Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eprosartan is a nonpeptide angiotensin II receptor antagonist which has a high affinity for the AT1 receptor subtype. When administered at dosages of 400 to 800 mg/day (once or twice daily) for 13 weeks to patients with mild to moderate essential hypertension, eprosartan significantly reduced blood pressure compared with placebo. Eprosartan was at least as effective as enalapril 10 to 40 mg/day in a dose-titration study in patients with severe hypertension. Eprosartan is generally well tolerated; clinical trials have shown the drug to have a tolerability profile similar to that of placebo. As with other angiotensin II receptor antagonists, it does not cause cough. Eprosartan is not metabolised by the cytochrome P450 system and therefore has a low potential for drug interactions.
 ...
PMID:Eprosartan. 958 67

The angiotensin II (AII) receptor antagonist eprosartan is a highly selective, nonpeptide drug specific for the AT1 receptor subtype that completely inhibits pressor, aldosterone secretory, and renal vasoconstrictive effects produced by AII infusions in healthy humans. It increases effective renal plasma flow in both salt-replete and salt-restricted healthy men, and maintains glomerular filtration rates in patients with essential hypertension and those with renal insufficiency after either single or multiple doses. In healthy salt-restricted men, the drug suppresses and stimulates aldosterone and renin, respectively, in the initial few hours after administration. This feedback inhibition for renin release and suppression of aldosterone is reduced with normal sodium intake. Eprosartan is natriuretic in salt-restricted subjects and does not induce sodium retention even when it reduces blood pressure. These properties, in addition to antagonism of AII effect at the AT1 receptor, no doubt contribute to the agent's antihypertensive effect in patients with essential hypertension. Pharmacodynamic studies predict that doses of up to 400 mg are safe. Additional preliminary studies suggest that doses as high as 1200 mg are safe and well tolerated, while producing meaningful hemodynamic and neurohumoral effects in patients with essential hypertension.
 ...
PMID:The renal profile of eprosartan. 1021 27

Eprosartan is a new, structurally distinct, nonbiphenyl, nontetrazole, nonpeptide, orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor. In placebo-controlled trials, it led to a dose-related antihypertensive response, clinically significant reductions in blood pressure and full 24-hour blood pressure control with once/day administration of 600 mg. Eprosartan provides clinically significant reductions in blood pressure in patients with mild to severe hypertension regardless of age, gender, and race. The antihypertensive effect of eprosartan is comparable with those of other antihypertensive agents. Whereas a relationship exists between dosage and antihypertensive effect, there is no such relationship between dosage and adverse events, the frequency of which is comparable with that with placebo.
 ...
PMID:Clinical efficacy of eprosartan. 1021 28

Angiotensin-converting enzyme inhibitors have been used extensively in the management of hypertension and related cardiovascular conditions. However, this treatment approach is limited by lack of specificity and continued production of angiotensin II by other routes. Antagonism of the angiotensin II receptor offers the possibility of improved control of hypertension by providing a more complete blockade of the renin-angiotensin system than angiotensin-converting enzyme inhibition without bradykinin-related effects. Eprosartan is the only nonbiphenyl, nontetrazole competitive angiotensin II receptor antagonist clinically available and is highly selective for the AT1 receptor subtype. In clinical trials, eprosartan has been shown to lower blood pressure effectively in a once-daily regimen in hypertensive patients. In the recommended dose range of 600 to 1200 mg once daily, eprosartan is effective in patients with all grades of hypertension irrespective of age, sex, or race. Furthermore, the tolerability profile of eprosartan is comparable to that of placebo, and there are no known clinically relevant drug-drug interactions. A number of large-scale clinical studies are currently underway or planned to determine which of the increasing number of AT1 receptor antagonists may reduce cardiovascular morbidity and mortality rates in different groups of hypertensive patients. Meanwhile, current evidence suggests that the AT1 receptor antagonists represent a significant new approach to cardiovascular therapy and merit a fuller assessment in hypertension and other cardiovascular diseases.
 ...
PMID:Safety and efficacy of eprosartan, a new angiotensin II receptor blocker. 1046 19

