eprosartan and Heart-Failure

When angiotensin-converting enzyme (ACE) inhibition first became available to block the renin system, few could have predicted the evolution that would occur in this field. The advent of angiotensin II receptor 1 (AT(1)) blockers has created new opportunities. These agents, including eprosartan, are extraordinarily well tolerated, not only when compared with antihypertensive agents but also in comparison with the ACE inhibitors, which are rather well tolerated. The AT(1) blocker class is growing rapidly, at least in part because many believe that these drugs will share with the ACE inhibitors the special ability to reduce morbidity and mortality. Does eprosartan have a special role within this class? Eprosartan differs structurally from the other AT(1) blockers in that it is not a biphenyl tetrazole. It differs functionally in vitro in being a pure competitive antagonist, as opposed to the nonequilibrium, insurmountable characteristics of the other blockers. This feature may prove to be useful for titration in the fragile patient. The reduction in catecholamine release induced by eprosartan that has been observed in animal models may account for some special examples of increased efficacy. One such example pertains to the difference in the dose-response relationship for the action of eprosartan on the renal blood supply in comparison with other AT(1) blockers. Eprosartan doses well below those required for control of blood pressure have a pronounced effect on the kidney. If research already under way supports these early suggestions, then eprosartan will be an important addition to our therapeutic armamentarium.

Topics: Acrylates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Heart Failure; Humans; Hypertension; Imidazoles; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Sympathetic Nervous System; Thiophenes; Treatment Outcome

Pressure overload of the heart is associated with a perturbed gene expression of the cardiomyocyte leading to an impaired pump function. The ensuing neuro-endocrine activation results in disordered influences of angiotensin II and catecholamines on gene expression. To assess whether angiotensin II type 1 receptor inhibition can also counteract a raised sympathetic nervous system activity, spontaneously hypertensive rats fed a hypercaloric diet were treated with eprosartan (daily 90 mg/kg body wt) and cardiovascular parameters were monitored with implanted radiotelemetry pressure transducers. Both, blood pressure and heart rate were increased (p < 0.05) by the hypercaloric diet. Although eprosartan reduced (p < 0.05) the raised systolic and diastolic blood pressure, the diet-induced rise in heart rate was blunted only partially. In addition to drugs interfering with the enhanced catecholamine influence, compounds should be considered that selectively affect cardiomyocyte gene expression via 'metabolic' signals.

Topics: Acrylates; Amino Acid Sequence; Animals; Antihypertensive Agents; Calcium-Transporting ATPases; Catecholamines; Gene Expression Regulation; Heart Failure; Humans; Hypertension; Imidazoles; Molecular Sequence Data; Myocardium; Myosin Heavy Chains; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sequence Alignment; Sequence Homology, Amino Acid; Thiophenes

The efficacy of ACE-inhibitors and beta blockers is well documented in the therapy of heart failure. As pharmacological mechanisms of ATI-receptor-antagonists differ, an additional positive effect can be expected when combining these drugs.. Eighty patients (67.9 +/- 9.9 years) with severe chronic heart failure receiving long-term medication with diuretics, ACE-inhibitors and partially beta blockers (72.5%), were randomized after clinical recompensation to eprosartan (477.5 +/- 143.7 mg/d), telmisartan (65.9 +/- 17.7 mg), candesartan (11.9 +/- 4.0 mg) or no sartan, according to a prospective study. Haemodynamic measurements by impedance cardiography were performed (mean observation time 15.8 days).. Additional sartan treatment resulted in an improvement of cardiac output from 2.32 +/- 0.69 to 3.12 +/- 1.24 l/min (P = 0.003) in the eprosartan group, from 2.24 +/- 0.59 to 2.76 +/- 0.91 l/min (P = 0.001) in the telmisartan group and from 2.76 +/- 0.84 to 3.11 +/- 0.94 l/min (P = 0.02) in the candesartan group. Furthermore, a significant decrease of the total peripheral resistance was measured under eprosartan (23%; P = 0.002), telmisartan (18%; P = 0.002) and candesartan treatment (11.5%; P = 0.049); in the subgroup of combined therapy with beta blockers, ACE-inhibitors and ATI-antagonists a significant increase in cardiac output was also observed. No change was observed in the control group without additional sartan treatment concerning cardiac output and resistance reduction.. The additional treatment with different ATI-receptor-antagonists resulted in an increase of the cardiac output and a decrease of the peripheral resistance. This beneficial effect may be due to the additional property of sartans to block the interaction of locally and not-ACE-generated angiotensin II with their vascular and myocardial ATI-receptors.

