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The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist  [PDF]
Catherine E. Erickson, Rukhsana Gul, Christopher P. Blessing, Jenny Nguyen, Tammy Liu, Lakshmi Pulakat, Murat Bastepe, Edwin K. Jackson, Bradley T. Andresen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071980
Abstract: Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs.
Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic
Volpe M, Tocci G
Vascular Health and Risk Management , 2012, DOI: http://dx.doi.org/10.2147/VHRM.S28359
Abstract: tionale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic Original Research (2712) Total Article Views Authors: Volpe M, Tocci G Published Date June 2012 Volume 2012:8 Pages 371 - 380 DOI: http://dx.doi.org/10.2147/VHRM.S28359 Received: 18 November 2011 Accepted: 23 December 2011 Published: 11 June 2012 Massimo Volpe,1,2 Giuliano Tocci2 1Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome, Sapienza, Sant'Andrea Hospital, Rome, 2IRCCS Neuromed, Pozzilli, Italy Abstract: Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) are combined with calcium channel blockers (CCBs) and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ). Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should lead to improvement in blood pressure control and aid compliance with long-term therapy, optimizing the management of this chronic condition.
Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic  [cached]
Volpe M,Tocci G
Vascular Health and Risk Management , 2012,
Abstract: Massimo Volpe,1,2 Giuliano Tocci21Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome, Sapienza, Sant'Andrea Hospital, Rome, 2IRCCS Neuromed, Pozzilli, ItalyAbstract: Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) are combined with calcium channel blockers (CCBs) and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ). Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should lead to improvement in blood pressure control and aid compliance with long-term therapy, optimizing the management of this chronic condition.Keywords: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, triple therapy, hypertension
Critical review of cancer risk associated with angiotensin receptor blocker therapy  [cached]
Wuerzner G,Burnier M,Waeber B
Vascular Health and Risk Management , 2011,
Abstract: Grégoire Wuerzner1,3, Michel Burnier1, Bernard Waeber2,31Service of Nephrology and Hypertension Consultation, Centre Hospitalier Universitaire Vaudois, 2Division of Clinical Pathophysiology, Centre Hospitalier Universitaire Vaudois, 3Clinical Research Centre, Unil/Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandAbstract: The role of drugs in new cancer occurrence and cancer-related death is a major concern. Recently, a meta-analysis raised the possibility that angiotensin receptor blockers (ARBs) might have an adverse effect on patients. This generated a significant debate until the publication of two further meta-analyses, neither of which demonstrated an increased risk of new cancer occurrence or cancer-related death with the use of ARBs in patients with hypertension, heart failure, and/or nephropathy. This illustrates that the results of meta-analyses should be interpreted cautiously and critically as bias, such as selection bias, might lead to erroneous conclusions. Overall, the bulk of evidence today indicates that ARBs are not associated with increased cancer risk.Keywords: hypertension, cancer, angiotensin receptor blocker, meta-analyses
Summertime dosage-dependent hypersensitivity to an angiotensin II receptor blocker  [PDF]
Donald R Forsdyke
PeerJ , 2015, DOI: 10.7287/peerj.preprints.144v2
Abstract: Summertime dips in blood pressure (BP), both in normotensive and hypertensive subjects, are well known. However, the dips are small and are not related to particular forms or doses of antihypertensive medication. Nevertheless it is the practice in some quarters to decrease antihypertensive medication in summer, and/or increase in winter. Large scale studies being inconclusive, there are calls for long-term examination of the relationship between environmental temperature and blood pressure in single individuals under medication. While analyzing data from a subject whose BP had been controlled for a decade with the angiotensin-II receptor blocker losartan, an extreme, dosage-dependent, summertime dip came to light. Downward dosage adjustment appeared essential and may have prevent hypotension-related pathology. The benefits of aggressive medication (the “J curve” phenomenon) being debated, the possibility of seasonal hypersensitivity, explicable in terms of differential signaling by countervailing receptors, should be taken into account when considering dosage adjustments in hypertensive subjects.
Critical review of cancer risk associated with angiotensin receptor blocker therapy
Wuerzner G, Burnier M, Waeber B
Vascular Health and Risk Management , 2011, DOI: http://dx.doi.org/10.2147/VHRM.S13552
Abstract: itical review of cancer risk associated with angiotensin receptor blocker therapy Review (2444) Total Article Views Authors: Wuerzner G, Burnier M, Waeber B Published Date December 2011 Volume 2011:7 Pages 741 - 747 DOI: http://dx.doi.org/10.2147/VHRM.S13552 Grégoire Wuerzner1,3, Michel Burnier1, Bernard Waeber2,3 1Service of Nephrology and Hypertension Consultation, Centre Hospitalier Universitaire Vaudois, 2Division of Clinical Pathophysiology, Centre Hospitalier Universitaire Vaudois, 3Clinical Research Centre, Unil/Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Abstract: The role of drugs in new cancer occurrence and cancer-related death is a major concern. Recently, a meta-analysis raised the possibility that angiotensin receptor blockers (ARBs) might have an adverse effect on patients. This generated a significant debate until the publication of two further meta-analyses, neither of which demonstrated an increased risk of new cancer occurrence or cancer-related death with the use of ARBs in patients with hypertension, heart failure, and/or nephropathy. This illustrates that the results of meta-analyses should be interpreted cautiously and critically as bias, such as selection bias, might lead to erroneous conclusions. Overall, the bulk of evidence today indicates that ARBs are not associated with increased cancer risk.
