Angiotensin II-converting Enzyme Inhibitors Research Articles

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end-stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin-II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

COVID-19 and the Use of Angiotensin II Receptor Blockers in Older Chronic Hypertensive Patients: Systematic Review and Meta-Analysis.

Angiotensin II-converting enzyme inhibitors (ACEIs) and selective angiotensin II receptor antagonists (ARAIIs) are widely used antihypertensive agents. Their use has generated controversy due to their possible influence on the health status of chronic patients infected with COVID-19. The objective of this work is to analyze the influence of COVID-19 on chronic hypertensive patients treated with ACEI and ARAII inhibitors. A systematic review and meta-analysis in the databases Pubmed, Pro-Quest and Scopus were carried out. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search equation descriptors were obtained from the Medical Subject Headings (MeSH) thesaurus. The search equation was: "Older AND hypertension AND (COVID-19 OR coronavirus) AND primary care" and its equivalent in Spanish. Nineteen articles were obtained, with n = 10,806,159 subjects. Several studies describe the COVID-19 association with ACEI or ARAII treatment in hypertension patients as a protective factor, some as a risk factor, and others without a risk association. In the case of ACEI vs. ARAII, the risk described for the former has an odds ratio (OR) of 0.55, and for ARAII, an OR of 0.59. Some authors talk about mortality associated with COVID-19 and ACEI with a half ratio (HR) of 0.97, and also associated ARAIIs with an HR of 0.98. It is recommended to maintain the use of the renin-angiotensin-aldosterone axis in the context of the COVID-19 disease.

Sacubitril/Valsartan in Dialysis Patients: Update on Current Perspectives.

Sacubitril/Valsartan is a combination of neprilysin inhibitor and angiotensin II receptor blocker that proved its own efficacy and safety in heart failure patients to ameliorate cardiovascular morbidity and mortality compared to angiotensin II-converting enzyme inhibitors alone. However, end-stage renal disease patients have not been included in the randomized controlled trials, so the beneficial effects as well as the risk profile of this association remain still undefined in these patients. Only observational studies on this drug association have been carried out in end-stage renal disease patients investigating mostly biohumoral or echocardiographic markers. Therefore, its application is still controversial and not free of complications due to the potential risk of hypotension and hyperkaliemia. The efficacy to improve biohumoral markers and cardiac function in dialysis patients and the potential application especially in those patients with severe and resistant hypertension and/or left ventricular dysfunction could be crucial in end-stage renal disease patients. Ongoing long-term randomized controlled trials should thoroughly define the effective benefits and/or adverse effects in patients on substitutive treatment.

Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning

Context Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated. Objective To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone. Methods This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients >14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected. Results There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg, p < 0.001), more frequently had hypotension (OR 4.5, 95%CI: 1.7–11.9) or bradycardia (OR 8.8, 95%CI: 1.1–70). Multivariable analysis indicated the mixed overdoses had an 11.5 mmHg (95%CI: 4.9–18.1) lower minimum systolic blood pressure (SBP) compared with the single group; other factors associated with a lower minimum SBP were higher doses [2.3 mmHg (95%CI: 1.1–3.5) lower per 10 defined daily doses] and younger age [2.2 mmHg (95%CI: 0.3–4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenous fluids (OR 5.7, 95%CI: 1.8–18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004–8.6). Conclusion Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone.

SARS-CoV-2 Infection &amp; Cardiology: Overview on Renin-Angiotensin-Aldosterone System Inhibition

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a coronavirus strain, and its main way to get access to the cells is via the angiotensin converting enzyme 2 (ACE2) and causes the Coronavirus Disease 2019 (COVID-19). ACE2 is an important enzyme in the pathogeneses of hypertension. For the treatment of hypertension, it is commonly used angiotensin II receptor blockers (ARBs) and angiotensin II converting enzyme inhibitors (ACEIs). It is clear that there is a lot of uncertainty and controversy regarding SARS-CoV-2 and its interaction with ACE2. These issues should be solved with more studies. Thus, the use of medications such as ACEIs and ARBs should be individualized and in the majority of times its' suspension is not necessary.

Human Endomyocardial Biopsy Specimen-Derived Stromal Cells Modulate Angiotensin II-Induced Cardiac Remodeling.

