Patients with Parkinson's disease (PD) exhibit attenuated cardiovascular responses to exercise. The underlying mechanisms that are potentially contributing to these impairments are not fully understood. Therefore, we sought to test the hypothesis that patients with PD exhibit blunted cardiovascular responses to isolated muscle metaboreflex activation following exercise. For this, mean blood pressure, cardiac output, and total peripheral resistance were measured using finger photoplethysmography and the Modelflow method in 11 patients with PD [66 ± 2 yr; Hoehn and Yahr score: 2 ± 1 a.u.; time since diagnosis: 7 ± 1 yr; means ± SD) and 9 age-matched controls (66 ± 3 yr). Measurements were obtained at rest, during isometric handgrip exercise performed at 40% maximal voluntary contraction, and during postexercise ischemia. Also, a cold pressor test was assessed to confirm that blunted cardiovascular responses were specific to exercise and not representative of generalized sympathetic responsiveness. Changes in mean blood pressure were attenuated in patients with PD during handgrip (PD: ∆25 ± 2 mmHg vs. controls: ∆31 ± 3 mmHg; P < 0.05), and these group differences remained during postexercise ischemia (∆17 ± 1 mmHg vs. ∆26 ± 1 mmHg, respectively; P < 0.01). Additionally, changes in total peripheral resistance were attenuated during exercise and postexercise ischemia, indicating blunted reflex vasoconstriction in patients with PD. Responses to cold pressor test did not differ between groups, suggesting no group differences in generalized sympathetic responsiveness. Our results support the concept that attenuated cardiovascular responses to exercise observed in patients with PD are, at least in part, explained by an altered skeletal muscle metaboreflex. NEW & NOTEWORTHY Patients with Parkinson's disease (PD) presented blunted cardiovascular responses to exercise. We showed that cardiovascular response evoked by the metabolic component of the exercise pressor reflex is blunted in patients with PD. Furthermore, patients with PD presented similar pressor response during the cold pressor test compared with age-matched controls. Altogether, our results support the hypothesis that attenuated cardiovascular responses to exercise observed in patients with PD are mediate by an altered skeletal muscle metaboreflex.

Sex differences have been reported in the respective contribution of cardiac output (Q̇) and vascular constriction to the pressor response to isometric handgrip exercise (IHE). Differently from men, the majority of the blood pressure (BP) response to IHE in young women is due to elevated Q̇ rather than elevations in total peripheral resistance (TPR). The underlying mechanisms for these differences are unknown, but previous data suggest that the β‐adrenergic receptors offset α‐adrenergic vasoconstriction in young women under resting condition. Whether this could be extended to an exercise condition remains to be determined. Given this, the aim of the present study was to investigate whether the β‐adrenergic receptors play a pivotal role in sex‐related differences in the BP regulation during ischemic IHE. Ten men (21 ± 0.6 years) and 9 women (23 ± 1.3 years) healthy and physically active volunteers were recruited. All women were non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. To make the forearm ischemic prior to exercise, a 3 min period of circulatory arrest was achieved by inflating an upper arm cuff to supra systolic pressure. This cuff remained inflated for 2 min of isometric exercise at 30% of maximal voluntary contraction force, and 2 min of post‐exercise circulatory occlusion (PECO). Beat‐to‐beat heart rate (HR) (electrocardiography) and arterial BP (finger photopletysmography) were continuously measured. Beat‐to‐beat changes in stroke volume (SV) was obtained with Modelflow method and matched with the responses of heart rate (HR) to estimate Q̇ (Q̇=SV x HR) and TPR (TPR=Mean BP/Q). The exercise and PECO responses were analyzed using the peak change. Two trials were randomly conducted in different days either placebo or non‐selective β‐adrenergic blockade (40mg propranolol). During ischemic IHE under placebo condition, mean BP increased from rest in both men and women, however the magnitude of these responses was greater in men. During PECO, the mean BP remained elevated and the sex differences persisted. The β‐adrenergic blockade attenuated the mean BP response during ischemic IHE from rest in men (Δ 51 ± 6 mmHg vs Δ 39 ± 6 mmHg, P<0.01) but not in women (Δ 28 ± 5 mmHg vs Δ 32 ± 5mmHg, P=0.17). This attenuated mean BP response observed in men under β‐blockade could be explained by a reduction in Q̇ (Δ 3.0 ± 0.4l/min vs Δ 1.2 ± 0.2 l/min, P<0.01). This was less pronounced in women (Δ 2.0 ± 0.4 l/min vs Δ 1.0 ± 0.2 l/min, P=0.05). In addition, vascular constriction was increased during ischemic IHE and PECO in men and these responses were not affected by β‐blockade. In contrast, increases in TPR were greater in women under β‐adrenergic blockade during both ischemic IHE (Δ 1.2 ± 0.7 mmHg.L‐1.min vs Δ 3.3 ± 0.9 mmHg.L‐1.min, P=0.03) and PECO (Δ 4.5 ± 0.9 mmHg.L‐1.min vs Δ 6.8 ± 1.1 mmHg.L‐1.min, P=0.04). These findings demonstrate for the first time that the sex differences in arterial BP regulation during ischemic IHE are mediated by β‐adrenergic re...

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Previous studies have indicated that central GABAergic mechanisms are involved in the heart rate (HR) responses at the onset of exercise. On the basis of previous research that showed similar increases in HR during passive and active cycling, we reasoned that the GABAergic mechanisms involved in the HR responses at the exercise onset are primarily mediated by muscle mechanoreceptor afferents. Therefore, in this study, we sought to determine whether central GABA mechanisms are involved in the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. Twenty-eight healthy subjects (14 men and 14 women) aged between 18 and 35 yr randomly performed three bouts of 5-s passive and active cycling under placebo and after oral administration of diazepam (10 mg), a benzodiazepine that produces an enhancement in GABA activity. Beat-to-beat HR (electrocardiography) and arterial blood pressure (finger photopletysmography) were continuously measured. Electromyography of the vastus lateralis was obtained to confirm no electrical activity during passive trials. HR increased from rest under placebo and further increased after administration of diazepam in both passive (change: 12 ± 1 vs. 17 ± 1 beats/min, P < 0.01) and active (change: 14 ± 1 vs. 18 ± 1 beats/min, P < 0.01) cycling. Arterial blood pressure increased from rest similarly during all conditions ( P > 0.05). Importantly, no sex-related differences were found in any variables during experiments. These findings demonstrate, for the first time, that the GABAergic mechanisms significantly contribute to the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. NEW & NOTEWORTHY We found that passive and voluntary cycling evokes similar increases in heart rate and that these responses were enhanced after diazepam administration, a benzodiazepine that enhances GABA activity. These findings suggest that the GABAergic system may contribute to the muscle mechanoreflex-mediated vagal withdrawal at the onset of exercise in humans.

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships ( r ≥ −0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (−2.27 ± 1.27%·cardiac cycle−1·mmHg−1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (−0.13 ± 0.18 spikes·cardiac cycle−1·mmHg−1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, −2.08 ± 1.08 vs. −2.46 ± 1.42%·cardiac cycle−1·mmHg−1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension. NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.