Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.
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PMID:Eprosartan does not affect the pharmacodynamics of warfarin. 970 51

Systolic hypertension is a major risk factor for cardiovascular disease. The determinants of systolic blood pressure are peripheral resistance and arterial compliance. Arterial vasoconstriction, vascular growth and fluid retention, induced by the renin-angiotensin system directly or indirectly by enhancing sympathetic nervous system activity, are important factors in increasing peripheral resistance, decreasing arterial compliance and, consequently, elevating systolic blood pressure. Selective blockade of the angiotensin II type 1 (AT1) receptor represents a novel mechanism for interrupting the renin-angiotensin system. This provides the additional benefit of blocking angiotensin II generated by non-angiotensin-converting-enzyme pathways without altering either bradykinin metabolism or the potential beneficial effects of AT2 receptor stimulation. Eprosartan is a potent (1.4 nmol/l) AT1 receptor antagonist that inhibits angiotensin-II-induced vascular contraction in a competitive manner. Eprosartan is effective in reducing disease progression in animal models of hypertension, heart failure, renal disease and stroke. Furthermore, eprosartan causes a large increase in arterial compliance in hypertensive rats fed high-salt and high-fat diets. Eprosartan also possesses sympathoinhibitory activity as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, other angiotensin II receptor antagonists, such as losartan, used at equivalent angiotensin II blocking activity, do not appear to alter sympathetic nervous system activity. Angiotensin II receptor antagonists, such as eprosartan, that have the ability to block both the direct effects of angiotensin II and the indirect effects mediated by enhanced sympathetic neurotransmission, may represent an important advance in the treatment of elevated systolic blood pressure.
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PMID:Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. 1046 64

Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1 (AT1) receptor antagonists provided the opportunity to obtain the benefits of selectively blocking the RAAS at the level of the AT1 receptor that mediates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT1 receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT1 receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT1 receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS.
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PMID:Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. 1048 32

All components of the renin-angiotensin system have been demonstrated in the brain and AT1 receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT1 receptor antagonists, which are increasingly used in the treatment of arterial hypertension and chronic heart failure, have the potential to mediate action via the central renin-angiotensin system. Therefore, we tested the in vivo access of the non-peptide AT1 receptor antagonist, eprosartan (30 and 60 mg per kg of body weight (BW) for 4 weeks, i.p. administered by osmotic minipumps), to angiotensin II receptors in the rat brain by in vitro autoradiography with 125I- (Sar1- Ile8) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and six-fold at doses of 30 and 60 mg x kg(-1), respectively (P< 0.05 vs CTRL). In the brain, eprosartan produced a dose-dependent inhibition of AT receptor binding in the median cerebral artery ( 850 +/- 249 and 650 +/- 106 vs 1072 +/- 116 dpm x mm(-2) of CTRL; P< 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT1 receptors both outside and within the blood-brain barrier, such as the paraventricular nucleus ( 180 +/- 47 and 130 +/- 18 vs 545 +/- 99 dpm x mm(-2)of CTRL; P< 0.05), the subfornical organ ( 106 +/- 26 and 112 +/- 17 vs 619 +/- 256 dpm x mm(-2)of CTRL; P< 0.05), and the organum vasculosum laminae terminalis ( 461 +/- 110 and 763 +/- 136 vs 1033 +/- 123 dpmx mm(-2)of CTRL; P< 0.05). These results emphasize that eprosartan readily crosses the blood-brain barrier in vivo and selectively inhibits binding to AT1 receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT1 receptor antagonists overall therapeutic efficacy in cardiovascular disease.
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PMID:Central inhibition of AT1receptors by eprosartan--in vitro autoradiography in the brain. 1140 17

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.
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PMID:Eprosartan for the treatment of hypertension. 1251 47

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.
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PMID:Effects of the AT1-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure. 1254 May 20

