K _V channel antagonism blunts vasodilatation in skeletal muscle of humans

Voltage-dependent potassium (K_V) channels play a pivotal role in regulating vascular tone via negative feedback control of membrane potential. Despite substantial evidence in animal models, many aspects of their regulation are not fully understood in humans, particularly within the skeletal muscle microcirculation. Therefore, we tested the hypothesis that K_V channel antagonism would attenuate pharmacologically induced vasodilatation in skeletal muscle of humans. We utilised microdialysis to directly measure the local hyperaemic response to methacholine (55 mm; endothelium-dependent) and sodium nitroprusside (42 mm; endothelium-independent) in the vastus lateralis muscle of 17 healthy adults (seven women). At separate sites, the K_V channel antagonist, 4-aminopyridine (26.6 mm), was co-perfused with each vasodilator agent. Local skeletal muscle blood flow was assessed using the ethanol washout technique. Baseline blood flow did not differ between probes perfused with 0.9% saline and those perfused with 4-aminopyridine (P = 0.375). However, the hyperaemic response to methacholine (Δ 28 ± 12 mL min^-1 100 g^-1) was abolished when co-perfused with 4-aminopyridine (Δ 3 ± 9 mL min^-1 100 g^-1, P < 0.001). Likewise, the hyperaemic response to sodium nitroprusside (Δ 59 ± 27 mL min^-1 100 g^-1) was reduced when co-perfused with 4-aminopyridine (Δ 14 ± 10 mL min^-1 100 g^-1, P < 0.001). These data suggest that K_V channels play a major role in pharmacologically induced vasodilatation in skeletal muscle of humans and serve as major downstream effectors in the nitric oxide-cyclic guanosine monophosphate-protein kinase G (i.e. NO/cGMP/PKG) signalling pathway. KEY POINTS: Voltage-dependent potassium (K_V) channels play a pivotal role in regulating vascular tone via negative feedback control of membrane potential. Despite substantial evidence in animal models, many aspects of their regulation are not fully understood in humans, particularly within the skeletal muscle microcirculation. We tested the hypothesis that K_V channel antagonism would attenuate the vasodilatation induced by methacholine and sodium nitroprusside in the vastus lateralis muscle of young healthy humans. Utilising microdialysis, we found that K_V channel antagonism, via perfusion of 4-aminopyridine, blunted the hyperaemic response to methacholine and sodium nitroprusside in the vastus lateralis muscle. We identified a critical role for K_V channels in the vasodilatation induced by methacholine and sodium nitroprusside in skeletal muscle of humans. Because both pharmacological agents induce vasodilatation via nitric oxide-cyclic guanosine monophosphate-protein kinase G (i.e. NO/cGMP/PKG) signalling, these findings suggest that K_V channels are major downstream effectors of this pathway.