Topics: Acrylates; Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Biomarkers; Biphenyl Compounds; Blood Pressure; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Female; Heart Failure; Heart Rate; Humans; Imidazoles; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Telmisartan; Tetrazoles; Thiophenes; Treatment Outcome; Vascular Resistance

The safety and efficiency of the therapy with the angiotenzin-II receptor blocker--teveten were compared with the ACE inhibitor prestarium and their combination in patients with NYHA functional classes II-III of the chronic heart failure (CHF), who were on conventional therapy with diuretics and cardiac glycosides. The special attention was given to the influence of a combination of teveten and prestarium on morphofunctional performance of the myocardium and vessels, the neurohumoral status, quality of life and survival in patients with left ventricular dysfunction. Our study confirmed that Prestarium or Teveten monotheraphy gives approximately identical result, while their combination have better influence on the quality of life and hemodynamic parameters. The combined use of teveten and the ACE inhibitor prestarium is the most optimal treatment regimen in patients with moderate and severe CHF.

Topics: Acrylates; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Female; Heart Failure; Humans; Imidazoles; Male; Perindopril; Thiophenes

Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT1) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone.. Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT1 receptor antagonist (400 to 800 mg daily, n = 18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects.. There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], -20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (-7.3 mm Hg [95% CI, -14.2 to -0.4] diastolic; -8.9 mm Hg [95% CI, -18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged.. When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan.

Topics: Acrylates; Aged; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Catheterization, Swan-Ganz; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Imidazoles; Male; Middle Aged; Norepinephrine; Prognosis; Prospective Studies; Radionuclide Ventriculography; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Safety; Thiophenes

The efficacy of ACE-inhibitor therapy is well documented in the treatment of chronic heart failure. As pharmacological mechanisms of ACE-inhibition and angiotensin II AT1-receptor-antagonists differ, an additional positive effect concerning left ventricular function can be expected in combining both classes of drugs.. Twenty patients (64.9+/-8.5 years) with advanced chronic heart failure (NYHA class III) receiving long-term medication with digitalis, diuretics and ACE-inhibitors were randomized to either eprosartan (540+/-96 mg/day) or placebo, according to a blinded protocol. Hemodynamic measurements by impedance cardiography were performed at baseline and after 8.85+/-1. 5 days of study medication treatment.. Additional treatment with eprosartan resulted in a higher cardiac output than in the control group (P<0.05). While in the active treatment group cardiac output increased significantly from baseline (2.27-3.24 l/min, P=0. 039), there was no change in the control group.. The additional treatment with the AT1-receptor antagonist eprosartan, given to severe heart failure patients, who received digitalis, diuretics and ACE-inhibitors, resulted in a beneficial effect by increasing cardiac output. This effect may be due to eprosartan's additional property of blocking the autocrine interaction of locally and not ACE-generated angiotensin II with their respective vascular and myocardial AT1-receptors as well as the influence on prejunctional AT1-receptors located on sympathetic nerve terminals.

Topics: Acrylates; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiac Output; Drug Therapy, Combination; Female; Heart Failure; Humans; Imidazoles; Male; Middle Aged; Pilot Projects; Thiophenes; Ventricular Function, Left

Angiotensin-converting enzyme (ACE)-2 is a newly described enzyme with antagonistic effects to those of the classical ACE (ACE-1). Both ANG II and aldosterone play an important role in the pathophysiology of congestive heart failure (CHF) and in the adverse cardiac remodeling during its development. In this study, we examined the effects of experimental CHF induced by an aortocaval fistula (ACF) and of its treatment with ANG II and aldosterone inhibitors on the relative levels of ACE-1 and ACE-2. We also compared the effects of spironolactone, an aldosterone antagonist, and eprosartan, an ANG II receptor antagonist, on heart hypertrophy and fibrosis in rats with ACF. Spironolactone (15 mg x kg(-1) x day(-1) ip, via minipump) or eprosartan (5 mg x kg(-1) x day(-1) ip, via minipump) was administered into rats with ACF for 14 and 28 days. Specific antibodies were used to determine the protein levels of myocardial ACE-1 and ACE-2. ACF increased the cardiac levels of ACE-1 and decreased those of ACE-2. Heart-to-body weight ratio significantly increased from 0.30 +/- 0.004% in sham-operated controls to 0.50 +/- 0.018% and 0.56 +/- 0.044% (P < 0.001) in rats with ACF, 2 and 4 wk after surgery, respectively, in association with increased plasma levels of aldosterone. The area occupied by collagen increased from 2.33 +/- 0.27% to 6.85 +/- 0.65% and 8.03 +/- 0.93% (P < 0.01), 2 and 4 wk after ACF, respectively. Both spironolactone and eprosartan decreased cardiac mass and collagen content and reversed the shift in ACE isoforms. ACF alters the ratio between ACE isoforms in a manner that increases local ANG II and aldosterone levels. Early treatment with both ANG II and aldosterone antagonists is effective in reducing this effect. Thus ACE isoform shift may represent an important component of the development of cardiac remodeling in response to hemodynamic overload, and its correction may contribute to the beneficial therapeutic effects of renin-angiotensin-aldosterone system inhibitors.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Arteriovenous Fistula; Carboxypeptidases; Cardiomegaly; Disease Models, Animal; Heart Failure; Imidazoles; Male; Mineralocorticoid Receptor Antagonists; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Spironolactone; Thiophenes; Ventricular Remodeling