Despite effective pharmacological treatment with angiotensin II type I receptor antagonists or angiotensin II-converting enzyme inhibitors, morbidity and mortality associated with heart failure are still substantial, prompting the search of novel therapeutic strategies. There is accumulating evidence supporting the use of cell therapy for cardiac repair. This study demonstrates that cells derived from human endomyocardial biopsies, cardiac-derived adherent proliferating cells (CardAPs), have the potential to reduce angiotensin II-induced cardiac remodeling and improve left ventricular function in angiotensin II mice. The mechanism involves antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. These findings support the potential of CardAPs for the treatment of heart failure.

Recent trends in the use of antidiabetic medications from 2008 to 2013: A nation-wide population-based study from Taiwan.

Studies from other countries indicate that utilization patterns of antidiabetic drugs change significantly after the introduction of newer classes of antidiabetic drugs (e.g. dipeptidyl peptidase-4 inhibitors [DPP-4i]). Evidence on recent trends regarding antidiabetic drug use in Taiwan is lacking, especially for times after the introduction of newer classes of drugs (e.g. DPP-4i). Therefore, the aim of the present study was to assess: (i) recent trends in the use and spending on antidiabetic drugs; (ii) changes in utilization patterns after introduction of newer classes of antidiabetic drugs; and (iii) factors associated with the choice of newer versus older classes of antidiabetic drugs. Cases of type 2 diabetes were derived from Taiwan's National Health Insurance Research Database. Antidiabetic drug use was measured in terms of total quantity of drug exposure and healthcare spending in each calendar year from 2008 to 2103. Multiple logistic regression analysis was used to assess factors associated with drug choice. The use of and healthcare spending on DPP-4i increased significantly from 2008 to 2013, whereas healthcare spending on sulfonylureas decreased. For monotherapy, sulfonylureas were the most common alternatives to metformin, whereas in dual and triple antidiabetic therapies, a DPP-4i was the most common alternative to initial regimens. The use of a DPP-4i was positively associated with the use of beta-blockers, angiotensin II-converting enzyme inhibitors and/or angiotensin receptor blockers, and lipid-lowering agents, but negatively correlated with age, hypertension, severity of diabetes complications, and the use of diuretics and calcium channel blockers. With growing spending on newer antidiabetic drugs, future research on the comparative cost-effectiveness and safety of antidiabetic drugs is anticipated.

Enalapril in Combination with Benznidazole Reduces Cardiac Inflammation and Creatine Kinases in Mice Chronically Infected with Trypanosoma cruzi.

The protozoan Trypanosoma cruzi triggers an inflammatory process in mammalian heart causing events such as fibrosis, changes in the architecture and functionality in this organ. Enalapril, an angiotensin II-converting enzyme inhibitor, is a drug prescribed to ameliorate this heart dysfunction, and appears to exert a potential role in immune system regulation. Our aim was to evaluate the chronic cardiac inflammatory parameters after therapeutic treatment with enalapril and benznidazole in C57BL/6 mice infected with the VL-10 strain of T. cruzi. After infection, animals were treated with oral doses of enalapril (25 mg/kg), benznidazole (100 mg/kg), or both during 30 days. Morphometric parameters and levels of chemokines (CCL2, CCL5), IL-10, creatine kinases (CKs), and C-reactive protein were evaluated in the heart and serum at the 120th day of infection. Enalapril alone or in combination with benznidazole did not change the number of circulating parasites, but reduced cardiac leukocyte recruitment and total collagen in the cardiac tissue. Interestingly, the combination therapy (enalapril/benznidazole) also reduced the levels of chemokines, CK and CK-MB, and C-reactive proteins in chronic phase. In conclusion, during the chronic experimental T. cruzi infection, the combination therapy using enalapril plus benznidazole potentiated their immunomodulatory effects, resulting in a low production of biomarkers of cardiac lesions.

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

BackgroundMutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of LmnaH222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in LmnaH222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. MethodsMale LmnaH222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. ResultsTreatment of LmnaH222P/H222P mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age. ConclusionsBoth ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in LmnaH222P/H222P mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.

