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Hypertension Research : Official... Jun 2012Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the...
Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT(2) receptor activation in OZR. Infusion of C21 (1 and 5 μg kg(-1) min(-1)) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (U(Na)V). These effects of C21 were blocked by pre-infusion of the AT(2) receptor antagonist, PD123319, (50 μg kg(-1) min(-1)), suggesting involvement of the AT(2) receptor. Infusion of C21 (5 μg kg(-1) min(-1)) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg(-1) body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg(-1) body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg(-1) min(-1)). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT(2) receptor agonist, C21, promotes natriuresis via AT(2) receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.
Topics: Amiloride; Angiotensin II Type 1 Receptor Blockers; Animals; Bendroflumethiazide; Disease Models, Animal; Dose-Response Relationship, Drug; Epithelial Sodium Channels; Imidazoles; Male; Natriuresis; Natriuretic Agents; Obesity; Pyridines; Rats; Rats, Zucker; Receptor, Angiotensin, Type 2; Sodium; Sodium Chloride Symporter Inhibitors; Sodium Chloride Symporters; Sulfonamides; Thiophenes; Urination
PubMed: 22297475
DOI: 10.1038/hr.2012.13 -
International Journal of Cardiology Apr 2010ASCOT-BPLA study demonstrates that in hypertensive subjects, atenolol+bendroflumethiazide therapy is associated with higher incidence of adverse cardiovascular outcomes... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
ASCOT-BPLA study demonstrates that in hypertensive subjects, atenolol+bendroflumethiazide therapy is associated with higher incidence of adverse cardiovascular outcomes and developing diabetes than an amlodipine+perindopril regimen. This is not explained by changes in blood pressure alone. We hypothesized that distinct vascular and metabolic effects of anti-hypertensive drugs may explain these differential effects.
METHODS
Either placebo or one class of anti-hypertensive drug (atenolol 100 mg, amlodipine 10 mg, hydrochlorothiazide 50 mg, ramipril 10 mg, or candesartan 16 mg) was given daily during 8 weeks to 31 patients in each of 6 arms of a randomized, single-blind, placebo-controlled, parallel study.
RESULTS
Atenolol, amlodipine, and candesartan therapies significantly reduced systolic blood pressure when compared with ramipril (P<0.05 by ANOVA). Atenolol and thiazide therapies increased triglycerides levels greater than ramipril or candesartan (P=0.005 by ANOVA). Amlodipine significantly increased HDL cholesterol levels greater than atenolol (P=0.011 by ANOVA). Ramipril and candesartan therapies improved FMD and increased adiponectin levels and insulin sensitivity to a greater extent than atenolol or thiazide therapies (P<0.001 and P<0.015 by ANOVA). Amlodipine therapy increased adiponectin levels greater than atenolol therapy (P<0.05 by ANOVA). Ramipril, candesartan, and amlodipine therapies significantly decreased leptin levels to a greater extent when compared with atenolol or thiazide therapies (P<0.001 by ANOVA). Amlodipine therapies significantly decreased resistin levels greater than ramipril or candesartan therapies (P=0.001 by ANOVA).
CONCLUSIONS
We observed differential effects of anti-hypertensive drugs on endothelial dysfunction and plasma adipocytokines.
Topics: Adipokines; Adiponectin; Adult; Aged; Amlodipine; Antihypertensive Agents; Atenolol; Benzimidazoles; Biphenyl Compounds; Cholesterol, HDL; Comorbidity; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Single-Blind Method; Tetrazoles; Triglycerides
PubMed: 19059660
DOI: 10.1016/j.ijcard.2008.11.017 -
British Medical Journal Jan 1971
Topics: Adult; Bendroflumethiazide; Cerebrovascular Disorders; Coronary Disease; Diuretics; Female; Humans; Hypertension; Male; Methyldopa; Middle Aged; Obesity; Pyelonephritis
PubMed: 5539142
DOI: No ID Found -
European Journal of Heart Failure Sep 2008High doses of aspirin counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. It is not known how low-dose aspirin, with concomitant... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
High doses of aspirin counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. It is not known how low-dose aspirin, with concomitant ACE-inhibitor treatment, affects renal function.
