eplerenone and olmesartan

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design.

Topics: Amides; Antihypertensive Agents; Benzimidazoles; Benzopyrans; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Control Groups; Double-Blind Method; Drug Resistance; Eplerenone; Ethanolamines; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Nebivolol; Oxadiazoles; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Regression Analysis; Research Design; Spironolactone; Sympathectomy; Tetrazoles; Treatment Outcome

Epithelial sodium channels (ENaC) are ion transporters in the aldosterone-sensitive distal nephron that play an important role in sodium reabsorption in the terminal nephron. Our study of inbred C57Bl6/J mice given a high-sodium diet showed increased ENaC expression accompanied by tubular renin activation on qRT-PCR of laser-captured tubule specimens and Western blotting of membrane proteins, despite inhibition of aldosterone. Treatment with an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) effectively lowered blood pressure. In addition to lowering blood pressure, ACEI and ARB inhibition downregulated ENaC and renin expression in renal tubules. These effects would act to suppress sodium reabsorption via ENaC and normalize molecular mechanisms that elevate blood pressure in response to increased salt intake.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Down-Regulation; Epithelial Sodium Channels; Eplerenone; Hypertension; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Perindopril; Renin; Sodium; Sodium Chloride, Dietary; Spironolactone; Tetrazoles

We recently reported that aldosterone-induced cellular senescence via an increase in p21, a cyclin-dependent kinase (CDK) inhibitor, in rat kidney and cultured human proximal tubular cells. In the present study, we investigated the contribution of aldosterone to the renal p21 expression and senescence during the development of angiotensin II (AngII)-induced hypertension.. Mice received 1% salt in drinking water and vehicle or AngII, and were divided into five groups: 1, vehicle; 2, AngII; 3, AngII+olmesartan; 4, AngII+eplerenone; and 5, AngII+hydralazine.. Plasma aldosterone levels were increased by AngII infusion. Eplerenone further elevated the plasma aldosterone level, but olmesartan and hydralazine did not. AngII group showed significant increase in blood pressure compared to vehicle. Olmesartan and hydralazine, but not eplerenone, suppressed the AngII-salt hypertension. The increase in urinary protein excretion by AngII-salt was suppressed only by olmesartan. AngII with high salt induced a greater expression of p21 mRNA in the kidney than vehicle. Olmesartan abolished the increase in p21 expression, whereas neither eplerenone nor hydralazine affected it. AngII with high salt did not change the expression of p16, another CDK inhibitor. The mice lacking p21 showed identical changes on blood pressure and albuminuria in response to AngII with high salt compared to wild type.. These results suggest that aldosterone does not predominantly contribute to renal p21 expression and senescence during the development of AngII-salt hypertension, and that the increase in p21 in the kidney is not likely involved in the development of hypertension and albuminuria.

Topics: Actins; Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cellular Senescence; Eplerenone; Genes, p16; Genes, p53; Hydralazine; Hypertension; Imidazoles; Kidney; Mice; Mice, Inbred C57BL; p21-Activated Kinases; Sirtuin 1; Sodium Chloride; Spironolactone; Tetrazoles

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.

Topics: Acute Kidney Injury; Aldosterone; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Eplerenone; Hypertension; Imidazoles; Immunohistochemistry; Kidney; Male; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Reverse Transcriptase Polymerase Chain Reaction; Sodium Chloride; Spironolactone; Tetrazoles