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Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

Yamamoto E, Kataoka K, Dong YF, Koibuchi N, Toyama K, Sueta D, Katayama T, Yasuda O, Ogawa H, Kim-Mitsuyama S - PLoS ONE (2012)

Bottom Line: However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP.The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway.These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

ABSTRACT
The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

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Related in: MedlinePlus

Effect on vascular phospho-eNOS (p-eNOS) (A), total eNOS (t-eNOS) (B), phospho-Akt (p-Akt) (C), and total Akt (t-Akt) (D) of salt-loaded SHRSP.Abbreviations used are the same as in Fig. 1. The upper panels in (A), (B), (C), and (D) indicate representative western blots in each group. Each value represents the mean ± SEM (n = 4 in each group).
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pone-0039162-g004: Effect on vascular phospho-eNOS (p-eNOS) (A), total eNOS (t-eNOS) (B), phospho-Akt (p-Akt) (C), and total Akt (t-Akt) (D) of salt-loaded SHRSP.Abbreviations used are the same as in Fig. 1. The upper panels in (A), (B), (C), and (D) indicate representative western blots in each group. Each value represents the mean ± SEM (n = 4 in each group).

Mentions: As shown in Fig. 4 (A) and (B), the salt-loaded SHRSP showed decreased vascular phospho-eNOS and total eNOS levels, compared to the WKY rats. Olmesartan with azelnidipine or with hydrochlorothiazide significantly reversed the decrease in phospho-eNOS and total eNOS levels in the salt-loaded SHRSP. However, olmesartan combined with azelnidipine resulted in a greater reversal of the decrease in phospho-eNOS (P<0.01) and total eNOS (P<0.01) than did olmesartan with hydrochlorothiazide.


Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

Yamamoto E, Kataoka K, Dong YF, Koibuchi N, Toyama K, Sueta D, Katayama T, Yasuda O, Ogawa H, Kim-Mitsuyama S - PLoS ONE (2012)

Effect on vascular phospho-eNOS (p-eNOS) (A), total eNOS (t-eNOS) (B), phospho-Akt (p-Akt) (C), and total Akt (t-Akt) (D) of salt-loaded SHRSP.Abbreviations used are the same as in Fig. 1. The upper panels in (A), (B), (C), and (D) indicate representative western blots in each group. Each value represents the mean ± SEM (n = 4 in each group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375277&req=5

pone-0039162-g004: Effect on vascular phospho-eNOS (p-eNOS) (A), total eNOS (t-eNOS) (B), phospho-Akt (p-Akt) (C), and total Akt (t-Akt) (D) of salt-loaded SHRSP.Abbreviations used are the same as in Fig. 1. The upper panels in (A), (B), (C), and (D) indicate representative western blots in each group. Each value represents the mean ± SEM (n = 4 in each group).
Mentions: As shown in Fig. 4 (A) and (B), the salt-loaded SHRSP showed decreased vascular phospho-eNOS and total eNOS levels, compared to the WKY rats. Olmesartan with azelnidipine or with hydrochlorothiazide significantly reversed the decrease in phospho-eNOS and total eNOS levels in the salt-loaded SHRSP. However, olmesartan combined with azelnidipine resulted in a greater reversal of the decrease in phospho-eNOS (P<0.01) and total eNOS (P<0.01) than did olmesartan with hydrochlorothiazide.

Bottom Line: However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP.The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway.These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

ABSTRACT
The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

Show MeSH
Related in: MedlinePlus