Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of heart failure attempts to reduce symptoms, increase functional capacity and prolong survival. Optimal therapy usually requires a combination of several drugs. At present, ACE inhibitors are the drugs of first choice, but must be combined with diuretics in symptomatic patients. Digitalis glycosides are still an important supplement to diuretics and ACE inhibitors. Specific angiotensin receptor antagonists such as losartan have an effect comparable with that of ACE inhibitors and may possess certain advantages because of their direct effect at the receptor level. Extensive research has been conducted in the treatment of heart failure. Newer direct acting vasodilators such as flosequinan and epoprostenol have demonstrated improved exercise tolerance but have an adverse effect on mortality. Positive inotropic agents consisting of a heterogeneous group of drugs have been evaluated. Although novel agents such as xamoterol, milrinone, pimobendan and vesnarinone have demonstrated improved haemodynamics and improved symptoms, they are not advisable at present due to increased mortality related to treatment or a high incidence of adverse events. beta-Blockers, used judiciously, may improve functional capacity as well as mortality and may be an important supplement to current conventional treatment. The new generation of beta-blockers with vasodilating properties such as carvedilol and bucindolol appear promising.
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PMID:Novel drugs and current therapeutic approaches in the treatment of heart failure. 888 74

The randomized angiotensin receptor antagonist--angiotensin converting enzyme (ACE)--Inhibitor Study (RAAS) was designed to test the hypothesis that the addition of an angiotensin II type 1 receptor blocking agent, losartan 50 mg/day, to an ACE-inhibitor, enalapril 10 mg twice a day (group 1), will be more effective than standard-dose enalapril 10 mg twice a day (group 2) or high-dose enalapril alone 20 mg twice a day (group 3), in blocking the activation of the renin angiotensin aldosterone system in patients with heart failure and left ventricular systolic dysfunction. The addition of an angiotensin II type 1 receptor blocking agent to an ACE inhibitor would theoretically block ACE as well as non-ACE-dependent angiotensin II formation while maintaining the potential beneficial effect of ACE inhibitor-induced bradykinin formation. One hundred twenty patients with left ventricular systolic dysfunction and moderate to severe heart failure despite treatment with an ACE inhibitor will be randomized to 1 of the 3 groups and followed for 6 weeks, with an optional long-term week extension to determine the safety and tolerability of the combination of losaratan and enalapril, its effectiveness in preventing rest and exercise-induced neurohumoral activation (plasma norepinephrine, N-terminal proatrial natriuretic factor, angiotensin II, and aldosterone), as well as quality of life and exercise performance (6-minute walk test).
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PMID:Rationale, background, and design of the randomized angiotensin receptor antagonist--angiotensin-converting enzyme inhibitor study (RAAS). 891 76

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.
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PMID:The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure. 894 34

The introduction of nonpeptide angiotensin II antagonists in clinical use has necessarily led to comparison with the various and clinically established angiotensin converting enzyme inhibitors. In essence, losartan, the first approved angiotensin receptor antagonist, has a clinical profile highly similar to that of the converting-enzyme inhibitors, although much higher doses are required but with the advantage of no dry cough. On the other hand, the emergence of the concept of inverse agonism on other receptor systems has led to the search for pathological situations mediated through constitutive receptor activity as well as antagonists with inverse agonistic properties on the angiotensin receptor. Basic research on angiotensin peptide antagonists has led to the identification of molecular characteristics that produce antagonism. The combination of these characteristics then led to angiotensin antagonists that possessed a long in vivo duration of action. Studies with angiotensin converting enzyme inhibitors and nonpeptide antagonists on animal models of post-angioplastic restenosis revealed that both classes of compounds have similar partial efficacy on the inhibition of neointima formation. A peptide antagonist produced on the rat carotid model a complete inhibition of neointima formation. This increased efficacy is now tentatively attributed to potential inverse agonistic activity of this peptide antagonist. This concept would give angiotensin antagonists therapeutic opportunities where convertase inhibitors should be ineffective.
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PMID:What can angiotensin antagonists do that converting-enzyme inhibition can't: the case of post-angioplastic restenosis. 894 74

This review article looks at the emerging concepts about the renin angiotensin system. The specific aspects it covers include angiotensin II receptors, angiotensin receptor antagonists and alternative enzymatic pathways for the conversion of angiotensin I to angiotensin II other than angiotensin converting enzyme. The review, additionally, looks at the current and future clinical applications of the above concepts.
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PMID:Emerging concepts about the renin angiotensin system: present and future clinical applications. 899 Dec 44

Single drug therapy for the treatment of hypertension has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the US Food and Drug Administration. The advantages of combinations may be a synergistic or additive antihypertensive effect, metabolic improvement, or both. The combination of a thiazide-type diuretic and a potassium-sparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. The combination of beta-adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect that permits the effective use of very low thiazide doses. The mechanism of antihypertensive effects of each member of the combination are complimentary with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by beta1-adrenergic blockade. Combinations not used as first-line therapy, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockade and a thiazide diuretic, have complimentary antihypertensive mechanisms and have been useful in treating patient groups who do not respond well to converting enzyme inhibitor monotherapy. The combination of a calcium antagonist with diuretic therapy has an additive hypertensive effect as well; however, the complimentary mechanisms are less obvious. Finally, the combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations for diuretics and beta1-receptor blockers have been useful for achieving increased antihypertensive effect with decreased adverse drug effect.
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PMID:Pharmacological properties of combination therapies for hypertension. 905 2

