Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) inhibitors continue to find new uses. The Heart Outcomes Prevention Evaluation study has demonstrated their wide application as a preventive measure for patients at high risk of cardiovascular disease, but the available clinical trials in hypertensive subjects do not so far suggest any clear superiority over conventional treatment. The available trials may have been underpowered to detect non-blood pressure-related benefits on smooth muscle growth, endothelial function, left ventricular hypertrophy, and plaque rupture, when used in relatively low-risk subjects with uncomplicated hypertension. Clinical trials have also shown that two or more drugs are needed to lower blood pressure even to 140/90. Few patients have uncomplicated hypertension, so the choice of their drugs will be powerfully influenced by their other clinical problems. Nevertheless, there is a strong case for an attack on the renin-angiotensin system. Whether this will be by ACE inhibition, angiotensin-II receptor blockade, or both, is the subject of current clinical trials.
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PMID:The role of angiotensin-converting enzyme inhibitors in the treatment of hypertension. 1160 83

The spectrum of disorders associated with an elevated blood pressure (BP) encompasses chronic uncomplicated hypertension and the hypertensive crises, including hypertensive urgencies and emergencies. Although these syndromes vary widely in their presentations, clinical courses, and outcomes they share pathophysiologic mechanisms and, consequently, therapeutic responses to specifically targeted antihypertensive drug types. Nevertheless, hypertensive crises are often treated with drugs which, in that setting are either unsafe or are of unsubstantiated efficacy. The purpose of this review is to examine the pathophysiology of commonly encountered hypertensive crises, including stroke, hypertensive encephalopathy, aortic dissection, acute pulmonary edema, and preeclampsia-eclampsia and to provide a rational approach to their treatment based upon relevant pathophysiologic and pharmacologic principles. Measurement of plasma renin activity (PRA) level often provides insight regarding pathophysiology and predicts efficacy of antihypertensive treatments in the individual patient. However, in hypertensive crises, drug therapy is initiated before the PRA level is known. Nevertheless, the renin-angiotensin dependence (R-type) or volume dependence (V-type) of hypertension can often be deduced by the BP response to drugs that interrupt the renin system (R-drugs) or that decrease body volume (V-drugs). Based upon these considerations, a treatment algorithm is provided to guide drug selection in patients presenting with a hypertensive crisis.
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PMID:Management of hypertensive crises: the scientific basis for treatment decisions. 1172 16

Current clinical guidelines state that only beta-blockers, diuretics, calcium channel antagonists and ACE inhibitors should be used for initial pharmacotherapy for uncomplicated hypertension. On basis of experience, efficacy and costs beta-blockers and diuretics are first choice. However, the importance of the renin-angiotensin-aldosterone-system in the pathophysiology of hypertensive end-organ damage is increasingly recognised nowadays, and modulation of this system may therefore exert favourable effects on cardiovascular and cerebrovascular complications. In the LIFE study, a recently published double-blinded, randomised trial, the angiotensin-II receptor (A-II) antagonist losartan was compared with the beta-blocker atenolol in patients with essential hypertension and left ventricular hypertrophy (LVH). Patients randomised to the A-II antagonist suffered statistically significantly fewer clinical end-points, specifically fewer cerebrovascular accidents, whereas both treatments resulted in a similar decrease in blood pressure. In the subset of diabetic patients, the use of the A-II antagonist yielded an even more favourable outcome. In our opinion, it should now also be permitted to prescribe A-II antagonists as initial pharmacotherapy for patients with uncomplicated essential hypertension. It might be considered to prescribe A-II antagonists as preferred treatment for patients with essential hypertension and known LVH, especially in diabetic patients.
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PMID:[Treatment of hypertension: angiotensin-II antagonists potentially better than beta-blockers in the occurrence of cardiovascular and cerebrovascular damage; the LIFE study in perspective]. 1267 53