Significance of initial blood pressure and comorbidity for the efficacy of a fixed combination of an angiotensin receptor blocker and hydrochlorothiazide in clinical practice
Roland E Schmieder, Markus Schwertfeger, Peter Bramlage
Vascular Health and Risk Management , 2009, DOI: http://dx.doi.org/10.2147/VHRM.S7756
Abstract: nificance of initial blood pressure and comorbidity for the efficacy of a fixed combination of an angiotensin receptor blocker and hydrochlorothiazide in clinical practice Original Research (4815) Total Article Views Authors: Roland E Schmieder, Markus Schwertfeger, Peter Bramlage Published Date November 2009 Volume 2009:5 Pages 991 - 1000 DOI: http://dx.doi.org/10.2147/VHRM.S7756 Roland E Schmieder1, Markus Schwertfeger2, Peter Bramlage3 1Department of Nephrology and Hypertension, University Hospital of Erlangen; Germany; 2Sanofi-Aventis Deutschland GmbH, Berlin, Germany; 3Institute of Cardiovascular Pharmacology and Epidemiology, Mahlow, Germany Background: Two-thirds of all patients with arterial hypertension need drug combinations to achieve blood pressure (BP) goals. Fixed combinations have high efficacy and result in high patient compliance. 300 mg irbesartan plus 25 mg hydrochlorothiazide (HCTZ) has been investigated only in clinical trials but not in daily practice. Methods: A multicenter, noninterventional, noncontrolled observational study with 8123 patients seen by 1604 physicians in daily practice. BP reduction (office measurements), co-morbid disease and tolerability were documented over a 6-month observational period. Results: At mean baseline BP of 161 ± 15/94 ± 10 mmHg, administering of fixed combination resulted in a substantial BP reduction averaging 28 ± 15/14 ± 10 mmHg (P < 0.001). Decrease of systolic BP ran parallel with increasing systolic baseline BP (Spearman’s Rho –0.731; P < 0.0001; diastolic BP vs diastolic baseline BP Rho 0.740; P < 0.0001), independent from patient characteristics (age, obesity, diabetes or nephropathy) but enhanced with short history of hypertension (P < 0.0001 vs long history), prior beta blockers (P = 0.001 vs prior angiotensin receptor blockers [ARBs]), prior calcium channel blockers (P = 0.046 vs prior ARBs) and no prior medication (P = 0.012 vs prior ARBs). High compliance (>98%) and low incidence of adverse events (0.66%) were documented. Conclusions: The fixed combination of 300 mg irbesartan with 25 mg HCTZ was efficacious and tolerable in an unselected patient population in primary care.
Calcium Channel Blocker Enhances Beneficial Effects of an Angiotensin II AT1 Receptor Blocker against Cerebrovascular-Renal Injury in type 2 Diabetic Mice  [PDF]
Kazi Rafiq, Shamshad J. Sherajee, Hirofumi Hitomi, Daisuke Nakano, Hiroyuki Kobori, Koji Ohmori, Hirohito Mori, Hideki Kobara, Tsutomu Masaki, Masakazu Kohno, Akira Nishiyama
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082082
Abstract: Recent clinical trials have demonstrated that combination therapy with renin-angiotensin system inhibitors plus calcium channel blockers (CCBs) elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB) against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-Ay mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB) disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day) reduced blood pressure in saline-drinking KK-Ay mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day) exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes.
A New Framework for Interpreting the Outcomes of Imperfectly Blinded Controlled Clinical Trials  [PDF]
Ognjen Arandjelovi?
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048984
Abstract: It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient's expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.
The Significance of Angiotensin Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Use in Sudden Cardiac Death  [PDF]
Makoto Onodera, Satoshi Kikuchi, Yasuhisa Fujino, Yoshihiro Inoue, Yuji Fujita
International Journal of Clinical Medicine (IJCM) , 2017, DOI: 10.4236/ijcm.2017.88046
Abstract: Objectives: To investigate the relationship between the use of angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and hyperkalemia in patients diagnosed with sudden cardiac death. Methods: We examined oral ACE inhibitor or ARB use among cardiopulmonary arrest patients brought by ambulance to our emergency room during a 5-year period from January 2012 to December 2016. The cause of death was determined to be sudden cardiac death, despite temporary return of spontaneous circulation after starting cardiopulmonary resuscitation. Subjects were dichotomized into 2 groups, those taking and those not taking an ACE inhibitor or ARB. Variables determined retrospectively included serum potassium, estimated glomerular filtration rate as an index of kidney function and time from cardiopulmonary arrest to return of spontaneous circulation. The Mann-Whitney U-test was used to compare continuous data, and the chi-square test to compare categorical data between groups. The results are expressed as the median plus range. Statistical significance was assumed at p < 0.05. Results: Thirty-five patients met the inclusion criteria. The mean age was 77.1 years (range, 35 - 93 years), and there were 26 males and 9 females. Eleven subjects were ACE inhibitor or ARB users, and 24 were non-users. The serum potassium level was significantly higher in users than non-users (median, 6.2 mEq/L (range, 4.5 - 10.0) vs. 5.2 mEq/L (range, 3.6 - 8.3); p = 0.001). The estimated glomerular filtration rate was significantly lower in users than non-users (median, 25.1 mL/min/1.73 m2 (range, 4.6 - 60.3) vs. 46.9 mL/min/1.73 m2 (range, 19.8 - 97.1); p = 0.009). There was no significant difference in time from cardiopulmonary arrest to return of spontaneous circulation between the 2 groups (median, 24 minutes (range, 3 - 111) vs. 29 minutes (range, 10 - 54); p = 0.355). Conclusion: It is possible that hyperkalemia induced by ACE inhibitor or ARB use is a cause of sudden cardiac death, especially in patients with chronic kidney disease.
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