Individual responses to converting enzyme inhibitors and calcium antagonists.

This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration. Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system. CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistent change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.

Neutral endopeptidase versus angiotensin converting enzyme inhibition in essential hypertension.

OBJECTIVE: To evaluate the antihypertensive efficacy of sinorphan, an orally active inhibitor of neutral endopeptidase EC 3.4.24.11. DESIGN: The ability of sinorphan (100 mg twice a day) to lower blood pressure was compared with that of the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg twice a day) using a randomized-sequence, double-blind crossover design in 16 patients with essential hypertension. Each treatment was administered for 4 weeks and treatments were separated by a 3-week placebo period. At the end of the last phase of treatment sinorphan was combined with captopril for a further 4-week period. The changes in systolic (SBP) and diastolic blood pressure (DBP) were monitored using repeated ambulatory blood pressure monitoring. RESULTS: When given as monotherapy for 4 weeks, neither sinorphan nor captopril significantly reduced the 24-h or the 14-h daytime mean SBP or DBP. However, a significant decrease in DBP was observed during the first 6 h after the morning administration of captopril. With sinorphan only a significant decrease in night-time SBP was found. With the combined therapy of sinorphan and captopril, significant decreases both in SBP and in DBP were observed, which were sustained over 24 h. After 4 weeks of sinorphan alone or in combination with captopril, no change in plasma atrial natriuretic peptide level was found. However, urinary cyclic GMP excretion increased transiently after administration of the neutral endopeptidase inhibitor. CONCLUSIONS: Neutral endopeptidase inhibition with sinorphan has a limited effect on blood pressure in hypertensive patients when given alone. However, simultaneous neutral endopeptidase and ACE inhibition induces a synergistic effect, and might therefore represent an interesting new therapeutic approach to the treatment of essential hypertension.

Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.

RATIONALE: The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self-antigen-presenting cells and promotes autoreactive CD4(+) T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease. OBJECTIVE: The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure. METHODS AND RESULTS: Using alpha-myosin heavy chain peptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cell responses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure. CONCLUSIONS: Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF.

BACKGROUND: Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1beta, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS: One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS: There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS: IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IVF.

Regulation of interleukin 1α secretion by inflammasomes.

The crucial role of the proinflammatory cytokine interleukin 1β (IL-1β) in driving inflammatory disorders, such as Muckle-Wells syndrome and gout, has been extensively characterised. Owing to its high potency to induce inflammation the activation and secretion of IL-1β is tightly regulated. The sensing of various host 'dangers', including infections and metabolic deregulation, results in the formation of large protein complexes, termed inflammasomes. Formation of the inflammasomes leads to the cleavage and activation of caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1β. Biologically active IL-1β is subsequently secreted by the cell. In contrast to IL-1β, little is known about mechanisms underlying the activation and secretion of its close homologue IL-1α. Moreover, the physiological role of IL-1α is still not well defined. Several studies hypothesise that IL-1α serves as a danger signal, which is passively released from dying cells. However, recent studies suggest a more complex function of this cytokine. Indeed, NLRP3 inflammasome agonists such as uric acid crystal or nigericin induce IL-1α cleavage and secretion, leading to the cosecretion of both IL-1β and IL-1α. Depending on the type of NLRP3 agonist, release of IL-1α is NLRP3-inflammasome/caspase-1 dependent or independent, but in both cases IL-1α processing depends on calpain protease activity. Taken together, these results suggest that the promotion and progression of inflammatory diseases is not solely due to IL-1β but also to its close relative IL-1α. This should be considered when IL-1 blockade is applied as a therapeutic strategy for diseases such as cryopyrin-associated periodic syndromes or gout.

Traitement chronique de l'hypertension arterielle par un inhibiteur de l'enzyme de conversion de l'angiotensine. [Chronic treatment of hypertension by an inhibitor of angiotensin converting enzyme]

Captopril, or SQ 14,225 an orally active inhibitor of angiotensin-converting enzyme, produced a significant blood pressure reduction in 26 hypertensives. This new drug, alone or combined with a diuretic, has normalized the blood pressure of the 22 patients on long-term treatment.

Interleukin-1 as a therapeutic target in gout.

PURPOSE OF REVIEW: To give an overview of current evidence for interleukin (IL)-1 blockade in the management of gout. RECENT FINDINGS: Three IL-1 blockers are currently available for clinical use: anakinra, rilonacept and canakinumab. Recent studies have focused on drugs with a long half-life: rilonacept and canakinumab. For treatment of acute gouty arthritis, three randomized controlled trials (RCTs) showed efficacy of canakinumab with some safety concerns and one RCT failed to show efficacy of rilonacept. For prevention of gout flare when starting uric acid lowering therapy (ULT), four RCTs showed efficacy of rilonacept and one RCT showed efficacy of canakinumab. SUMMARY: There is sufficient evidence supporting the use of IL-1 blockers for treatment of acute gouty arthritis or for prevention of gout flares when starting ULT in selected patients, with contraindications or intolerance to conventional therapy. More data are needed to assess safety and to specify their use in routine practice.

Interleukin-1 receptor antagonist gene polymorphism and circulating levels of human immunodeficiency virus type 1 RNA in Brazilian women.

Interleukin-1 receptor antagonist (IL-1ra) gene polymorphisms in 83 human immunodeficiency virus (HIV)-seropositive women were evaluated. Fourteen of the subjects (16.9%) were homozygous for IL-1ra allele 2 (IL-1RN*2). These women had a lower median level of HIV RNA than did women homozygous for allele 1 (IL-1RN*1) (P = 0.01) or heterozygous for both alleles (P = 0.04). Among 46 subjects not receiving antiretroviral treatment, HIV levels were also reduced in IL-1RN*2 homozygous individuals (P < 0.05). There was no relation between IL-1ra alleles and CD4 levels.

Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor

Résumé en français Jusqu'alors, il n'avait jamais été formellement démontré qu'une forte dose d'un antagoniste de l'angiotensine II à longue durée d'action pouvait être aussi efficace sur le blocage du système rénine-angiotensine que l'association d'un inhibiteur de l'enzyme de conversion avec le même antagoniste de l'angiotensine II à des doses plus faibles. Dans cette étude randomisée en double aveugle, nous avons étudié le blocage du système rénine-angiotensine obtenu avec trois doses d'olmesartan medoxomil (20, 40 et 80 mg) chez 30 volontaires sains que nous avons comparé au blocage obtenu par du lisinopril (20 mg), seul ou associé à de l'olmesartan medoxomil (20 et 40 mg). L'étude s'est déroulée en deux phases selon un design par crossover. A deux reprises, chaque volontaire à reçu durant une semaine l'un des six traitements possibles. Un intervalle d'une semaine a été respecté entre les deux phases (période de washout). L'objectif principal était d'étudier, 24 heures après la dernière dose, le blocage de l'élévation de la pression systolique en réponse à l'administration d'angiotensine I. Ce blocage était de 58% ± 19% (moyenne ± déviation standard) avec 20 mg de lisinopril, de 58% ± 11% avec 20 mg d'olmesartan medoxomil, de 62% ± 16% avec 40 mg d'olmesartan medoxomil, et de 76% ± 12% avec la plus forte dose d'olmesartan medoxomil (80 mg) (P=.016 versus 20 mg de lisinopril et P=.0015 versus 20 mg d'olmesartan medoxomil). Le blocage était de 80% ± 22% avec 20 mg de lisinopril associé à 20 mg d'olmesartan medoxomil et de 83% ± 9% avec 20 mg de lisinopril associé à 40 mg d'olmesartan medoxomil (P= .3 versus 80 mg d'olmesartan medoxomil). Ces résultats montrent, que chez les volontaires sains, une dose suffisamment élevée d'olmesartan medoxomil peut induire un blocage à 24 heures quasi complet de l'élévation de la pression artérielle en réponse à l'administration d'angiotensine I. De même, en terme de blocage de l'effet vasculaire de l'angiotensine I, une dose suffisamment élevée d'un antagoniste de l'angiotensine II de longue durée d'action est tout aussi efficace que ce même antagoniste à des doses plus faibles associé avec à un inhibiteur de l'enzyme de conversion.

Polyene macrolide antifungal drugs trigger interleukin-1β secretion by activating the NLRP3 inflammasome.

The use of antimycotic drugs in fungal infections is based on the concept that they suppress fungal growth by a direct killing effect. However, amphotericin and nystatin have been reported to also trigger interleukin-1β (IL-1β) secretion in monocytes but the molecular mechanism is unknown. Here we report that only the polyene macrolides amphotericin B, nystatin, and natamycin but none of the tested azole antimycotic drugs induce significant IL-1β secretion in-vitro in dendritic cells isolated from C57BL/6 mouse bone marrow. IL-1β release depended on Toll-like receptor-mediated induction of pro-IL-1β as well as the NLRP3 inflammasome, its adaptor ASC, and caspase-1 for enzymatic cleavage of pro-IL-1β into its mature form. All three drugs induced potassium efflux from the cells as a known mechanism for NLRP3 activation but the P2X7 receptor was not required for this process. Natamycin-induced IL-1β secretion also involved phagocytosis, as cathepsin activation as described for crystal-induced IL-1β release. Together, the polyene macrolides amphotericin B, nystatin, and natamycin trigger IL-1β secretion by causing potassium efflux from which activates the NLRP3-ASC-caspase-1. We conclude that beyond their effects on fungal growth, these antifungal drugs directly activate the host's innate immunity.

UV irradiation of human keratinocytes activates the inflammasome

Human keratinocytes represent a potent source of the pro-inflammatory cytokines pro-interleukin(IL)-1α and -β. ProIL-1β requires processing by caspase-1 (IL-1β-converting enzyme, ICE) for activation and receptor binding. ProIL-1α and -β lack a signal peptide and leave the cell via the alternative secretion pathway, which is independent of the classical ER/Golgi pathway. Both cytokines are stored in the cytoplasm and can be activated and released upon UV irradiation. In macrophages maturation of proIL-1β requires the activation of inflammasomes, innate multiprotein immune complexes, which are essential for the activation of caspase-1 and thereby for processing of proIL-1β. However, the intracellular pathways, which are responsible for activation of proIL-1β and secretion of IL-1β in keratinocytes, are unknown. We show that human keratinocytes express inflammasome proteins in vitro and in vivo. UVB irradiation of keratinocytes results in an increase of cytoplasmic Ca2+ from intracellular stores. This shift is required for inflammasome-dependent activation of caspase-1 and subsequent processing of proIL-1β and secretion of IL-1β. In contrast to macrophages, caspase-1 cannot activate proIL-18 in keratinocytes, although secretion of this cytokine is also induced by UVB irradiation. In vivo, caspase-1 is also essential for UVB-induced inflammation in the skin, since caspase-1 knockout mice showed a strongly reduced inflammatory response after UVB irradiation. Our results suggest that keratinocytes are important immuno-competent cells under physiological and pathological conditions.