Key pointsr Intermittent hypoxia leads to long-lasting increases in muscle sympathetic nerve activity and blood pressure, contributing to increased risk for hypertension in obstructive sleep apnoea patients.r We determined whether augmented vascular responses to increasing sympathetic vasomotor outflow, termed sympathetic neurovascular transduction (sNVT), accompanied changes in blood pressure following acute intermittent hypercapnic hypoxia in men.r Lower body negative pressure was utilized to induce a range of sympathetic vasoconstrictor firing while measuring beat-by-beat blood pressure and forearm vascular conductance. r IH reduced vascular shear stress and steepened the relationship between diastolic blood pressure and sympathetic discharge frequency, suggesting greater systemic sNVT.r Our results indicate that recurring cycles of acute intermittent hypercapnic hypoxia characteristic of obstructive sleep apnoea could promote hypertension by increasing sNVT.Abstract Acute intermittent hypercapnic hypoxia (IH) induces long-lasting elevations in sympathetic vasomotor outflow and blood pressure in healthy humans. It is unknown whether IH alters sympathetic neurovascular transduction (sNVT), measured as the relationship between sympathetic vasomotor outflow and either forearm vascular conductance (FVC; regional sNVT) or diastolic blood pressure (systemic sNVT). We tested the hypothesis that IH augments sNVT by exposing healthy males to 40 consecutive 1 min breathing cycles, each comprising 40 s of hypercapnic hypoxia (P ETCO 2 : +4 ± 3 mmHg above baseline; P ETO 2 : 48 ± 3 mmHg) and 20 s of Troy J. R. Stuckless is a native of Bayside, Ontario in Canada. He attained his Bachelor of Science in Kinesiology from Queen's University and practiced as a kinesiologist in Calgary before pursuing an Master of Science from the University of British Columbia's Okanagan Campus under the supervision of Dr Glen Foster. His research interests include vascular endothelial cell function and interactions between the autonomic nervous system and cardiovascular health. Troy is currently completing the Doctor of Dental Surgery Program at the University of Toronto.normoxia (n = 9), or a 40 min air-breathing control (n = 7). Before and after the intervention, lower body negative pressure (LBNP; 3 min at -15, -30 and -45 mmHg) was applied to elicit reflex increases in muscle sympathetic nerve activity (MSNA, fibular microneurography) when clamping end-tidal gases at baseline levels. Ventilation, arterial pressure [systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP)], brachial artery blood flow (Q BA ), FVC (Q BA /MAP) and MSNA burst frequency were measured continuously. Following IH, but not control, ventilation [5 L min -1 ; 95% confidence interval (CI) = 1-9] and MAP (5 mmHg; 95% CI = 1-9) were increased, whereas FVC (-0.2 mL min -1 mmHg -1 ; 95% CI = -0.0 to -0.4) and mean shear rate (-21.9 s -1 ; 95% CI = -5.8 to -38.0; all P < 0.05) were reduced. Systemic sNVT was increased following IH (0.25 mmHg burst -1...

Ventilatory long-term facilitation (vLTF) refers to respiratory neuroplasticity that develops following intermittent hypoxia in both healthy and clinical populations. r A sustained hypercapnic background is argued to be required for full vLTF expression in humans. r We determined whether acute intermittent hypercapnic hypoxia elicits vLTF during isocapnic-normoxic recovery in healthy males and females. We further assessed whether tonic peripheral chemoreflex drive is necessary and contributes to the expression of vLTF. r Following 40 min of intermittent hypercapnic hypoxia, minute ventilation was increased throughout 50 min of isocapnic-normoxic recovery. Inhibition of peripheral chemoreflex drive with hyperoxia attenuated the magnitude of vLTF. r Males and females achieve vLTF through different respiratory recruitment patterns.

Reducing the work of breathing during exercise improves locomotor muscle blood flow and reduces diaphragm and locomotor muscle fatigue and is thought to be the result of a sympathetically mediated reflex. Aim: The aim of this study was to assess muscle sympathetic nerve activity (MSNA) when the work of breathing is experimentally lowered during dynamic exercise. Methods: Healthy subjects (n = 12; age = 29 ± 9 years) performed semi-recumbent cycling trials at 40%, 60%, and 80% of peak workload. Exercise trials consisted of spontaneous breathing, reduced work of breathing (proportional assist ventilator), followed by further spontaneous breathing (post-ventilator). MSNA was recorded from the median nerve. Results: There was no difference in work of breathing between PAV and post-PAV at 40% peak work. At 60% peak work, the ventilator significantly (P < 0.05) reduced work of breathing (103 ± 39 vs 144 ± 47 J min −1 ), sympathetic nerve activity (35 ± 5 vs 42 ± 8 burst min −1 ), and _ VO 2 (2.4 ± 0.5 vs 2.6 ± 0.5 L min −1 ) without influencing ventilation (86 ± 9 vs 82 ± 10 L min −1 ; P > 0.05), for PAV and post-PAV respectively. During 80% peak work (n = 8), the ventilator significantly (P < 0.05) reduced work of breathing (235 ± 110 vs. 361 ± 150 J min −1 ), MSNA (48 ± 7 vs 54 ± 11 burst min −1 ), and _ VO 2 (2.9 ± 0.6 vs 3.2 ± 0.7 L min −1 ) but not ventilation (121 ± 20 vs 123 ± 20 L min −1 ; P > 0.05), for PAV and post-PAV respectively. There was a significant relationship between MSNA and _ VO 2 (P < 0.0001) with a significant interaction due to the ventilator (P < 0.05). Conclusion: Lowering the normally occurring work of breathing during exercise results in commensurate reductions in MSNA. Our findings provide evidence of a sympathetically mediated vasoconstrictor effect emanating from respiratory muscles during exercise. K E Y W O R D S blood flow distribution, exercise physiology, proportional assist ventilation, respiratory metaboreflex Paolo B. Dominelli and Keisho Katayama contributed equally to this work.

Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3-10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness. NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.