Both in human and in experimental heart failure (HF), the renin-angiotensin system and the sympathetic nervous system are activated. In a previous study a facilitatory action of angiotensin II (Ang II) was shown in the rabbit mesenteric artery, which was mediated via prejunctionally located Ang II type 1 (AT ) receptors. Very little is known about the effects of Ang II on sympathetic neurotransmission at the peripheral level in congestive heart failure (CFH). Accordingly, in the isolated mesenteric arteries obtained from rabbits with experimentally induced CHF, as well as in age-matched control rabbits, the effect of Ang II on contractions provoked by electrical field stimulation was investigated in the presence and absence of the AT receptor antagonist eprosartan. Additionally, to investigate a possible postjunctional facilitation, the effects of Ang II on alpha-adrenoceptor-mediated responses were studied using noradrenaline (NA). Lastly, the vasoconstrictor effects of Ang II were compared between HF rabbits and controls, by constructing concentration-response curves to Ang II. In control rabbits, Ang II 0.5 n caused an enhancement of stimulation-induced responses by a factor 3.2 +/- 0.5, 2.4 +/- 0.3, and 1.5 +/- 0.08, at 1, 2, and 4 Hz, respectively ( < 0.05 at all frequencies compared with vehicle). In rabbits with HF, the enhancement by Ang II (0.5 n ) amounted to a factor 2.1 +/- 0.2, 1.7 +/- 0.1, and 1.2 +/- 0.04, at 1, 2, and 4 Hz, respectively ( < 0.05 compared with vehicle at all frequencies). Accordingly, the enhancing effect of Ang II was more pronounced in the control group compared with rabbits with HF ( < 0.05 at each frequency). Eprosartan (1 nM -0.1 microM) could inhibit the facilitatory effects of Ang II in arteries from HF as well as from control rabbits. Contractile responses to exogenous NA (3 n -0.1 m ) were the same in HF rabbits and controls, and they were unaltered in the presence of Ang II 0.5 n Ang II (0.1 nM -1 microM) caused a concentration-dependent increase in contractile force, which was the same in HF rabbits and controls. From these findings it can be concluded that in rabbits with CHF as well as in control animals, Ang II facilitates the stimulation-induced vasoconstrictor responses via prejunctionally located AT receptors. The facilitating effect was decreased in vessels obtained from rabbits with CHF, whereas responses to exogenous Ang II were unchanged. These findings may be explained by downregulation or uncoupling of the prejunctional AT receptor.
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PMID:Decreased facilitation by angiotensin II of noradrenergic neurotransmission in isolated mesenteric artery of rabbits with chronic heart failure. 1260 13

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 not affected by Ang II. We conclude that Ang II-enhanced sympathetic neurotransmission is mediated by the prejunctional AT1-receptor in both control and CHF-preparations. The decreased facilitation of SNS effects by Ang II may be explained by down-regulation or desensitisation of the neuronal AT1-receptor. Additionally, the aortic contractile capacity in heart failure rabbits appears to be decreased, probably as a result of heart failure-associated neuroendocrine and functional changes.
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PMID:Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model. 1468 69

Moderate elevations in blood pressure translate to significant increases in cardiovascular and cerebro vascular risk. Beneficially, this relationship allows small decreases in blood pressure to be associated with risk reduction. Both the renin-angiotensin system and the sympathetic nervous system are involved in hypertension, hence targeting these systems is likely to be of benefit in the treatment of hypertension. Angiotensin II type 1 receptor blockers (ARBs) are used for controlling blood pressure and treating heart failure in a broad range of patients, including those with diabetes and the elderly. Not only have ARBs shown good efficacy and tolerability, they also appear to have a protective effect that goes beyond that expected from the reduction of blood pressure. The ARB eprosartan is a nonbiphenyl nontetrazole angiotensin II type 1 receptor (AT1) antagonist, which acts to decrease total peripheral resistance. Eprosartan acts at vascular AT1 receptors (postsynaptically) and at presynaptic AT1 receptors, where it inhibits noradrenaline release. In clinical studies, eprosartan has been shown to significantly reduce cardiovascular and cerebrovascular events, whilst avoiding the persistent cough that commonly occurs with the use of angiotensin-converting enzyme inhibitors. Eprosartan can also be differentiated from other ARBs due to its noradrenergic effects, which other ARBs used at therapeutic doses do not possess. Eprosartan, therefore, represents a useful therapeutic option in the management of patients with hypertension, including those with a history of stroke or with co-morbid type 2 diabetes mellitus.
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PMID:Introduction: The pharmacological profile of eprosartan--implications for cerebrovascular and cardiovascular risk reduction. 1809 7