GABA A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

The activation of the group III/IV skeletal muscle afferents is one of the principal mediators of cardiovascular responses to exercise; however, the neuronal circuitry mechanisms that are involved during the activation of group III/IV muscle afferents in humans remain unknown. Recently, we showed that GABAergic mechanisms are involved in the cardiac vagal withdrawal during the activation of mechanically sensitive (predominantly mediated by group III fibres) skeletal muscle afferents in humans. In the present study, we found that increases in muscle sympathetic nerve activity and mean blood pressure during isometric handgrip exercise and postexercise ischaemia were significantly greater after the oral administration of diazepam, a benzodiazepine that increases GABA activity, but not after placebo administration in young healthy subjects. These findings indicate for the first time that GABA receptors modulate sympathetic vasomotor outflow and the pressor responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. Animal studies have indicated that GABA receptors are involved in the neuronal circuitry of the group III/IV skeletal muscle afferent activation-induced neurocardiovascular responses to exercise. In the present study, we aimed to determine whether GABA receptors modulate the neurocardiovascular responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. In a randomized, double-blinded, placebo-controlled and cross-over design, 17 healthy subjects (eight women) performed 2 min of ischaemic isometric handgrip exercise at 30% of the maximal voluntary contraction followed by 2 min of postexercise ischaemia (PEI). Muscle sympathetic nerve activity (MSNA), blood pressure (BP) and heart rate (HR) were continuously measured and trials were conducted before and 60 min after the oral administration of either placebo or diazepam (10 mg), a benzodiazepine that enhances GABA activity. At rest, MSNA was reduced, whereas HR and BP did not change after diazepam administration. During ischaemic isometric handgrip, greater MSNA (pre: ∆13 ± 9 bursts min vs. post: ∆29 ± 15 bursts min , P