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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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Effect on blood pressure of salt-loaded SHRSP.Abbreviations used: Ve, vehicle-treated SHRSP; Ol, olmesartan-treated SHRSP; Az, azelnidipine-treated SHRSP; Hy, hydrochlorothiazide-treated SHRSP; Ol+Az, combined olmesartan and azelnidipine-treated SHRSP; Ol+Hy, combined olmesartan and hydrochlorothiazide-treated SHRSP; WKY, Wistar-Kyoto rats. Each value represents the mean ± SEM (n = 8 in Ve, n = 7 in Ol, n = 7 in Az, n = 4 in Hy, n = 7 in Ol+Az, n = 7 in Ol+Hy, n = 8 in WKY).
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pone-0039162-g001: Effect on blood pressure of salt-loaded SHRSP.Abbreviations used: Ve, vehicle-treated SHRSP; Ol, olmesartan-treated SHRSP; Az, azelnidipine-treated SHRSP; Hy, hydrochlorothiazide-treated SHRSP; Ol+Az, combined olmesartan and azelnidipine-treated SHRSP; Ol+Hy, combined olmesartan and hydrochlorothiazide-treated SHRSP; WKY, Wistar-Kyoto rats. Each value represents the mean ± SEM (n = 8 in Ve, n = 7 in Ol, n = 7 in Az, n = 4 in Hy, n = 7 in Ol+Az, n = 7 in Ol+Hy, n = 8 in WKY).

Mentions: As shown in Fig. 1, olmesartan or azelnidipine monotherapy significantly and similarly reduced the blood pressure of the salt-loaded SHRSP throughout the drug treatment. Monotherapy with hydrochlorothiazide significantly reduced the blood pressure of the SHRSP, although its hypotensive effect was smaller than the effect of monotherapy with olmesartan or azelnidipine. Combination therapy of olmesartan with amlodipine or with hydrochlorothiazide reduced the blood pressure of the salt-loaded SHRSP more than did monotherapy with olmesartan, azelnidipine, or hydrochlorothiazide. The addition of hydrochlorothiazide to olmesartan reduced the blood pressure of the SHRSP to a similar extent to the addition of amlodipine to olmesartan, indicating that hydrochlorothiazide added to olmesartan exerted a synergistic hypotensive effect in the salt-loaded SHRSP while azelnidipine added to olmesartan produced an additive hypotensive effect.


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 blood pressure of salt-loaded SHRSP.Abbreviations used: Ve, vehicle-treated SHRSP; Ol, olmesartan-treated SHRSP; Az, azelnidipine-treated SHRSP; Hy, hydrochlorothiazide-treated SHRSP; Ol+Az, combined olmesartan and azelnidipine-treated SHRSP; Ol+Hy, combined olmesartan and hydrochlorothiazide-treated SHRSP; WKY, Wistar-Kyoto rats. Each value represents the mean ± SEM (n = 8 in Ve, n = 7 in Ol, n = 7 in Az, n = 4 in Hy, n = 7 in Ol+Az, n = 7 in Ol+Hy, n = 8 in WKY).
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Related In: Results  -  Collection

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pone-0039162-g001: Effect on blood pressure of salt-loaded SHRSP.Abbreviations used: Ve, vehicle-treated SHRSP; Ol, olmesartan-treated SHRSP; Az, azelnidipine-treated SHRSP; Hy, hydrochlorothiazide-treated SHRSP; Ol+Az, combined olmesartan and azelnidipine-treated SHRSP; Ol+Hy, combined olmesartan and hydrochlorothiazide-treated SHRSP; WKY, Wistar-Kyoto rats. Each value represents the mean ± SEM (n = 8 in Ve, n = 7 in Ol, n = 7 in Az, n = 4 in Hy, n = 7 in Ol+Az, n = 7 in Ol+Hy, n = 8 in WKY).
Mentions: As shown in Fig. 1, olmesartan or azelnidipine monotherapy significantly and similarly reduced the blood pressure of the salt-loaded SHRSP throughout the drug treatment. Monotherapy with hydrochlorothiazide significantly reduced the blood pressure of the SHRSP, although its hypotensive effect was smaller than the effect of monotherapy with olmesartan or azelnidipine. Combination therapy of olmesartan with amlodipine or with hydrochlorothiazide reduced the blood pressure of the salt-loaded SHRSP more than did monotherapy with olmesartan, azelnidipine, or hydrochlorothiazide. The addition of hydrochlorothiazide to olmesartan reduced the blood pressure of the SHRSP to a similar extent to the addition of amlodipine to olmesartan, indicating that hydrochlorothiazide added to olmesartan exerted a synergistic hypotensive effect in the salt-loaded SHRSP while azelnidipine added to olmesartan produced an additive hypotensive effect.

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