Abstract 18590: The Underutilization of Guideline Recommended Antihypertensive Agents is Associated with a High Prevalence of Uncontrolled Hypertension in Urban Community Dwelling Older Adults

Background: Hypertension (HTN) is a major risk factor for cardiovascular disease. Despite numerous medication options and clear clinical practice guidelines (JNC 7), uncontrolled HTN disproportionately affects the elderly population. Hypothesis: We hypothesized that blood pressure (BP) control in adult seniors may be affected by their prescribed antihypertensive medication regimen. Methods: Adults 59-99 years old from two New York City boroughs were enrolled in the NHLBI-funded Cardiovascular Health of Seniors and the Built Environment Study from 2009 to 2011 (n=1,453). At the baseline visit, participants brought their medications and had three BP measurements performed. The average of the 2 nd and 3 rd measurements was recorded. Uncontrolled HTN was defined as a measured BP greater than 140/90 mmHg. Medications were grouped by class including thiazide diuretics, beta blockers (BB), calcium channel blockers (CCB), angiotensin II converting enzyme inhibitors (ACEI), and angiotensin II receptor blockers (ARB). All other agents were grouped together. Results: The prevalence of hypertension was 68.7%. Hypertension increased with age, affected more women (71%) compared to men (61%); and was higher among African Americans (75%) compared to Whites (63%) or Hispanics (63%). Nearly 70% of the hypertensive participants were treated with at least one medication, but in those with uncontrolled BPs (41%), only 65% were prescribed an antihypertensive agent. CCBs were prescribed most frequently (23%) followed by BBs (21%), ACEIs (17%), ARBs (17%), thiazide diuretics (14%), and second line agents (7%). Thiazide diuretics remained the least prescribed first line drug class regardless of underlying comorbidities (diabetes, heart disease, renal disease) or BP control. Conclusions: Despite longstanding consensus recommendations, more than a third of participants with uncontrolled HTN in our cohort were not prescribed any antihypertensive medication. Further, thiazide diuretics were prescribed less often than any other first line agent, contrary to the JNC 7 guidelines. Increased attention to the guideline recommended prescription of antihypertensives may have a beneficial population level effect on uncontrolled hypertension.

Renal oxygen content is increased in healthy subjects after angiotensin-converting enzyme inhibition

OBJECTIVE:The association between renal hypoxia and the development of renal injury is well established. However, no adequate method currently exists to non-invasively measure functional changes in renal oxygenation in normal and injured patients.METHOD:R2* quantification was performed using renal blood oxygen level-dependent properties. Five healthy normotensive women (50±5.3 years) underwent magnetic resonance imaging in a 1.5T Signa Excite HDx scanner (GE Healthcare, Waukesha, WI). A multiple fast gradient-echo sequence was used to acquire R2*/T2* images (sixteen echoes from 2.1 ms/slice to 49.6 ms/slice in a single breath hold per location). The images were post-processed to generate R2* maps for quantification. Data were recorded before and at 30 minutes after the oral administration of an angiotensin II-converting enzyme inhibitor (captopril, 25 mg). The results were compared using an ANOVA for repeated measurements (mean ± standard deviation) followed by the Tukey test. ClinicalTrials.gov: NCT01545479.RESULTS:A significant difference (p<0.001) in renal oxygenation (R2*) was observed in the cortex and medulla before and after captopril administration: right kidney, cortex = 11.08±0.56ms, medulla = 17.21±1.47ms and cortex = 10.30±0.44ms, medulla = 16.06±1.74ms, respectively; and left kidney, cortex = 11.79±1.85ms, medulla = 17.03±0.88ms and cortex = 10.89±0.91ms, medulla = 16.43±1.49ms, respectively.CONCLUSIONS:This result suggests that the technique efficiently measured alterations in renal blood oxygenation after angiotensin II-converting enzyme inhibition and that it may provide a new strategy for identifying the early stages of renal disease and perhaps new therapeutic targets.