AIM
To study renal effects of different doses of aspirin in elderly healthy volunteers who had an activated renin-angiotensin system.
METHODS
Sixteen subjects each received two different doses of aspirin (0 and160 mg or 80 and 320 mg) after pre-treatment with bendroflumethiazide and enalapril, in a randomised double-blind, cross-over fashion.
RESULTS
Least square means of the observations 30 to 180 min after dosing, showed that urine flow, GFR, excretion rates of sodium, osmolality clearance and free water clearance were significantly decreased in a dose-dependent manner. Urine flow, sodium excretion rate and free water clearance were significantly lower with 320 mg aspirin vs. 0 mg and 80 mg, and GFR was significantly lower with 320 mg vs. 80 mg. Urine flow, sodium excretion rate, free water and osmolality clearance was significantly lower with aspirin 160 mg vs. 0 mg.
CONCLUSION
The dose-dependent renal effects of aspirin are of clinical importance from a dose of 160 mg. The adverse influence of aspirin doses higher than 80 mg should be taken into consideration in patients with heart failure.
Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Chromatography, High Pressure Liquid; Cross-Over Studies; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Kidney; Least-Squares Analysis; Male; Middle Aged; Myocardial Ischemia
PubMed: 18794027
DOI: 10.1016/j.ejheart.2008.06.014 -
British Medical Journal Oct 1980In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of...
In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of spironolactone, produced significant reductions in blood pressure and body weight. The response did not depend on the presence of overt fluid retention, renal impairment, or the use of antihypertensive drugs of high potency. Women had larger responses than men. Expansion of the plasma or extracellular fluid volume is an important cause of resistance to treatment even when a thiazide diuretic is used. An increase in diuretic treatment should be tried before using the postganglionic adrenergic blockers or minoxidil in resistant hypertension.
Topics: Adult; Aged; Bendroflumethiazide; Body Weight; Cyclopenthiazide; Drug Resistance; Female; Furosemide; Humans; Hypertension; Male; Middle Aged; Spironolactone
PubMed: 7427599
DOI: 10.1136/bmj.281.6248.1101 -
British Medical Journal Aug 1973A study was designed to investigate the effect on morbidity and mortality of lowering diastolic blood pressure levels of between 100 and 120 mm Hg to below 100 mm Hg.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A study was designed to investigate the effect on morbidity and mortality of lowering diastolic blood pressure levels of between 100 and 120 mm Hg to below 100 mm Hg. Fifty-eight men and women, aged from 45-69 years, with blood pressure levels between 100 and 120 mm Hg were matched for age, sex, and blood pressure levels with 58 control patients. The maintenance of diastolic blood pressures at levels below 100 mm Hg was successfully carried out without serious drug side effects. Treatment effectively maintained diastolic pressures below 100 mm Hg, but no effect was shown on other terminating events. Few problems were found in the management of patients with minimally raised blood pressure, most of whom were symptom-free. The treatment and control groups became less comparable as increasing numbers of patients in the control group were withdrawn from the trial as diastolic pressures rose above 130 mm Hg.
Topics: Aged; Antihypertensive Agents; Bendroflumethiazide; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Debrisoquin; Female; Humans; Hypertension; Male; Methyldopa; Middle Aged; Placebos; Potassium; Prospective Studies
PubMed: 4580022
DOI: No ID Found -
Nature Medicine Oct 2011Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension...
Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.
