Tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate post‐occlusive reactive hyperemia in non‐glabrous human skin with no roles of NOS and COX

Abstract

Objectives Post‐occlusive reactive hyperemia (PORH) following arterial occlusion is widely used to assess cutaneous microvascular function, though the underlying mechanisms remain to be fully elucidated. We evaluated the hypothesis that Ca2+‐activated, ATP‐sensitive, and voltage‐gated K+ channels (KCa, KATP, and KV channels, respectively) contribute to PORH while nitric oxide synthase (NOS) and cyclooxygenase (COX) do not. Methods On separate occasions, cutaneous blood flow (laser Doppler flowmetry) was monitored before and following 5‐min arterial occlusion at forearm skin sites treated via microdialysis with the following: Experiment 1 (n = 11): (a) lactated Ringer solution (Control), (b) 10 mM Nω‐nitro‐L‐arginine (NOS inhibitor), (c) 10 mM ketorolac (COX inhibitor), and (d) combined NOS+COX inhibition; Experiment 2 (n = 14): (a) lactated Ringer solution (Control), (b) 50 mM tetraethylammonium (non‐selective KCa channel blocker), (c) 5 mM glibenclamide (non‐specific KATP channel blocker), and (d) 10 mM 4‐aminopyridine (non‐selective KV channel blocker). Results Separate and combined NOS and COX inhibition did not influence PORH. Conversely, tetraethylammonium and glibenclamide attenuated, whereas 4‐aminopyridine augmented PORH. Conclusions We showed that tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate PORH with no roles of NOS and COX in human non‐glabrous forearm skin in vivo. Thus, cutaneous PORH changes could reflect altered K+ channel function.

Does aging alter skin vascular function in humans when spatial variation is considered?

“…Our results indicate that aging attenuates skin vascular function by limiting the capacity of the vessels to rapidly increase blood flow in response to a vascular stimulus. Given PORH Time to Peak is associated with Ca 2+ -activated K + channel mechanisms in the skin, 23 it is plausible that aging modulates the activation of this channel, thereby delaying the response. However, further studies are required to confirm this possibility.…”

“…If aging modulates Ca 2+ -activated K + channels as discussed above, it may seem counterintuitive that PORH Amplitude and Area under the curve, both of which appear to be also partly mediated by Ca 2+ -activated K + channel mechanisms, 23 Note: Square brackets represent 95% confidence intervals.…”

“…That is, in addition to Ca 2+ -activated K + channels, ATP-sensitive K + channels are also involved in the PORH Amplitude and Area under the curve, but not PORH Time to Peak. 23 The presence of functional ATP-sensitive K + channels may be sufficient to maintain these PORH responses in older adults if Ca 2+ -activated K + channel function is impaired in this population. Alternatively, aging may also be associated with a compensatory upregulation of ATPsensitive K + channels in human skin, which would counteract any potential age-related alterations in Ca 2+ -activated K + channels, ultimately resulting in unchanged PORH Amplitude and Area under the curve.…”

The Impact of Disease Duration on Microcirculatory Dysfunction in Young Patients with Uncomplicated Type 1 Diabetes

“…PORH involves both myogenic and metabolic factors [43]. The role of nitric oxide (NO) in the test has been controversial and is now thought to have no role in the vasoconstriction response [43][44][45][46]. The changes in microcirculatory blood flow during the active congestion phase of the test can be demonstrated with a curve.…”