Angiotensin System Antagonists Research Articles

Maximising antihypertensive effects of angiotensin II receptor blockers with thiazide diuretic combination therapy: focus on irbesartan/hydrochlorothiazide.

BackgroundEvidence-based guidelines for the management of hypertension are now well established. Studies have shown that more than 60% of patients with hypertension will require two or more drugs to achieve current treatment targets.DiscussionCombination therapy is recommended as first-line treatment by the JNC-7 guidelines for patients with a blood pressure > 20 mmHg above the systolic goal or 10 mmHg above the diastolic goal, while the International Society of Hypertension in Blacks recommends combination therapy when BP exceeds targets by > 15/10 mmHg. Current European Society of Hypertension-European Society of Cardiology guidelines also recommend the use of low-dose combination therapy in the first-line setting. Furthermore, JNC-7 recommends that a thiazide-type diuretic should be part of initial first-line combination therapy. Thiazide/diuretic combinations are available for a variety of classes of antihypertensive, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers and centrally acting agents. This article focuses on clinical data investigating the combination of an ARB, irbesartan, with the diuretic, hydrochlorothiazide.ConclusionsThese data indicate that the ARB/HCTZ combination has greater potency and a similar side effect profile to ARB monotherapy and represents a highly effective approach for attaining goal BP levels using a therapeutic strategy that very effectively lowers BP, is well tolerated and minimises diuretic-induced metabolic effects.Review CriteriaThe PubMed and other searchable databases were utilized to collate information from original and review articles as well as from selected abstracts relevant to this topic.Message for the ClinicDiuretic-based combination antihypertensive drug therapy is a cornerstone of antihypertensive drug therapy. Most hypertensive patients will require more than one antihypertensive drug to lower blood pressure (BP) below target levels. The combination of diuretics with renin angiotensin system antagonists is highly logical given the significant augmentation of BP response and the minimization of drug-specific side effects (e.g., hypo- and hyperkalemia) when these two drug classes are combined. The combined use of angiotensin receptor blockers and diuretics is better tolerated, but more costly, than generic angiotensin converting enzyme inhibitors and diuretics, mostly because of the absence of cough and much lower incidence of angioedema.

Intratracheal delivery of angiotensin II causes pulmonary collagen accumulation: A new model for studying lung fibrosis both ex vivo and in vivo

Recent studies from this lab demonstrated that pulmonary Angiotensin II (ANG II) is increased in the fibrotic lungs induced by bleomycin and angiotensin system antagonists such as antisense oligonucleotides against angiotensinogen (ANGEN) mRNA, ACE inhibitors, and AT1 receptor antagonists attenuate bleomycin-induced alveolar epithelial cells (AECs) apoptosis and pulmonary fibrosis in rats. Those studies demonstrated that the pulmonary angiotensin system plays an important role in the development of pulmonary fibrosis. Therefore, we hypothesize that administration of angiotenisn II to the lung will cause apoptosis of AECs and pulmonary fibrosis. Lung explants were cultured from normal PBS-perfused lungs and exposed to ANG II (10-7M) or ANG II plus the non-selective angiotensin receptor antagonist saralasin (50ug/ml) for 14 days. Lung collagen was measured by hydroxyproline assay. The results showed that there was more collagen accumulation in explants treated with ANG II, which was blocked by saralasin, compare to explants without ANG II treatment. In vivo experiments were performed to confirm the results from lung explants. 5 rats per group were exposed to aerosolized ANG II or saline for 30 minutes administrated by a nebulizer, twice a day for 14 days. Administration of aerosolized ANG II caused significant collagen increase in the lungs which is consistent with the ex vivo data. An alternate study is to overexpress ANGEN only in the lung by using intratracheal (I.T.) delivery of adenovirus containing mouse ANGEN gene(Ad-ANGEN), leading to elevated pulmonary ANG II level. Both mRNA and protein level of ANGEN was increased in mice lungs after I.T. delivery of Ad-ANGEN in a dose and time dependent manner. The effect of Ad-ANGEN on apoptosis of AECs and lung fibrosis is currently being examined.

Epoetin Responsiveness in Peritoneal Dialysis Patients: A Multi‐center Slovenian Study

The objective of our study was to assess the influence of residual renal function and other factors on epoetin requirements in chronic peritoneal dialysis patients. Fifty-one stable patients (mean age +/- SD: 52 +/- 13 years; 20 women) without recent bleeding, bone marrow disease or malignancy were recruited in four Slovenian centers. The target hemoglobin was above 110 g/L. The peritoneal equilibration test results and relevant clinical and laboratory parameters were recorded. The epoetin resistance index was expressed as a weekly epoetin dose/body weight/hemoglobin concentration. Twenty-four percent of the patients did not need epoetin treatment, the rest were treated with epoetin-beta in a dose of 70 +/- 56 U/kg per week s.c.; the hemoglobin concentration was 124 +/- 15 g/L. Ferritin >100 microg/L and transferrin saturation >20% fulfilled 63% of patients whose epoetin resistance index was not significantly lower (0.43 +/- 0.5 U/kg per week per g/L vs 0.6 +/- 0.72 U/kg per week per g/L, P = 0.502). No difference was found between diabetic and non-diabetic patients. Treatment with angiotensin system antagonists, but not with aluminum phosphate binders, was associated with increased epoetin resistance index (0.56 +/- 0.59 vs 0.3 +/- 0.4 U/kg per week per g/L, P = 0.038). No correlation between epoetin resistance index and residual glomerular filtration rate was found (r = -0.2, P = 0.173). A multiple linear regression analysis showed C-reactive protein, intact parathormone level, female sex and treatment with angiotensin system antagonists to be the independent predictors influencing epoetin resistance index. Our results show that systemic inflammation, secondary hyperparathyroidism and angiotensin system antagonist treatment are the most important modifiable parameters affecting epoetin requirements in stable peritoneal dialysis patients.

