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. 2015 Jun;3(3):e00150.
doi: 10.1002/prp2.150. Epub 2015 May 20.

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

Billy W C Kong  1 , Ricky Y K Man  1 , Yuansheng Gao  2 , Paul M Vanhoutte  1 , Susan W S Leung  1
Affiliations

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

Billy W C Kong et al. Pharmacol Res Perspect. 2015 Jun.

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.

Keywords: Aging; endothelial dysfunction; endothelium-derived hyperpolarization; hypertension; small-conductance calcium-activated potassium channel; sodium–potassium ATPase.

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Figures

Figure 1
Figure 1
Mean arterial blood pressure of WKY and SHR at different ages. Values are means ± SEM of nine experiments. * P < 0.05 compared with corresponding WKY groups.
Figure 2
Figure 2
Acetylcholine-induced relaxations of superior mesenteric arteries of (Upper) WKY and (Lower) SHR at various ages in the presence of (Left) indomethacin (cyclooxygenase inhibitor; 10−5 mol/L) or (Right) indomethacin (10−5 mol/L) alone, TRAM-34 (IKCa inhibitor; 5 × 10−7 mol/L) and UCL 1684 (SKCa inhibitor; 5 × 10−7 mol/L). Values are means ± SEM of six to eight experiments. *P < 0.05 compared with corresponding 12-week-old groups.
Figure 3
Figure 3
Acetylcholine-induced relaxations of superior mesenteric arteries of (Upper) WKY and (Lower) SHR at various ages 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 to eight experiments. *P < 0.05 compared with corresponding 12-week-old groups.
Figure 4
Figure 4
Effect of inhibition of intermediate- and small-conductance calcium-activated K+ channels on EDH-type relaxation in (Upper) 12- and (Lower) 36-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with TRAM-34 (IKCa inhibitor; 5 × 10−7 mol/L) or UCL 1684 (SKCa inhibitor; 5 × 10−7 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 eight experiments. *P < 0.05 compared to the control.
Figure 5
Figure 5
Effect of inhibition of Na-K ATPase and inwardly rectifying K+ channels on EDH-type relaxation in (Upper) 12- and (Lower) 36-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with ouabain (Na-K ATPase inhibitor; 10−3 mol/L) and/or barium (KIR inhibitor; 3 × 10−5 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 eight experiments. *P < 0.05 compared to the control.
Figure 6
Figure 6
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.
Figure 7
Figure 7
Effect of the inhibition of adenosine monophospate-actived protein kinase (AMPK) on EDH-type relaxation in 12-week-old (Left) WKY and (Right) SHR superior mesenteric arteries. Arteries were incubated with compound C (AMPK inhibitor; 10−5 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.
Figure 8
Figure 8
The mechanism underlying the impairment of endothelium-dependent hyperpolarization (EDH)-type relaxations in aging or hypertensive rats. Aging or hypertension causes the dysfunction of small-conductance calcium-activated potassium chanels (SKCa) and sodium-potassium ATPase (Na-K ATPase), thus impairing EDH-mediated responses. In young hypertensive animals, the impairment is compensated by the facilitation of the activity of intermediate-conductance calcium-activated potassium chanels (IKCa), and the activation of adenosine monophosphate-activated protein kinase (AMPK) and silent information regulator T1 (sirtuin-1; SIRT1).
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