Biased modulation of EDH-type relaxations by AMPK in hypertension

Abstract

Introduction: Endothelium-dependent hyperpolarization (EDH) is a major vasodilator signal in small arteries, the vascular tone of which contributes largely to the regulation of peripheral resistance and arterial blood pressure. EDH is triggered by opening of intermediate- and small-conductance calcium-activated potassium channels (IKCa and SKCa, respectively); the resultant efflux of potassium ions (K+) causes hyperpolarization of the underlying smooth muscle cells, thus relaxation. Aims: The present study aimed to examine the involvement of adenosine monophosphate-activated protein kinase (AMPK) in EDH-type relaxations in hypertension. Methods: Isometric tension was recorded in rings (with or without endothelium) of superior mesenteric arteries of 25-weeks-old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Results: While compound C (AMPK-inhibitor; 10-5 M) did not affect acetylcholine-induced EDH-type relaxations in WKY mesenteric arteries, it significantly inhibited those in SHR preparations. In WKY mesenteric arteries, on a background of minimal but significant inhibition of EDH-type relaxations by TRAM-34 (IKCa-blocker; 10-6 M), compound C further reduced such relaxations. By contrast, UCL1684 (SKCa-blocker; 10-6 M), in the absence or presence of compound C, had no significant effect on EDH-type relaxations. In SHR preparations, TRAM-34 or UCL1684 alone significantly inhibited EDH-type relaxations with no further alteration by compound C. AMPKactivation with AICAR (10-4 M) almost abolished EDH-type relaxations in mesenteric arteries of WKY and SHR, but it did not affect K+-induced relaxations in rings without endothelium of both strains. Conclusion: In WKY mesenteric arteries, IKCa fully compensate for the absence of SKCa while in SHR preparations, neither IKCa nor SKCa compensate for each other’s absence; such loss of compensation is prevented by the constitutive AMPKactivity. Additional AMPK-activation with its activator AICAR inhibits EDH-type relaxations in both WKY and SHR preparations by acting upstream of smooth muscle hyperpolarization. Thus, in the rat mesenteric artery, various levels of AMPK-activity (constitutive versus additional stimulation by an exogenous activator) differently modulate EDH-type relaxations.