Blockade of Gamma‐Aminobutyric Acid Synthesis within the Nucleus Tractus Solitarii Reduces the Pressor Response to Muscle Mechanoreflex Activation in Normotensive but not Hypertensive Rats

Abstract

Forty percent of the world population is hypertensive and estimates predict an increase to over 60% in the next 10 years. Exercise has been shown to be effective at reducing hypertension more so than a majority of drug interventions. However, exercise in hypertensive patients carries an elevated risk for myocardial ischemia, infarction, cardiac arrest, stroke, and possibly death during physical activity due to accompanying exaggerations in blood pressure (BP). Understanding the mechanisms through which BP management becomes dysregulated during physical activity is critical to identifying strategies for hypertensive patients to safely benefit from exercise. Our laboratory has previously established that the muscle mechanoreflex, a cardiovascular regulating reflex engaged during contraction of skeletal muscle, contributes significantly to the potentiated BP response to exercise in hypertension. However, the mechanisms underlying the pathogenesis of this mechanoreflex dysfunction remain undetermined. Mechanoreflex sensory information is processed within the nucleus tractus solitarii (NTS) of the brainstem. The inhibitory neurotransmitter, gamma‐aminobutyric acid (GABA), is known to contribute to cardiovascular regulation within the NTS. Microinjection of GABA receptor agonists within the NTS has been shown to increase resting BP. It is logical, therefore, to hypothesize that the exaggerated BP response to mechanoreflex activation in hypertension is mediated by abnormal increases in GABA production within the NTS. To test this hypotheses, the role of central GABA on mechanoreflex function was investigated in 21 normotensive Wystar‐Kyoto (WKY) and 21 spontaneously hypertensive (SHR) age matched (12–16 week) male rats. The BP response to activation of the mechanoreflex, via passive stretch of the soleus and gastrocnemius muscles, was assessed before and after the microdialysis of 1) the GABA synthesis inhibitor 3‐mercaptopropionic acid (3‐MP; 850 μM, 10 μg total); 2) the GABAA receptor antagonist bicuculline methiodide (BIC; 88 nM, 5 ng total); or 3) the GABAB receptor antagonist 2‐hydroxy saclofen (SAC; 885 μM, 30 ng total) into the NTS for 45 minutes at 2.5 μL/min. The mechanoreflex‐induced change in BP from baseline before microdialysis (23 ± 2 mmHg/kg) was significantly attenuated after the administration of 3‐MP (12 ± 2 mmHg/kg) in WKY rats (p < 0.05). In contrast, 3‐MP did not affect the pressor response to stretch in SHR. Likewise, the dialysis of BIC and SAC did not significantly affect the BP response to stretch in either WKY or SHR. The results of the studies demonstrate that endogenous GABA synthesis within the NTS modulates the BP response to mechanoreflex activation in normotensive rats. However, it does not appear that abnormal elevations in NTS GABA account for mechanoreflex‐induced exaggerations in BP in hypertensive rats. The data do support the concept that the ability of GABA to modulate mechanoreflex‐mediated changes in BP is compromised in hypertensive animals.Support or Funding InformationSupported by NIH HL‐088422.