Selective blockade of the angiotensin II AT1 receptor represents a novel mechanism for interrupting the renin-angiotensin system without altering the potential benefits of AT2 receptor stimulation. This selective inhibition produces none of the disadvantages associated with reduced bradykinin metabolism and angiotensin II generated by non-angiotensin-converting enzyme pathways. Eprosartan is a potent (1.4 nmol/L) AT1 receptor antagonist that competitively blocks angiotensin II-induced vascular contraction. In various animal models of disease, including hypertension and stroke, eprosartan is effective in reducing disease progression. Eprosartan also has 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, some of the other angiotensin II receptor antagonists, such as losartan, at equivalent angiotensin II blocking doses, have no effect on sympathetic nervous system activity. Because eprosartan can inhibit both the direct effects of angiotensin II as well as the indirect effects that are mediated by enhanced sympathetic neurotransmission, this may represent an important advance in the treatment of elevated systolic blood pressure.
 ...
PMID:Pharmacology of eprosartan, an angiotensin II receptor antagonist: exploring hypotheses from clinical data. 1046 20

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.
 ...
PMID:Central inhibition of AT1receptors by eprosartan--in vitro autoradiography in the brain. 1140 17

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.
 ...
PMID:Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model. 1468 69

The present study was designed to investigate the influence of maturation (young versus adult) on the angiotensin II-mediated facilitation of sympathetic nerve traffic (prejunctional AT1-receptor) as well as on the angiotensin II-mediated vasoconstriction (postjunctional AT1-receptor). Additionally, we investigated the inhibitory effect of the selective AT1-receptor antagonist eprosartan on angiotensin II-mediated responses at both sites during maturation. Male New Zealand White rabbits, aged 12 to 14 and 35 to 38 weeks (young versus adult, respectively), were used. To study angiotensin II at the neuronal AT1-receptor we investigated its influence on electrical field stimulation (EFS)-evoked sympathetic neurotransmission in the isolated thoracic aorta in a noradrenaline spillover model. To study the effects of angiotensin II at the level of the vasculature concentration-response curves for angiotensin II were constructed. In both models the influence of eprosartan on angiotensin II-mediated responses was studied. Angiotensin II (0.01 nM-0.1 microM) concentration-dependently enhanced the EFS-evoked noradrenaline release in both groups. No differences concerning the relative (approximately 100%, P > 0.05) and absolute facilitation were observed between groups, although concentrations required in adult rabbits exceeded those in young animals by 1 unity log M increment. Eprosartan concentration-dependently attenuated the angiotensin II-enhanced (10 nM) sympathetic outflow. The inhibitory potency differed approximately by a factor ten between both groups (young; pIC50 7.91 +/- 0.12 and adult; pIC50 8.81 +/- 0.31, respectively, P < 0.05). Angiotensin II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force (young rabbits; Emax 20.62 +/- 2.24 mN, pD2 8.16 +/- 0.04, n = 10 and adult rabbits; Emax 21.64 +/- 3.86 mN, pD2 7.63 +/- 0.02, n = 7). We observed approximately a 0.5 unity log M increment difference in potency, although the maximal absolute contraction was similar in both groups. Eprosartan (0.1 nM-0.1 microM) inhibited the angiotensin II-mediated contractions in a competitive manner in preparations from young rabbits (pA2 8.90 +/- 0.11, n = 24), whereas a mixed form of antagonism, in the same concentration range, was observed in tissues from adult rabbits. One possible explanation concerning these experiments is that maturation influences the AT1-receptor density negatively, although further studies are necessary to test this question. In addition, the decreased AT1-receptor density offers a potential explanation for the discrepancy in the profile of antagonism displayed by eprosartan in young compared with adult rabbits.
 ...
PMID:Different prejunctional and postjunctional responses to angiotensin II and AT1-receptor inhibition: influence of maturation. 1507 28