Topics: Analysis of Variance; Animals; Bendroflumethiazide; Calcineurin Inhibitors; Calcium; Cell Line; Chlorides; Creatinine; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Humans; Hydrochlorothiazide; Hypertension; Immunoblotting; Immunohistochemistry; Kidney; Mice; Mice, Knockout; Sodium Chloride Symporters; Tacrolimus
PubMed: 21963515
DOI: 10.1038/nm.2497 -
British Medical Journal Dec 1976To compare findings in a hospital trial of hypotensive drugs with those in a general practice trial several patients with mild hypertension were studied at the same time... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
To compare findings in a hospital trial of hypotensive drugs with those in a general practice trial several patients with mild hypertension were studied at the same time in hospital and in general practice. They received bendrofluazide and potassium chloride or bendrofluazide, potassium chloride, and reserpine according to a double-blind crossover protocol, and blood biochemical values were studied over eight weeks and six months. When reserpine was withdrawn from nine women they followed a modified protocol comparing bendrofluazide and potassium chloride with potassium chloride alone. The blood pressure values measured by the general practitioners were similar to those measured in hospital. Both the diuretic alone and the diuretic with reserpine produced significant falls in blood pressures. Although plasma renin activity increased on diuretic treatment, continued treatment did not produce a further increase, and levels gradually declined towards normal.
Topics: Adult; Aged; Bendroflumethiazide; Blood Pressure; Clinical Trials as Topic; Drug Combinations; Family Practice; Female; Hospitalization; Humans; Hypertension; Male; Middle Aged; Potassium Chloride; Renin; Reserpine
PubMed: 793680
DOI: 10.1136/bmj.2.6050.1476 -
Trials Nov 2021Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential...
Evaluating Diuretics in Normal Care (EVIDENCE): protocol of a cluster randomised controlled equivalence trial of prescribing policy to compare the effectiveness of thiazide-type diuretics in hypertension.
INTRODUCTION
Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension.
METHODS AND ANALYSIS
The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies' effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies.
ETHICS AND DISSEMINATION
EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups.
TRIAL REGISTRATION
ISRCTN 46635087 . Registered on 11 August 2017 (pre-recruitment).
Topics: Diuretics; Humans; Hypertension; Policy; Prospective Studies; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; State Medicine; Thiazides
PubMed: 34789314
DOI: 10.1186/s13063-021-05782-9 -
British Journal of Clinical Pharmacology Nov 19821 The effect of long-acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Comparative pharmacological and pharmacokinetic observations on propranolol (long acting formulation) and bendrofluazide administered separately and concurrently to volunteers.
1 The effect of long-acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise tachycardia was studied in ten normal volunteers. 2 The preparations were given in random order, double-blind, on three separate study weeks. Observations were made 0, 1, 3, 6, 8, 24, 33 and 48 h after drug administration. 3 The three preparations produced a significant reduction in exercise tachycardia up to 48 h after drug administration, and the effects of the three preparations were not significantly different from each other. 4 Following LA propranolol, LA propranolol and bendrofluazide, and the combined formulation the mean reductions in exercise heart rate 24 h after drug administration were 16.7 +/- 2.1%, 13.0 +/- 1.8% and 16.2 +/- 1.7% respectively. 5 Plasma levels of propranolol and bendrofluazide were measured at 0, 1, 2, 3, 6, 8, 10, 12, 24, 33 and 48 h after dose administration. 6 There was no significant difference in plasma propranolol levels, Cmax propranolol or AUCo-x following the three preparations. The mean apparent t1/2 beta of propranolol after LA propranolol alone was significantly shorter than following the other two preparations (P less than 0.05), but this was not associated with a different pharmacodynamic response. 7 There was no significant difference in the pharmacokinetic parameters of bendrofluazide following the two preparations containing bendrofluazide. No bendrofluazide was detected in plasma after LA propranolol alone. 8 The new combined formulation produces similar pharmacodynamic and pharmacokinetic responses to LA propranolol and bendrofluazide given separately, and to LA propranolol given alone, and so may be of value in the treatment of hypertension.
Topics: Adolescent; Adult; Bendroflumethiazide; Delayed-Action Preparations; Drug Combinations; Drug Therapy, Combination; Female; Heart Rate; Humans; Kinetics; Male; Propranolol
PubMed: 7138752
DOI: 10.1111/j.1365-2125.1982.tb04964.x