1. We examined the effects of eprosartan, an AT(1) receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2. Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3. In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68+/-7 vs 82+/-9 ml, P<0.004, 43+/-1 vs 58+/-7 ml, P<0.003, respectively), and EF decreased (37+/-1 vs 29+/-1%, P<0.001). In dogs treated with low-dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high-dose eprosartan, EF increased (38+/-1 vs 42+/-1%, P<0.004) and ESV decreased (41+/-1 vs 37+/-1 ml, P<0.006), Eprosartan also decreased interstitial fibrosis and cardiomyocyte hypertrophy. 4. We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.

Topics: Acrylates; Angiotensin Receptor Antagonists; Animals; Disease Progression; Dogs; Heart Failure; Imidazoles; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Thiophenes; Ventricular Dysfunction, Left

Topics: Acrylates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Diuretics; Dizziness; Drug Combinations; Drug Interactions; Heart Failure; Humans; Hypertension; Imidazoles; Irbesartan; Kidney Diseases; Losartan; Olmesartan Medoxomil; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

Congestive heart failure (CHF) is characterised by activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Both systems are known to interact and to potentiate each other s activities. We recently demonstrated that angiotensin II (Ang II) enhances sympathetic nerve traffic via prejunctionally-located AT1-receptors. At present, little is known about the effects of Ang II at the level of the sympathetic neurones in CHF. Accordingly, we investigated the effect of Ang II in the presence and absence of the AT1-receptor antagonist, eprosartan, on stimulation-induced nerve traffic in isolated thoracic aorta preparations obtained from rabbits suffering from experimentally-induced CHF. Control-preparations were obtained from age-matched animals. Sympathetic activity was assessed by a [3H]noradrenaline spill-over model. Additionally, Ang II constrictor responses were compared between CHF and control vessels in the presence and absence of eprosartan. Additionally, to study postjunctional facilitation, the effects of Ang II on postsynaptic a-adrenoceptor-mediated responses were studied using noradrenaline. Stimulation-evoked SNS-neurotransmission was similar in both groups (CHF versus control). Ang II (0.1 nM 0.1 M) caused a concentration-dependent increase of the stimulation-evoked sympathetic outflow in both groups, with a maximum at 10 nM (control [n=7], FR2/FR1 2.03+0.11 and CHF- preparations [n=7], FR2/FR1 1.71+0.07). The enhancement by Ang II was decreased in CHF- preparations compared with controls (p<0.05). Eprosartan concentration-dependently attenuated the Ang II-enhanced (10 nM) sympathetic outflow in both CHF- and control preparations. The sympatho-inhibitory potency of eprosartan was similar in both groups (control pIC50 8.81 0.31; CHF 8.65+0.42). Ang II (1 nM 0.3 M) concentration-dependently increased the contractile force in control preparations (Emax 21.64+3.86 mN, pD2 7.63+0.02, n=7). Eprosartan (1 nM 0.1 M) influenced the Ang II- contractions via a mixed form of antagonism. In CHF-preparations, Ang II caused impaired vascular contraction. The KCl-induced contraction was decreased in the CHF- compared with control preparations (13.02+0.64 mN versus 30.40+0.89 mN). The relative Ang II contraction (% of KCl) was also decreased (2.3% vs. 58.0%). Concentration-response curves to noradrenaline (%KCl) were similar (control pD2 6.93+0.05, Emax 131.0+2.7; CHF pD2 7.00+0.05, Emax 136.7+2.6) (p>0.05) and were

Topics: Acrylates; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Dose-Response Relationship, Drug; Electric Stimulation; Heart Failure; Imidazoles; In Vitro Techniques; Male; Osmolar Concentration; Rabbits; Sympathetic Nervous System; Thiophenes

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Topics: Acrylates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart Failure; Hemodynamics; Imidazoles; Kidney; Male; Rats; Rats, Wistar; Renal Circulation; Sodium; Thiophenes