Cardiovascular Responses to Simultaneous Diving and Muscle Metaboreflex Activation

Background: The aim of study was to assess hemodynamic changes during the simultaneous activation of muscle metaboreflex (MM) and diving reflex (DR) in a laboratory setting. We hypothesized that as long as the exercise intensity is mild DR can overwhelm the MM.Methods: Ten trained divers underwent all four phases (randomly assigned) of the following protocol. (A) Postexercise muscle ischemia session (PEMI): 3 min of resting followed by 3 min of handgrip at 30% of maximum force, followed immediately by 3 min of PEMI on the same arm induced by inflating a sphygmomanometer. Three minutes of recovery was further allowed after the cuff was deflated for a total of 6 min of recovery. (B) Control exercise recovery session: the same rest-exercise protocol used for A followed by 6 min of recovery without inflation. (C) DR session: the same rest-exercise protocol used for A followed by 1 min of breath-hold (BH) with face immersion in cold water. (D) PEMI-DR session: the same protocol used for A with 60 s of BH with face immersion in cold water during the first minute of PEMI. Stroke volume (SV), heart rate (HR), and cardiac output (CO) were collected by means of an impedance method.Results: At the end of apnea, HR was decreased in condition C and D with respect to A (−40.8 and −40.3%, respectively vs. −9.1%; p < 0.05). Since SV increase was less pronounced at the same time point (C = +32.4 and D = +21.7% vs. A = +6.0; p < 0.05), CO significantly decreased during C and D with respect to A (−23 and −29.0 vs. −1.4%, respectively; p < 0.05).Conclusion: Results addressed the hypothesis that DR overcame the MM in our setting.

Chronic Ablation of TRPV1 Sensitive Skeletal Muscle Afferents Attenuates the Muscle Metaboreflex

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex- induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express Transient Receptor Potential Vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultra-potent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1 sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 μg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min) and stroke work (2.27 ± 0.2 L*mmHg vs. 1.01 ± 0.2 L*mmHg). Effects were maintained until 78 ± 14 days post RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 μg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre RTX vs +19.7 ± 3.1mmHg post RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Sympathetic Activation due to Limb Venous Distension Is Preserved during Muscle Metaboreceptor Stimulation

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e. muscle metaboreflex) would modify venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A, saline (5% forearm volume) was infused into the veins of an arterially occluded arm (non-handgrip trial). In trial B, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial A, the infusion increased MSNA and BP as expected (both P < 0.001). In trial B, handgrip significantly raised MSNA, BP and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (D8.6 ± 1.5 to D10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure (P = 0.844) evoked by the infusion during PECO were not significantly different from those in the non-handgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.