eplerenone and trandolapril

Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).. Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl. The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Drug Synergism; Eplerenone; Hypertension; Indoles; Kidney; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Spironolactone; Superoxide Dismutase; Transforming Growth Factor beta

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Adhesion Molecules; Drug Therapy, Combination; Eplerenone; Fibrinogen; Heart Failure; Indoles; Male; Microfilament Proteins; Mineralocorticoid Receptor Antagonists; Nitric Oxide; P-Selectin; Phosphoproteins; Platelet Activation; Rats; Rats, Wistar; Renin-Angiotensin System; Spironolactone

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).. 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.. 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.. 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.. 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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blotting, Western; Drug Therapy, Combination; Endothelium, Vascular; Eplerenone; Heart Failure; In Vitro Techniques; Indoles; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitroprusside; Rats; Rats, Wistar; Spironolactone; Vasodilator Agents

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).. Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure.. 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.. 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.. 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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Drug Synergism; Drug Therapy, Combination; Endothelium, Vascular; Eplerenone; Hemodynamics; Indoles; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitric Oxide Synthase; Rats; Spironolactone; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Drug Synergism; Drug Therapy, Combination; Eplerenone; Humans; Indoles; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Remodeling