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Reduced activity of SKC a and Na-K ATPase underlies the accelerated impairment of EDH-type relaxations in mesenteric arteries of aging spontaneously hypertensive rats.

Kong BW, Man RY, Gao Y, Vanhoutte PM, Leung SW - Pharmacol Res Perspect (2015)

Bottom Line: EDH-type relaxation in SHR was smaller than that in WKY arteries, and further reduction occurred with aging.Pharmacological experiments suggested a reduced involvement of SKC a and Na-K ATPase and activation of adenosine monophosphate-activated protein kinase and silent information regulator T1 (sirtuin-1; SIRT1) in mesenteric arteries of 12-week-old SHR.These pharmacological findings suggest that in superior mesenteric arteries of the rat, the reduction in EDH-type relaxation occurs with aging and that such a reduction is exacerbated in hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong Hong Kong SAR, China.

ABSTRACT
Aging is accompanied by endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) and/or reduced endothelium-dependent hyperpolarizations (EDH). This study examines the hypothesis that hypertension aggravates the impairment of EDH-type relaxation due to aging. EDH-type relaxations were studied in superior mesenteric arteries isolated from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats of 12, 36, 60, and 72 weeks of age. EDH-type relaxations in WKY were reduced with aging, and this was associated with an impairment of the function of small-conductance calcium-activated potassium channels (SKC a) and sodium-potassium ATPase (Na-K ATPase). EDH-type relaxation in SHR was smaller than that in WKY arteries, and further reduction occurred with aging. Pharmacological experiments suggested a reduced involvement of SKC a and Na-K ATPase and activation of adenosine monophosphate-activated protein kinase and silent information regulator T1 (sirtuin-1; SIRT1) in mesenteric arteries of 12-week-old SHR. These pharmacological findings suggest that in superior mesenteric arteries of the rat, the reduction in EDH-type relaxation occurs with aging and that such a reduction is exacerbated in hypertension. The latter exacerbation appears to involve proteins associated with the process of cellular senescence and is related to impaired function of SKC a and Na-K ATPase, a phenomenon that is also observed in mesenteric arteries of older normotensive rats.

No MeSH data available.


Related in: MedlinePlus

Effect of inhibition of SIRT1 on EDH-type relaxation in 12-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with EX-527 (SIRT1 inhibitor; 10−6 mol/L) for 40 min in the presence of indomethacin (cyclooxygenase inhibitor; 10−5 mol/L) and L-NAME (nitric oxide synthase inhibitor; 10−4 mol/L). Values are means ± SEM of six experiments. *P < 0.05 compared to the control.
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fig06: Effect of inhibition of SIRT1 on EDH-type relaxation in 12-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with EX-527 (SIRT1 inhibitor; 10−6 mol/L) for 40 min in the presence of indomethacin (cyclooxygenase inhibitor; 10−5 mol/L) and L-NAME (nitric oxide synthase inhibitor; 10−4 mol/L). Values are means ± SEM of six experiments. *P < 0.05 compared to the control.

Mentions: In the presence of indomethacin and L-NAME, EX-527 [SIRT1 inhibitor, 10−6 M (Orecchia et al. 2011)] or compound C [AMPK inhibitor, 10−5 M (Thors et al. 2008)] significantly inhibited acetylcholine-induced relaxation in mesenteric arteries of 12-week-old SHR but not in those of age-matched WKY (Figs.6, 7).


Reduced activity of SKC a and Na-K ATPase underlies the accelerated impairment of EDH-type relaxations in mesenteric arteries of aging spontaneously hypertensive rats.

Kong BW, Man RY, Gao Y, Vanhoutte PM, Leung SW - Pharmacol Res Perspect (2015)

Effect of inhibition of SIRT1 on EDH-type relaxation in 12-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with EX-527 (SIRT1 inhibitor; 10−6 mol/L) for 40 min in the presence of indomethacin (cyclooxygenase inhibitor; 10−5 mol/L) and L-NAME (nitric oxide synthase inhibitor; 10−4 mol/L). Values are means ± SEM of six experiments. *P < 0.05 compared to the control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492766&req=5

fig06: Effect of inhibition of SIRT1 on EDH-type relaxation in 12-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with EX-527 (SIRT1 inhibitor; 10−6 mol/L) for 40 min in the presence of indomethacin (cyclooxygenase inhibitor; 10−5 mol/L) and L-NAME (nitric oxide synthase inhibitor; 10−4 mol/L). Values are means ± SEM of six experiments. *P < 0.05 compared to the control.
Mentions: In the presence of indomethacin and L-NAME, EX-527 [SIRT1 inhibitor, 10−6 M (Orecchia et al. 2011)] or compound C [AMPK inhibitor, 10−5 M (Thors et al. 2008)] significantly inhibited acetylcholine-induced relaxation in mesenteric arteries of 12-week-old SHR but not in those of age-matched WKY (Figs.6, 7).

Bottom Line: EDH-type relaxation in SHR was smaller than that in WKY arteries, and further reduction occurred with aging.Pharmacological experiments suggested a reduced involvement of SKC a and Na-K ATPase and activation of adenosine monophosphate-activated protein kinase and silent information regulator T1 (sirtuin-1; SIRT1) in mesenteric arteries of 12-week-old SHR.These pharmacological findings suggest that in superior mesenteric arteries of the rat, the reduction in EDH-type relaxation occurs with aging and that such a reduction is exacerbated in hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong Hong Kong SAR, China.

ABSTRACT
Aging is accompanied by endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) and/or reduced endothelium-dependent hyperpolarizations (EDH). This study examines the hypothesis that hypertension aggravates the impairment of EDH-type relaxation due to aging. EDH-type relaxations were studied in superior mesenteric arteries isolated from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats of 12, 36, 60, and 72 weeks of age. EDH-type relaxations in WKY were reduced with aging, and this was associated with an impairment of the function of small-conductance calcium-activated potassium channels (SKC a) and sodium-potassium ATPase (Na-K ATPase). EDH-type relaxation in SHR was smaller than that in WKY arteries, and further reduction occurred with aging. Pharmacological experiments suggested a reduced involvement of SKC a and Na-K ATPase and activation of adenosine monophosphate-activated protein kinase and silent information regulator T1 (sirtuin-1; SIRT1) in mesenteric arteries of 12-week-old SHR. These pharmacological findings suggest that in superior mesenteric arteries of the rat, the reduction in EDH-type relaxation occurs with aging and that such a reduction is exacerbated in hypertension. The latter exacerbation appears to involve proteins associated with the process of cellular senescence and is related to impaired function of SKC a and Na-K ATPase, a phenomenon that is also observed in mesenteric arteries of older normotensive rats.

No MeSH data available.


Related in: MedlinePlus