Some hypertension treatment guidelines published in the late 1990's recommended that diuretics and betha-blockers be used as 1st line drugs for treating uncomplicated hypertension, reserving new antihypertensive drugs for special indications. This recommendation is predicated on the fact that large trials showing cardiovascular protection with antihypertensive drugs used betha-blockers and diuretics. Other guidelines suggested all antihypertensives are equal and that drug selection should be individualized. These disparate guidelines arise from the controversy over "are all antihypertensives created equal?" Since these guidelines, many large hypertension trials have been conducted. This paper will review the recent hypertension trials, the meta-analyses of some of these trials, highlight some of the flaws inherent in the trials that making interpretation difficult, and finally outline a rationale approach to initial treatment of the uncomplicated hypertensive patient. It will provide a rationale for 1) using diuretic and not beth-blocker as the 1st line agent in treating uncomplicated hypertension, 2) switching to an angiotensin converting enzyme inhibitor or angiotensin receptor blocker should side effects occur on diuretic, 3) reserving calcium channel blocker, betha-blocker, and alpha-blocker for 2nd or 3(rd) line therapy, 4) employing a diuretic in combination with any other antihypertensive class, and 5) considering use of lower doses of 2 or more antihypertensives to limit side effects while optimizing blood pressure control. If the incidence of de novo diabetes is indeed higher with diuretics and cost-analysis confirm long-term savings with using a more expensive but less diabetogenic drug to treat hypertension, then the recommendation may shift to using an antihypertensive that acts on the renin-angiotensin axis.
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PMID:Initial therapy for uncomplicated hypertension: insights from the alphabetic maze of recent studies. 1460 87

Unlike the majority of patients with uncomplicated hypertension in whom minimal renal damage develops in the absence of severe blood pressure (BP) elevations, patients with diabetic and nondiabetic chronic kidney disease (CKD) exhibit an increased vulnerability to even moderate BP elevations. Investigations in experimental animal models have revealed that this enhanced susceptibility is a consequence of an impairment of the renal autoregulatory mechanisms that normally attenuate the transmission of elevated systemic pressures to the glomeruli in uncomplicated hypertension. The markedly lower BP threshold for renal damage and the steeper slope of relationship between BP and renal damage in such states necessitates that BP be lowered into the normotensive range to prevent progressive renal damage. When BP is accurately measured using radiotelemetry in animal models, the renal protection provided by renin-angiotensin system (RAS) blockade is proportional to the BP reduction with little evidence of BP-independent protection. A critical evaluation of the clinical data also suggests that the BP-independent renoprotection by RAS blockade has been overemphasized and that achieving lower BP targets is more important than the selection of antihypertensive regimens. However, achievement of such BP goals is difficult in CKD patients without aggressive diuresis, because of their proclivity for salt retention. The effectiveness of RAS blockers in lowering BP in patients who have been adequately treated with diuretics, along with their potassium-sparing and magnesium-sparing effects, provides a more compelling rationale for the use of RAS blockade in the treatment of CKD patients than any putative BP-independent renoprotective superiority.
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PMID:Pathophysiology of hypertensive renal damage: implications for therapy. 1545 24

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.
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PMID:Renal protection in hypertensive patients: selection of antihypertensive therapy. 1639 60

Thiazide diuretics were the first tolerated efficient antihypertensive drugs that significantly reduced cardiovascular morbidity and mortality in placebo-controlled clinical studies. Although these drugs today still are considered a fundamental therapeutic tool for the treatment of hypertensive patients, the following considerations should be taken into account. Although there are some indications that chlorthalidone can offer additional advantages as compared with other compounds, a recent meta-analysis of placebo-controlled trials suggested that the beneficial effects of thiazide diuretics could be a class effect. Thiazide diuretics must be used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the smallest occurrence of side effects, including alterations in glucose and lipid profiles and hypokalemia. Moreover, because thiazide diuretics can increase the incidence of new-onset diabetes, especially when combined with beta blockers, caution is advised in using these drugs above all in patients who are at high risk for developing diabetes, in whom thiazide diuretics should be used at the lowest active dose and possibly in combination with drugs that block the renin-angiotensin system. Finally, the current debate on whether thiazide diuretics are the first-choice drug for most patients with uncomplicated hypertension, as stated in the Seventh Joint National Committee Report, or are included in the major classes of antihypertensive agents that are suitable for initiation and maintenance of therapy, as reported in the European Society of Hypertension-European Society of Cardiology Guidelines, derives from different interpretations of controlled clinical trial data on drug class comparison and of cost-benefit analyses. However, considering that the benefit of antihypertensive drugs seems to be due principally to BP lowering per se without definitive evidence of the superiority of a particular drug class and that there is no cost-benefit analysis showing the superiority of thiazide diuretics, it is believed that these drugs should not be considered as the only first-choice drug but included among first-choice drugs.
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PMID:Thiazide diuretics in the treatment of hypertension: an update. 1656 43

