Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT(1)R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal renal arterial FMD (MF-FMD) and in 89 controls. The age of NIF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 + 11.1 years vs 35.5 +/- 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs 0.47, P = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele.

A critical appraisal of the intrinsic pancreatic angiotensin-generating system

The pancreas is a relative newcomer to the stable of tissues with an intrinsic angiotensin-generating system. The involvement of this system in pancreatic activity will be dependent on the angiotensin-generating paths present in the pancreas and their precise cellular location. Thus far, renin, angiotensin-converting enzyme (ACE), angiotensin II and AT1 and AT2 receptors have been found. These are components of the "classical" renin-angiotensin system. But there is uncertainty as to their location and site of action. Furthermore, it is not known which, if any, alternative enzymes to renin and ACE are present, which angiotensins in addition to angiotensin II are generated and whether or not there are receptors to angiotensin IV and angiotensin-(1-7). Future research should focus on these aspects in order to provide a mechanistic basis to pancreatic physiological functions and to pathological conditions of clinical relevance.

Quality of care of patients hospitalized with acute coronary syndromes

Background: Measurement and improvement of quality of care is a priority issue in health care. Patients hospitalized with acute coronary syndromes (ACS) constitute a high-risk population whose care, if shown to be suboptimal on the basis of available research evidence, may benefit from quality improvement interventions. Aim: To evaluate the quality of in-hospital care for patients with ACS, using explicit quality indicators. Methods: Retrospective case note review was undertaken of 397 patients admitted to three teaching hospitals in Brisbane, Queensland, Australia, between 1 October 2000 and 17 April 2001. The main out-come measures were 12 process-of-care quality indicators, calculated as either: (i) the proportion of all patients who received specific interventions or (ii) the proportion of ideal patients who received -specific interventions (i.e. patients with clear indi-cations and lacking contraindications). Results: Quality indicators with values above 80% included: (i) patient selection for thrombolysis (100%) and discharge prescription of beta-blockers (84%), (ii) antiplatelet agents (94%) and (iii) lipid-lowering agents (82%). Indicators with values between 50% and 80% included: (i) timely per-formance of electrocardiogram (ECG) on admission (61%), (ii) early coronary angiography (75%), (iii) measurement of serum lipids (71%) and (iv) discharge prescription of angiotensin-converting-enzyme (ACE) inhibitors (73%). Indicators with values <50% included: (i) timely administration of thrombolysis (35%), (ii) non-invasive risk assessment (23%) and (ii) formal in-hospital and post-hospital cardiac rehabilitation (47% and 7%, respectively). Conclusion: There were delays in performing ECG and administering thrombolysis to patients who presented to emergency departments with ACS. Improvement is warranted in use of non-invasive procedures for identifying high-risk patients who may benefit from coronary revascularization as well as use of serum lipid measurements, ACE inhibitors and cardiac rehabilitation.

Present and future pharacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a β-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT1) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT1 antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of β-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional β-adrenoceptors, may give it additional benefits to selective β1-adrenoceptor antagonists. Celiprolol and bucindolol are not the β-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor α antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.

Acute myocardial infarction: clinical and epidemiological profile and factors associated with in-hospital death in the municipality of Rio de Janeiro

OBJECTIVE: To study the factors associated with the risk of in-hospital death in acute myocardial infarction in the Brazilian public health system in Rio de Janeiro, Brazil. METHODS: Sectional study of a sample with 391 randomly drawn medical records of the hospitalizations due to acute myocardial infarction recorded in the hospital information system in 1997. RESULTS: The diagnosis was confirmed in 91.7% of the cases; 61.5% males; age = 60.2 ± 2.4 years; delta time until hospitalization of 11 hours; 25.3% were diabetic; 58.1% were hypertensive; 82.6% were in Killip I class. In-hospital mortality was 20.6%. Thrombolysis was used in 19.5%; acetylsalicylic acid (ASA) 86.5%; beta-blockers 49%; angiotensin-converting enzyme (ACE) inhibitors 63.3%; calcium channel blockers 30.5%. Factors associated with increased death: age (61-80 years: OR=2.5; > 80 years: OR=9.6); Killip class (II: OR=1.9; III: OR=6; IV: OR=26.5); diabetes (OR=2.4); ventricular tachycardia (OR=8.5); ventricular fibrillation (OR=34); recurrent ischemia (OR=2.7). The use of ASA (OR=0.3), beta-blockers (OR=0.3), and ACE inhibitors (OR=0.4) was associated with a reduction in the chance of death. CONCLUSION: General lethality was high and some interventions of confirmed efficacy were underutilizated. The logistic model showed the beneficial effect of beta-blockers, and ACE inhibitors on the risk of in-hospital death.

Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/beta-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic < or =90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

Granzyme A is an interleukin 1 beta-converting enzyme.

Apoptosis is critically dependent on the presence of the ced-3 gene in Caenorhabditis elegans, which encodes a protein homologous to the mammalian interleukin (IL)-1 beta-converting enzyme (ICE). Overexpression of ICE or ced-3 promotes apoptosis. Cytotoxic T lymphocyte-mediated rapid apoptosis is induced by the proteases granzyme A and B. ICE and granzyme B share the rare substrate site of aspartic acid, after which amino acid cleavage of precursor IL-1 beta (pIL-1 beta) occurs. Here we show that granzyme A, but not granzyme B, converts pIL-1 beta to its 17-kD mature form. Major cleavage occurs at Arg120, four amino acids downstream of the authentic processing site, Asp116. IL-1 beta generated by granzyme A is biologically active. When pIL-1 beta processing is monitored in lipopolysaccharide-activated macrophage target cells attacked by cytotoxic T lymphocytes, intracellular conversion precedes lysis. Prior granzyme inactivation blocks this processing. We conclude that the apoptosis-inducing granzyme A and ICE share at least one downstream target substrate, i.e., pIL-1 beta. This suggests that lymphocytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.