The essential problem of the vicious circle leading to end-stage cardiovascular disease is atherosclerosis. This paper focuses on the functional changes centred on the endothelium that accompany the development of atherosclerosis, examining in particular pathological alterations in the L-arginine/nitric oxide (NO) pathway. Changes in the NO system are associated with altered platelet and monocyte interactions with the vessel wall, abnormal vasoconstriction and altered vascular structure. Diabetes, hyperglycaemia, hypertension and hypercholesterolaemia are all involved in this process. Endothelin is a vasoconstrictor peptide produced by endothelial cells which is upregulated under these conditions. Normalising endothelial function could involve platelet inhibition, lipid-lowering agents to prevent foam cell formation and decrease the lipid load of the blood vessel wall, and agents to interfere with some of the mechanisms involved in vasoconstriction, proliferation and migration, including ACE-inhibitors and angiotensin receptor antagonists, and possibly new tools such as endothelin receptor antagonists.
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PMID:The internist and the vessel wall. 917 1

Using indomethacin (2.5 mg/kg/day, i.m.) in rats, we confirmed the well-known interaction of NSAID's and the urinary elimination of lithium. This is due to an increase in the tubular reabsorption of lithium, probably associated with an increase in the reabsorption of sodium in the ascending limb of the loop of Henle, following inhibition of the synthesis of prostaglandins. With ramipril (1 mg/kg/day, p.o.), we confirmed an interaction with lithium pharmacokinetics in rats, also associated with an increase in the tubular reabsorption of sodium. In contrast, the angiotensin receptor antagonist losartan (10 mg/kg/day, p.o.) had no effect in this paradigm. Since the effects of ramipril were partially inhibited by an i.v. infusion of an antagonist of the bradykinin B2 receptor icatibant (0.1 mg/kg/day), we suggest that bradykinin contributes to the interaction between angiotensin converting enzyme inhibitors and renal excretion of lithium.
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PMID:[Mechanisms of drug interactions with renal elimination of lithium]. 931 48

Large randomised clinical trials have shown ACE inhibitors to improve survival after acute myocardial infarction (AMI). The precise mechanism underlying this benefit is not fully established, despite extensive research. There is also controversy with regard to the clinical use of these drugs, particularly the need for selection of patients prior to treatment and the timing of drug initiation and withdrawal for maximum benefit. Animal models of AMI used to assess drug effects are of limited value in understanding the mechanisms of benefit because they involve significantly different pathophysiology from that which occurs in humans. Here we propose that the benefit of ACE inhibitor therapy is largely confined, post-AMI, to those with evidence of left ventricular dysfunction clinically or on investigation, and suggest the continuing importance of treatment distant from the acute event. We argue that the beneficial effects are, at least in part, related to a reduction in the direct toxic effects of angiotensin II and catecholamines on cardiomyocytes resulting from the long term excess stimulation of the renin-angiotensin and sympathetic systems in these patients. Importantly, we believe that for some patients after AMI there is little or no benefit to be gained from treatment and that, in fact, careful analysis of the trials suggests that ACE inhibitors may be associated with adverse outcomes in some individuals. Finally, since ACE inhibitors also potentiate bradykinin and other peptides, their beneficial action may not simply be due to reducing the formation of angiotensin II. The proportion of the benefit that may be via bradykinin is difficult to assess, especially in humans. However, the advent of the angiotensin receptor antagonists has provided the opportunity to investigate this important issue.
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PMID:Do ACE inhibitors provide protection for the heart in the clinical setting of acute myocardial infarction? 942 45

To examine the role of the type 1A (AT1A) angiotensin receptor in renal growth and development, we analyzed F2 progeny from a series of crosses between F1 mice that were heterozygous for a targeted disruption of the AT1A receptor gene [Agtr1A-(+/-)]. Among 21-day-old weanling F2 mice, we found that 194 (32%) were homozygous for the wild-type allele Agtr1A-(+/+), 299 (49%) were Agtr1A-(+/-), and 119 (19%) were Agtr1A-(-/-). This differed significantly from the proportions predicted by Mendelian genetics (P = 0.01), suggesting that the complete absence of AT1A receptors is associated with a mild survival disadvantage. Agtr1A-(-/-) mice grew normally, and we found no significant differences in body weight or heart and kidney weights in Agtr1A-(+/+) and Agtr1A-(-/-) mice examined at 21, 60, and 100 days. Protein and DNA content of kidneys and hearts were also similar in weanling or adult Agtr1A-(+/+) and Agtr1A-(-/-) mice. By light microscopy with immunohistochemistry, kidneys from Agtr1A-(-/-) were essentially normal, with two exceptions: 1) there was marked hypertrophy of the juxtaglomerular apparatus (JGA) and proximal expansion of renin-producing cells along the afferent arterioles, and 2) some glomeruli showed evidence of mesangial expansion. We did not find the severe renal vascular lesions or papillary atrophy that have been observed in angiotensinogen- or angiotensin converting enzyme-deficient animals. We conclude that the AT1A receptor is not essential for the normal organogenesis of the kidney; however, its absence is associated with mild mesangial expansion and JGA hypertrophy.
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PMID:Renal growth and development in mice lacking AT1A receptors for angiotensin II. 945 22


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