Recommendations for the treatment of hypertension in the elderly and very elderly: a scotoma within international guidelines

The recommendations of international scientific societies for the treatment of hypertension in the geriatric population are different. Lack of outcome trials, non-standardised terminology as well as differing levels of evidence contribute to the inconsistencies in the guidelines. This review article compares six international guidelines (ESH-ESC 2007/2009, SHG 2009, DHL 2008, CHEP 2010, NICE 2011 and JNC7 2003) as well as the consensus document of the ACCF/AHA 2011 in terms of their recommendations of drug classes, target blood pressure values and the use of combination therapy. Generally, antihypertensive therapy appears to be clinically beneficial in geriatric patients. Target blood pressure values of <140-150/90 mm Hg and <140/90 mm Hg can be used as a general guideline for octogenarians (80-89 yrs) and septuagenarians (70-79 yrs) respectively. While angiotensin-II converting enzyme inhibitors and diuretics appear to be advantageous in treating combined systolic-diastolic hypertension, calcium-channel blockers and diuretics are to be recommended in the management of isolated systolic hypertension. Combination therapy often increases the efficacy of the treatment as well as patient medication adherence. Furthermore, by making the most of drug combination synergy, lower doses may be used resulting in fewer side-effects.

300 Dose comparison of angiotensin II-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure

300 Dose comparison of angiotensin II-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure

Stimulation of Renin Secretion by Angiotensin II Blockade is Gsα-Dependent

Angiotensin II converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) presumably stimulate renin secretion by interrupting angiotensin II feedback inhibition. The increase in cytosolic calcium caused by activation of Gq-coupled AT1 receptors may mediate the renin-inhibitory effect of angiotensin II at the cellular level, implying that ACEI and ARB may work by reducing intracellular calcium. Here, we investigated whether angiotensin II blockade acts predominantly through Gs-mediated stimulation of adenylyl cyclase (AC) by testing the effect of ACEI and ARB in mice with juxtaglomerular cell-specific deficiency of the AC-stimulatory Gsalpha. The ACEI captopril and quinaprilate and the ARB candesartan significantly increased plasma renin concentration (PRC) to 20 to 40 times basal PRC in wild-type mice but did not significantly alter PRC in Gsalpha-deficient mice. Captopril also completely abrogated renin stimulation in wild-type mice after co-administration of propranolol, indomethacin, and L-NAME. Treatment with enalapril and a low-NaCl diet for 7 days led to a 35-fold increase in PRC among wild-type mice but no significant change in PRC among Gsalpha-deficient mice. Three different pharmacologic inhibitors of AC reduced the stimulatory effect of captopril by 70% to 80%. In conclusion, blockade of angiotensin II stimulates renin synthesis and release indirectly through the action of ligands that activate the cAMP/PKA pathway in a Gsalpha-dependent fashion, including catecholamines, prostaglandins, and nitric oxide.

Bosentan for Digital Ulcers in Patients with Systemic Sclerosis: A Prospective 3-year Followup Study

To the Editor: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by cutaneous and visceral fibrosis and widespread vascular pathology1. Digital ulcers (DU) are a major clinical problem in SSc, occurring in about one-third of patients2. DU cause local pain and functional impairment and have a negative effect on quality of life for patients with SSc2. Therapeutic agents potentially used for management of DU include calcium channel blockers, α-adrenergic inhibitors, angiotensin II-converting enzyme inhibitors, prostacyclin analogs, phosphodiesterase-5 inhibitor, and others2. Bosentan is a specific orally active dual endothelin receptor antagonist that has been used for the treatment of pulmonary hypertension (PH) and recently for DU3–5. The objective of our study was to examine the effectiveness and safety of bosentan for healing DU in patients with SSc over the long term. For a cohort of 110 patients with SSc, 30 patients with DU were identified. All patients fulfilled the American College of Rheumatology criteria for SSc6 and all were refractory to calcium channel antagonists, angiotensin II inhibitors, or sildenafil. … Address reprint requests to Prof. Drosos. E-mail: adrosos{at}cc.uoi.gr

Prevention of Recurrent Lone Atrial Fibrillation by the Angiotensin-II Converting Enzyme Inhibitor Ramipril in Normotensive Patients