The role of beta-blockers in uncomplicated hypertension has been challenged recently. Compared with other antihypertensives, beta-blockers are less effective for preventing cardiovascular events in patients with uncomplicated hypertension. Moreover, a recent meta-analysis of placebo-controlled clinical trials concluded that atenolol is not more efficacious than placebo for preventing cardiovascular events in patients with hypertension. Although these agents lower blood pressure measured conventionally over the brachial artery with a blood pressure cuff, they do not exert a commensurate effect on blood pressure in the central aorta. Central aortic blood pressure and aortic augmentation index are strong predictors of left ventricular hypertrophy, an independent risk factor for cardiovascular events. Emerging data are illuminating the antihypertensive paradox whereby antihypertensive agents may elicit discordant effects on central and peripheral blood pressure and hemodynamics. Vasodilatory antihypertensives, such as renin-angiotensin-aldosterone system inhibitors and calcium channel blockers, elicit reductions in central aortic blood pressure equal to or greater than that in the brachial artery. Conversely, beta-blockers lower central aortic blood pressure to a lesser degree even when blood pressure measured by sphygmomanometry is reduced substantially. Given the strong relationship between central aortic blood pressure and target organ damage, the effectiveness of beta-blockers may be overestimated in practice on the basis of conventional blood pressure measurements alone. Differences in central and peripheral blood pressure may account for the lack of cardiovascular protection afforded by beta-blockers in clinical trials and could account for a portion of the apparent "benefit beyond blood pressure" reduction with other classes of antihypertensive agents. Future studies should aim to better clarify the role of central aortic blood pressure in the treatment of hypertension. In the meantime, the effects of antihypertensive drugs on blood pressure "beyond the brachial blood pressure cuff" should be considered when prescribing antihypertensive agents for a patient.
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PMID:Discordant effects of beta-blockade on central aortic systolic and brachial systolic blood pressure: considerations beyond the cuff. 1772 86

Relative aldosterone excess is associated with endothelial dysfunction and higher incidence of end organ damage. We sought to investigate whether plasma aldosterone-to-renin ratio (ARR) is associated with left ventricular (LV) longitudinal function reserve to exercise in patients with controlled hypertension. In the patients with controlled and uncomplicated hypertension without overt LV hypertrophy, plasma aldosterone concentrations (ng/dL) and renin activities (ng/mL/h) were measured. Then 28 consecutive patients with higher ARR (group II, ARR > or = 30, 55 +/- 10 years) and 56 age- and sex-matched patients with lower ARR (group I, ARR < 30) underwent supine bicycle exercise echocardiography. Despite similar 24-hour blood pressure, LV mass index was significantly higher in group II (91.1 +/- 16.4 vs 101.7 +/- 18.2 g/m(2), P = .008). Early diastolic and systolic mitral annular velocity (E' and S', cm/s) at 50-W exercise was significantly lower in group II compared with group I (9.91 +/- 1.66 vs 8.67 +/- 1.65 cm/s, P = .002; 9.52 +/- 1.71 vs 8.46 +/- 1.79, P = .010, respectively) despite similar resting values. Longitudinal diastolic functional reserve at 25-W and 50-W exercise, defined as DeltaE' (change from resting E', cm/s) of group II was significantly lower than that of group I (2.60 +/- 1.42 vs 1.85 +/- 1.44 cm/s, P = .016; 3.40 +/- 1.48 vs 2.36 +/- 1.43 cm/s, P = .003, respectively). In conclusion, in patients with hypertension without overt LV hypertrophy, increased ARR is associated with increased LV mass, and impaired LV longitudinal functional reserve during exercise.
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PMID:Increased plasma aldosterone-to-renin ratio is associated with impaired left ventricular longitudinal functional reserve in patients with uncomplicated hypertension. 1786 62

Hypertension is a major risk factor for cardiovascular morbidity and mortality and currently has been estimated at 30% of the US population. Of these, only 36.8% have their blood pressure reduced to recommended levels of lower than 140/90 mmHg for uncomplicated hypertension, or less than 130/80 mmHg for patients with diabetes mellitus or renal disease. Since monotherapy controls blood pressure in less than 50% of treated hypertensive patients, combination therapy is often required to bring blood pressure to the recommended levels of the 7th Joint National Committee report. One of the most effective and widely used combinations is the combination of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide (HCTZ). Aliskiren, a new blocker of the renin-angiotensin system has been developed and approved by the US FDA on 18th January 2008 for the treatment of hypertension. Aliskiren is a direct inhibitor of renin, the rate-limiting enzyme for the production of angiotensin II, a powerful vasoconstrictive peptide. Several randomized clinical trials have demonstrated that aliskiren administered in single daily doses of 150, 300 or 600 mg alone and in combination with HCTZ 12.5 and 25 mg is effective in lowering blood pressure, and is safe and well tolerated. In this article, the pharmacokinetic and pharmacodynamic profile and the clinical application of aliskiren alone and in combination with HCTZ will be discussed.
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PMID:Aliskiren-hydrochlorothiazide combination for the treatment of hypertension. 1832 92


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