ml) in drinking water (CLH) to assess the contribution of endogenous nitric oxide formation. RESULTS: Administration of cerivastatin attenuated hypertrophy after MI, and this effect was completely abolished by NOS inhibition (increase of LV mass from 4 to 12 weeks after MI: 235.3 +/- 33.7 mg with P vs. 59.8 +/- 20.5 mg with C vs. 239.5 +/- 16.0 mg with CLH; p < 0.05 vs. P and CLH). Left ventricular dilation was not changed (increase of end-diastolic volume from 4 to 12 weeks after MI: 108.7 +/- 28.8 with P vs. 126.6 +/- 20.5 with C vs. 173.7 +/- 25.1 with CLH; p = NS). The CO was higher in the cerivastatin group (12 weeks: 76.1 +/- 2.9 ml/min with P vs. 95.8 +/- 4.8 ml/min with C; p < 0.05). The effects of cerivastatin were abolished by NOS inhibition in the CLH group (CO at 12 weeks: 69.3 +/- 2.8 ml/min, p < 0.05 vs. C). CONCLUSIONS: Left ventricular remodeling was profoundly changed by statin treatment. Hypertrophy was attenuated, and global function was improved. These positive effects were abolished by NOS inhibition.

Animals↗
PubMed2002

Time course of right ventricular remodeling in rats with experimental myocardial infarction.

Right ventricular (RV) weight increases dependent on time after myocardial infarction (MI) and on MI size. The sequential changes in RV volume and hemodynamics and their relations to left ventricular (LV) remodeling after MI are unknown. We therefore examined the time course of RV remodeling in rats with LV MI. MI was produced by left coronary artery ligation. Four, eight, and sixteen weeks later, LV and RV hemodynamic measurements were performed and pressure-volume curves were obtained. For serial measurement of RV volumes and performance, cine-MRI was performed 2 and 8 wk after MI. The ratios of beta-myosin heavy chain (MHC) to alpha-MHC and skeletal to cardiac alpha-actin were determined for the RV and LV after large MI or sham operation. RV weight increased in rats with MI, as did RV volume. RV pressure-volume curves were shifted toward larger volumes 16 wk after large MI. RV systolic pressure increased gradually over time; however, the gain in RV weight was always in excess of RV systolic pressure. The ratios of skeletal to cardiac alpha-actin and beta-MHC to alpha-MHC were increased after MI in both ventricles in a similar fashion. Because RV wall stress was not increased after infarction, mechanical factors may not conclusively explain hypertrophy, which maintained balanced loading conditions for the RV even after large LV infarction.

Animals↗
PubMed2002

Trauma induced by nontraumatic coronary devices and its impact on vascular reactivity and morphology.

This study evaluated the impact of low-pressure balloon devices on coronary morphology and function. An active coronary perfusion catheter (2.5-mm balloon diameter, inflation with 1 bar for 30 min) was placed in the left anterior descending coronary artery of 12 German landrace pigs under general anesthesia. After 3 mo, coronary segments with balloon contact were compared with control segments taken from the right coronary artery as to histology, vascular reactivity, and expression of endothelial nitric oxide synthase. Thirty-three balloon treated segments were analyzed. Twenty of these segments (61%) showed neointima formation. In these segments endothelium-independent relaxation induced by sodium nitroprusside was preserved. However, endothelium-dependent bradykinin-induced relaxation was significantly attenuated compared with both the control segments and the balloon-treated segments without neointima formation. In >60% of the ballooned arterial segments examined, low-pressure balloon devices induced neointima formation accompanied by reduced endothelium-dependent relaxation. Thus interventions with so-called nontraumatic coronary devices can induce relevant vascular injury, with potential adverse clinical consequences.

Angioplasty, Balloon, Coronary↗
PubMed2002

Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression.

OBJECTIVES: We sought to investigate the effects of adding spironolactone (SP) to angiotensin-converting enzyme (ACE) inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Adding SP to ACE inhibitors reduces mortality and morbidity in CHF. Endothelial vasomotor dysfunction contributes to increased peripheral vascular resistance and reduced myocardial perfusion in CHF. METHODS: Seven days after extensive myocardial infarction (CHF) or sham operation, Wistar rats were treated with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), SP (10 mg/kg per day) or a combination of both for 11 weeks. RESULTS: Maximal acetylcholine-induced, nitric oxide (NO)-dependent relaxation was significantly attenuated in aortic rings from rats with CHF as compared with sham-operated animals (R(max) 44 +/- 3% vs. 63 +/- 3%). Spironolactone alone had no influence (46 +/- 5%) and TR improved NO-mediated relaxation (55 +/- 4%), whereas treatment with both completely restored endothelium-dependent vasorelaxation (64 +/- 4%). Aortic superoxide formation was significantly increased in rats with CHF as compared with sham-operated animals, but was normalized by treatment with SP or SP plus TR. In addition, aortic messenger ribonucleic acid expression of the oxidase subunit p22(phox) in rats with CHF was significantly reduced by SP or TR plus SP. Endothelial NO synthase expression was increased in TR-treated animals. Incubation of isolated porcine coronary arteries with SP dose-dependently attenuated superoxide formation. CONCLUSIONS: Spironolactone added to an ACE inhibitor normalizes NO-mediated relaxation in experimental CHF by beneficially modulating the balance of NO and superoxide anion formation.

Angiotensin-Converting Enzyme Inhibitors↗