The aim of the present study was to verify whether angiotensin-II converting enzyme (ACE) inhibition is also effective in preventing relapses of lone atrial fibrillation (LAF), that is, in the absence of hypertension and/or heart disease. Several studies have shown that ACE inhibitors are effective in preventing atrial fibrillation (AF) relapses in patients with arterial hypertension or several forms of heart disease, that is, in the presence of clinical conditions that are recognized as causing a higher risk of atrial arrhythmias. Sixty-two patients admitted to the emergency department of our institution for a first-ever episode of LAF were enrolled in the study after excluding the presence of cardiac or extracardiac conditions known to be associated with an increased risk of AF, by medical history, physical examination, complete echocardiographic study, and the evaluation of blood pressure, thyroid function, urinary catecholamines, serum electrolytes, blood glucose, red blood cell count, and arterial blood gases. After cardioversion to sinus rhythm by intravenous propafenone, patients were randomized to either ramipril 5 mg/day (n = 31) or placebo (n = 31). Holter monitoring and clinical examination were performed every 3 months. After a 3-year follow-up, AF relapses were observed in 3 patients treated with ramipril and in 10 patients allocated to placebo (p < 0.03, Kaplan-Meier, log-rank test). During follow-up, none of the patients developed arterial hypertension or other cardiac or extracardiac condition known to be associated with increased risk of AF, that is, in all patients the diagnosis of LAF was confirmed. Ramipril is effective in preventing relapses of LAF.

Connexin40 regulates renin production and blood pressure

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.

Carvedilol accelerate elevation of serum potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate or candesartan cilexetil

To retrospectively investigate the effect of carvedilol and spironolactone plus furosemide, administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) to patients with chronic heart failure (CHF). Patients with CHF, who visited Departments of Cardiovascular Internal Medicine at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine (Scr) and serum sodium were measured in every patient at the time of start of treatment and after 3 and 12 months of treatment. Data from patients in groups A (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I) and B (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + ARB) were compared. When 20 mg/day carvedilol plus 25 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril, group A) or 8 mg/day candesartan cilexetil (candesartan, group B) plus 40 mg/day furosemide were used concomitantly, the mean serum potassium increased significantly in both groups of patients. Seven of 59 (11.9%) patients had hyperkalemia (>5.5 mEq/L) during 12 months of treatment whereas 8.5% of patients (five of 59) had hypokalemia (< or =3.5 mEq/L). When carvedilol is used concomitantly with spironolactone, furosemide and enalapril or candesartan, it is necessary to monitor serum potassium concentration, even if spironolactone is administered at a low dose of 25 mg/day.

Thiazide-Associated Glucose Abnormalities: Prognosis, Etiology, and Prevention

Thiazide diuretics have been recommended as the preferred class of antihypertensive (AHT) drugs for initial therapy and for inclusion in a regimen of multiple drugs.1 This recommendation is based on 4 decades of randomized clinical events trials with placebo (or usual care) comparators, meta-analyses of such trials, and active-controlled trials, including the very large Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT).2,3 In the latter, treatment beginning with the thiazide-like diuretic chlorthalidone reduced the risk for major coronary events (the primary outcome) similar to treatment based on representatives of newer drug classes (amlodipine, doxazosin, and lisinopril); diuretic-based treatment was more effective at preventing heart failure, and in some comparisons, other cardiovascular disease (CVD) events. However, in ALLHAT mean fasting blood glucose (FBG) and incident diabetes mellitus (IDM) were slightly but significantly increased in the chlorthalidone compared with the other arms.3 Although the design precluded distinguishing between a benefit of the alternate drugs (especially lisinopril) and an adverse effect of the diuretic, previous evidence suggested that thiazides can cause dysglycemia (impaired glucose tolerance, impaired fasting glucose, or diabetes).4 One point about the ALLHAT results that has not received enough emphasis is that if the calcium channel blocker is taken as metabolically neutral, the 4-year IDM rates in the diuretic and calcium channel blocker arms (11.6% and 9.8%, respectively) imply that 83% of IDM occurring in association with thiazide use is not because of the diuretic. Nevertheless, based on the assumption that there is a direct relationship between thiazide exposure and dysglycemia, several key questions need to be addressed: (1) What are the long-term morbidity/mortality consequences, if any? (2) What are the mechanisms? and (3) Are the changes preventable and/or reversible? The role of potassium may be important to addressing each of these issues. Evidence …

Angiotensin II Regulates Vascular and Endothelial Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor Signaling in the Vasculature

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.