2 Renal Anemia Treatment In Peritoneal Dialysis Patients: A Multicenter Slovenian Study

Objectives The aim of our study was to: (i) assess the number of patients who need epoetin treatment and the adequacy of iron treatment, (ii) assess the influence of presence of diabetes mellitus, polycystic kidney disease and the influence of therapy with aluminum phosphate binders and angiotensin system antagonists on the epoetin requirements, (iii) assess the role of other factors possibly influencing epoetin resistance – secondary hyperparathyroidism, inflammation, dialysis dose and residual renal function.Design and Methods Fifty‐one stable peritoneal dialysis (PD) patients (mean age ± SD was 52 ± 13 years, 20 women) without recent bleeding, surgery, bone marrow disease, malignancy, or hypothyroidism were recruited in four Slovenian centers. The dose of epoetin was adjusted to maintain a target hemoglobin of above 110 g/L. At the time of inclusion (median 36 months of PD, range 3–124 months) the PET test results and relevant clinical and laboratory parameters were recorded. Index of epoetin resistance (IRE) was expressed as weekly epoetin dose/body weight/hemoglobin concentration.Results Twenty four percent of patients did not need epoetin treatment, the rest were treated with Epoetin‐beta at a dose of 70 ± 56 U/kg/week s.c.; hemoglobin concentration was 124 ± 15 g/L; 14% had hemoglobin below 110 g/L. Iron adequacy parameters (ferritin > 100 µg/L and TSAT > 20%) were fulfilled by 63% of patients, and their IRE was lower (0.43 ± 0.5 U/kg/week/g/L vs. 0.6 ± 0.72 U/kg/week/g/L), but not significantly (P = 0.502). Patients with polycystic kidneys had lower IRE (0.13 ± 0.3 vs. 0.52 ± 0.55 U/kg/week/g/L, P = 0.011) and majority of them (71%) did not need epoetin treatment (P = 0.006). No difference was found for diabetic patients. Treatment with angiotensin system antagonists, but not with aluminum phosphate binders, is associated with increased IRE (0.56 ± 0.59 vs. 0.3 ± 0.4 U/kg/week/g/L, P = 0.038). A statistically significant correlation was found for IRE and CRP (r = 0.48, P = 0.001) and iPTH (r = 0.46, P = 0.001). No correlation between IRE and residual renal function was found (r = −0.2, P = 0.173). Stepwise linear regression analysis for multiple variables (residual renal glomerular filtration rate, total weekly creatinine clearance, CRP, iPTH, iron adequacy, angiotensin system antagonist treatment, presence of polycystic kidneys) showed CRP and treatment with angiotensin system antagonists to be the most significant variables influencing IRE.Conclusion Our results show that systemic inflammation and angiotensin system antagonist treatment are the most important parameters affecting epoetin requirements in stable peritoneal dialysis patients.

Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, beta-, and angiotensin receptor activation.

Norepinephrine (NE) induces apoptosis in cardiac myocytes, and autocrine production of angiotensin (ANG) II is required for apoptosis of alveolar epithelial cells (AECs) (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 277: L1245--L1250, 1999; Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, and Uhal BD. J Cell Physiol 185: 253--259, 2000). On this basis, we hypothesized that NE might induce apoptosis of AECs in a manner inhibitable by ANG system antagonists. Purified NE induced apoptosis in the human A549 AEC-derived cell line or in primary cultures of rat AECs, with EC(50) values of 200 and 20 nM, respectively. Neither the alpha-agonist phenylephrine nor the beta-agonist isoproterenol could mimic NE when tested alone but when applied together could induce apoptosis with potency equal to NE. Apoptosis and net cell loss (47--59% in 40 h) in response to NE was completely abrogated by the ANG-converting enzyme inhibitor lisinopril or the ANG II receptor antagonist saralasin, each at concentrations capable of blocking Fas- or tumor necrosis factor-alpha-induced apoptosis. These data suggest that NE induces apoptosis of human and rat AECs through a mechanism involving the combination of alpha- and beta-adrenoceptor activation followed by autocrine generation of ANG II.

Diastolic Heart Failure.

The diagnosis of diastolic heart failure (DHF) can be made when a patient has both symptoms and signs on physical exam of congestive heart failure (CHF), and normal left ventricular volume and ejection fraction. Documentation of abnormal diastolic function is confirmatory but not mandatory. Diastolic heart failure is a frequent cause of CHF (prevalence is 35% to 50%) and has a significant effect on mortality (5-year mortality rate is 25% to 35%) and morbidity (1-year readmission rate is 50%). Treatment should be targeted at symptoms, causal clinical disease, and underlying basic mechanisms. Symptom-targeted therapy: decrease pulmonary venous pressure using diuretics and long-acting nitrates, maintain atrial contraction and atrial ventricular synchrony, reduce heart rate using beta-adrenergic blockers and calcium channel blockers; increase exercise tolerance by reducing exercise- induced increases in blood pressure and heart rate using angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium channel blockers. Disease-targeted therapy: prevent or treat myocardial ischemia, prevent or regress left ventricular hypertrophy. Mechanism-targeted therapy (future directions): modify neurohumoral activation using renin, angiotensin, and aldosterone system antagonists (ACE inhibitors, angiotensin II receptor blockade, aldosterone and renin antagonist); endothelin antagonists; nitric oxide agonists; and atrial natruretic peptide agonists; alter intracellular mechanisms; alter extracellular matrix structures.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II