K_IR channel activation contributes to onset and steady-state exercise hyperemia in humans

Abstract

We tested the hypothesis that activation of inwardly rectifying potassium (KIR) channels and Na(+)-K(+)-ATPase, two pathways that lead to hyperpolarization of vascular cells, contributes to both the onset and steady-state hyperemic response to exercise. We also determined whether after inhibiting these pathways nitric oxide (NO) and prostaglandins (PGs) are involved in the hyperemic response. Forearm blood flow (FBF; Doppler ultrasound) was determined during rhythmic handgrip exercise at 10% maximal voluntary contraction for 5 min in the following conditions: control [saline; trial 1 (T1)]; with combined inhibition of KIR channels and Na(+)-K(+)-ATPase alone [via barium chloride (BaCl2) and ouabain, respectively; trial 2 (T2)]; and with additional combined nitric oxide synthase (N(G)-monomethyl-l-arginine) and cyclooxygenase inhibition [ketorolac; trial 3 (T3)]. In T2, the total hyperemic responses were attenuated ~50% from control (P < 0.05) at exercise onset, and there was minimal further effect in T3 (protocol 1; n = 11). In protocol 2 (n = 8), steady-state FBF was significantly reduced during T2 vs. T1 (133 ± 15 vs. 167 ± 17 ml/min; Δ from control: -20 ± 3%; P < 0.05) and further reduced during T3 (120 ± 15 ml/min; -29 ± 3%; P < 0.05 vs. T2). In protocol 3 (n = 8), BaCl2 alone reduced FBF during onset (~50%) and steady-state exercise (~30%) as observed in protocols 1 and 2, respectively, and addition of ouabain had no further impact. Our data implicate activation of KIR channels as a novel contributing pathway to exercise hyperemia in humans.

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

“…Animal models indicate endothelium-dependent dilation is heavily reliant on EDHF in females (Huang et al 2001; Pak et al 2002; Scotland et al 2005; Villar et al 2008), providing rationale to pursue EDHF contributions as potential mechanisms for the sex differences observed. In part via EDHF, potassium (K + ) channels hold great influence over vascular tone (Jackson 2005) but studies investigating responses to contraction do not directly compare men to women (Crecelius et al 2013, 2014). Thus, K + channel involvement in regulating steady-state exercise vasodilation between the sexes is unclear in humans.…”

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…Rat (970, 1359) and cat (371) pial arterioles also constrict in response to Ba 2+ . With the exception of one study (292), infusion of Ba 2+ into human forearm [plasma concentrations of Ba 2+ of ~50 µmol/L (318)] causes vasoconstriction (294, 295, 318). Given that the arteriolar endothelium poses a significant barrier to the passage of charged molecules (848), the precise concentration of Ba 2+ to which the vascular SMCs were exposed in these in vivo experiments is unknown.…”

“…In hamster cremaster muscles, Ba 2+ attenuates vasodilation induced by muscle contraction, particularly the rapid onset of dilation, suggesting a role for K IR channels in coupling muscle contraction to vascular function in this tissue (63). Studies in human forearm also have shown that Ba 2+ inhibits the rapid-onset vasodilation induced by muscle contraction (293), as well as the steady-state functional vasodilation in that tissue (294). Barium also attenuates reactive hyperemia induced by blood flow occlusion to the forearm, supporting a role for K IR channels in this response (295).…”

Adrenergic and non-adrenergic control of active skeletal muscle blood flow: Implications for blood pressure regulation during exercise

“…Together, these findings and others highlight the complex interaction and redundancy among vasodilator systems, and a general consensus has been established that no single vasodilatory compound can account for exercise hyperemia (Clifford and Hellsten, 2004;Hellsten et al, 2012;Joyner and Wilkins, 2007;Laughlin et al, 2012;Saltin et al, 1998;Segal, 2005). However, emerging evidence points to similar mechanisms being active at the onset and during steady-state exercise with a major role for potassium (Crecelius et al, 2014).…”