GABAA Receptors Modulate Muscle Sympathetic Nerve Activity and Pressor Responses to Skeletal Muscle Metaboreflex Activation in Humans

Abstract

The cardiovascular responses to exercise are mediated by several interactive neural mechanisms including central command, arterial baroreflex and the exercise pressor reflex (EPR). Although all three neural mechanisms are relevant for cardiovascular regulation during exercise, considerable attention has been given to the EPR due to its importance determining the magnitude of sympathoexcitation during exercise. The sensory component of the EPR is comprised of group III and IV skeletal muscle afferents that respond to both mechanical (i.e., muscle mechanoreflex) and metabolic (i.e., muscle metaboreflex) stimuli. Despite it is well accepted that EPR is one of the principal mediators of the cardiovascular response to exercise, the possible neurotransmitters involved during EPR activation are not fully understood. Recently, we showed that central GABAergic mechanisms are involved in the muscle mechanoreflex‐mediated cardiac vagal withdrawal at the onset of exercise in humans (Am J Physiol Heart Circ Physiol 2018;314:H716–H723). However, whether GABAergic mechanisms are involved in the neurocardiovascular responses evoked by the metabolic component of EPR remains unknown. Therefore, the present study was undertaken to test the hypothesis that GABAA receptors modulate muscle sympathetic nerve activity (MSNA) and arterial blood pressure (BP) responses to skeletal muscle metaboreflex activation in humans. Eight healthy subjects (2 women) aged between 18 to 24 years were enrolled. Experiments were conducted in a randomized, double‐blinded, placebo‐controlled, and crossover design, whereby each subject performed 2 min of ischemic isometric handgrip (IHG) exercise at 30% of maximal voluntary contraction followed by 2 min of post‐exercise ischemia (PEI) to isolate the muscle metaboreflex. Trials were randomly conducted before and after oral administration of placebo or diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. The MSNA (microneurography), BP (finger photoplethysmography) and heart rate (HR – electrocardiogram) were continuously measured at rest, during IHG, PEI and recovery. During IHG, MSNA bursts frequency and diastolic BP increased from rest before diazepam administration (Δ11 ± 6 bursts/min and Δ26 ± 10 mmHg, respectively) and further increased after diazepam (Δ31 ± 14 bursts/min and Δ34 ± 9 mmHg, respectively) (P<0.05). During PEI, MSNA and diastolic BP remained elevated from baseline before diazepam administration (Δ9 ± 5 bursts/min and Δ25 ± 11 mmHg, respectively) and this elevation was increased after diazepam (Δ19 ± 10 bursts/min and Δ28 ± 11 mmHg, respectively) (P<0.05). Systolic BP and HR responses to IHG and PEI were similar before and after diazepam (P>0.05). Importantly, oral administration of placebo pill had no effect on any neurocardiovascular variables (all P>0.05). In summary, these findings demonstrate for the first time that GABAA receptors modulate MSNA and pressor responses to activation of metabolically sensitive skeletal muscle afferents in healthy subjects. These findings allow us to suggest that muscle metaboreflex is a potential source of synaptic drive to GABAergic neurons in humans.Support or Funding InformationCNPq, FAPDF and CAPES.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.