Recent clinical trials with omapatrilat: new developments.

Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.

Angiotensin II is an endogenous neurotransmitter for rat and human mesenteric resistance blood vessels

Angiotensin II (Ang II) is one of the most potent vasoconstrictors. We document here the innervation of rat and human mesenteric resistance arteries (MRA) by angiotensinergic neurons of the rat and human sympathetic coeliac ganglia. Angiotensinogen (Ang-N)-mRNA and angiotensin converting enzyme-mRNA but no renin-mRNA were detected by using quantitative real time polymerase chain reaction in total RNA extracts of rat coeliac ganglia. In the same extracts, cathepsin D-mRNA was detected: This protease also cleaves Ang I from Ang-N and could therefore account for the generation of neuronal Ang peptides in the absence of renin. In situ hybridization confirmed the presence of Ang-N-mRNA in the cytoplasm of rat coeliac ganglia. By using solid-phase extraction, high performance liquid chromatography and subsequent radioimmunoassay, Ang II and its metabolites were detected in rat and also in human coeliac ganglia. Immunoreactivity for Ang II was demonstrated in rat and human coeliac ganglia neurons and their projections innervating MRA. In addition, segmental angiotensinergic innervation of MRA was also observed. By means of confocal laser scanning microscopy we were able to demonstrate the presence of angiotensinergic synapses en passant along side of vascular smooth muscle cells. Our findings could indicate that Ang II is synthesized inside the neurons of sympathetic coeliac ganglia and may act as an endogenous neurotransmitter locally in MRA.

State-of-the-art treatment of hypertension: established and new drugs.

The treatment of essential hypertension is based essentially on the prescription of four major classes of antihypertensive drugs, i.e. blockers of the renin-angiotensin system, calcium channel blockers, diuretics and beta-blockers. In recent years, very few new drug therapies of hypertension have become available. Therefore, it is crucial for physicians to optimize their antihypertensive therapies with the drugs available on the market. In each of the classes of antihypertensive drugs, questions have recently been raised: are angiotensin-converting enzyme (ACE) inhibitors superior to angiotensin II receptor blockers (ARB)? Is it possible to reduce the incidence of peripheral oedema with calcium antagonists? Is hydrochlorothiazide really the good diuretic to use in combination therapies? The purpose of this review is to discuss these various questions in the light of the most recent clinical studies and meta-analyses. These latter suggest that ACE inhibitors and ARB are equivalent except for a better tolerability profile of ARB. Third generation calcium channel blockers enable to reduce the incidence of peripheral oedema and chlorthalidone is certainly more effective than hydrochlorothiazide in preventing cardiovascular events in hypertension. At last, studies suggest that drug adherence and long-term persistence under therapy is one of the major issues in the actual management of essential hypertension.

Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice.

Angiotensin II is a potent arterial vasoconstrictor and induces hypertension. Angiotensin II also exerts a trophic effect on cardiomyocytes in vitro. The goals of the present study were to document an in vivo increase in cardiac angiotensins in the absence of elevated plasma levels or hypertension and to investigate prevention or regression of ventricular hypertrophy by renin-angiotensin system blockade. We demonstrate that high cardiac angiotensin II is directly responsible for right and left ventricular hypertrophy. We used transgenic mice overexpressing angiotensinogen in cardiomyocytes characterized by cardiac hypertrophy without fibrosis and normal blood pressure. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent or normalize ventricular hypertrophy. Surprisingly, in control mice, receptor blockade decreases tissue angiotensin II despite increased plasma levels. This suggests that angiotensin II may be protected from metabolization by binding to its receptor. Blocking of the angiotensin II type 1 receptor rather than enhanced stimulation of the angiotensin II type 2 receptor may prevent remodeling and account for the beneficial effects of angiotensin antagonists.

Peptides from Lactobacillus hydrolysates of bovine milk caseins inhibit prolyl-peptidases of human colon cells.

Prolyl-rich peptides derived from hydrolysates of bovine caseins have been previously shown to inhibit angiotensin converting enzyme (ACE) activity, suggesting that they may also be able to inhibit the enzymatic activities of prolyl-specific peptidases. This study shows that peptides derived from α(S1)-casein and β-casein inhibited the enzymatic activities of purified recombinant matrix metalloprotease (MMP)-2, MMP-7, and MMP-9. The inhibitory efficacy was sequence-dependent. These peptides also selectively inhibited the enzymatic activities of prolyl-amino-peptidases, prolyl-amino-dipeptidases, and prolyl-endopeptidases in extracts of HT-29 and SW480 human colon carcinoma cells, but not in intact cells. They were not cytotoxic or growth inhibitory for these cells. Thus, the prolyl-rich selected peptides were good and selective inhibitors of MMPs and post-proline-cleaving proteases, demonstrating their potential to control inadequate proteolytic activity in the human digestive tract, without inducing cytotoxic effects.