Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Effects of CBD supplementation on ambulatory blood pressure and serum urotensin-II concentrations in Caucasian patients with essential hypertension: A sub-analysis of the HYPER-H21-4 trial.

HYPER-H21-4 was a randomized crossover trial that aimed to determine if cannabidiol (CBD), a non-intoxicating constituent of cannabis, has relevant effects on blood pressure and vascular health in patients with essential hypertension. In the present sub-analysis, we aimed to elucidate whether serum urotensin-II concentrations may reflect hemodynamic changes caused by oral supplementation with CBD. The sub-analysis of this randomized crossover study included 51 patients with mild to moderate hypertension that received CBD for five weeks, and placebo for five weeks. After five weeks of oral CBD supplementation, but not placebo, serum urotensin concentrations reduced significantly in comparison to baseline (3.31 ± 1.46 ng/mL vs. 2.08 ± 0.91 ng/mL, P < 0.001). Following the five weeks of CBD supplementation, the magnitude of reduction in 24 h mean arterial pressure (MAP) positively correlated with the extent of change in serum urotensin levels (r = 0.412, P = 0.003); this association was independent of age, sex, BMI and previous antihypertensive treatment (ß ± standard error, 0.023 ± 0.009, P = 0.009). No correlation was present in the placebo condition (r = -0.132, P = 0.357). In summary, potent vasoconstrictor urotensin seems to be implicated in CBD-mediated reduction in blood pressure, although further research is needed to confirm these notions.

CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial.

Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.

Cerebrovascular function is preserved during mild hyperthermia in cervical spinal cord injury.

STUDY DESIGN: Experimental study. OBJECTIVES: Compromised cerebrovascular function likely contributes to elevated neurological risk in spinal cord injury (SCI). Passive heating offers many cardiovascular and neurological health benefits; therefore, we aimed to determine the effects of an acute bout of heating on cerebrovascular function in chronic SCI. METHODS: Persons with cervical SCI (n = 15) and uninjured controls (CON; n = 15) completed 60 min of lower limb hot water immersion (40 °C). Assessments of middle cerebral (MCA) and posterior cerebral artery (PCA) velocities, pulsatilities, and neurovascular coupling (NVC) were performed using transcranial Doppler ultrasound. Duplex ultrasonography was used to index cerebral blood flow via the internal carotid artery (ICA), and carotid-femoral pulse-wave velocity (PWV) was measured using tonometry. The NVC response was quantified as the peak hyperemic value during 30-s cycles of visual stimulation. RESULTS: Mean arterial pressure changed differentially with heating [mean (standard deviation); SCI: +6(14) mmHg, CON: -8(12) mmHg; P = 0.01]. There were no differences in any intracranial artery measures (all P > 0.05), except for small (~10%) increases in MCA conductance in CON after heating vs. SCI (interaction P = 0.006). Resting ICA flow was greater in SCI vs. CON (P = 0.03) but did not change with heating in either group (interaction P = 0.34). There were also no between-group differences in the NVC response (ΔPCA conductance) pre- [SCI: 29(19)% vs. CON: 30(9)%] or post-heating [SCI 30(9)% vs. 25(9)%; interaction P = 0.22]. CONCLUSIONS: Mild acute heating does not impair or improve cerebrovascular function in SCI or CON. Thus, further study of the effects of chronic heating interventions are warranted.

Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury.

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b-) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (-93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

Differential influence of vitamin C on the peripheral and cerebral circulation after diving and exposure to hyperoxia.

We examined if the diving-induced vascular changes in the peripheral and cerebral circulation could be prevented by oral antioxidant supplementation. Fourteen divers performed a single scuba dive to eighteen meter sea water for 47 min. Twelve of the divers participated in a follow-up study involving breathing 60% of oxygen at ambient pressure for 47 min. Before both studies, participants ingested vitamin C (2 g/day) or a placebo capsule for 6 days. After a 2-wk washout, the study was repeated with the different condition. Endothelium-dependent vasodilator function of the brachial artery was assessed pre- and postintervention using the flow-mediated dilation (FMD) technique. Transcranial Doppler ultrasound was used to measure intracranial blood velocities pre- and 90 min postintervention. FMD was reduced by ∼32.8% and ∼21.2% postdive in the placebo and vitamin C trial and posthyperoxic condition in the placebo trial by ∼28.2% ( P < 0.05). This reduction in FMD was attenuated by ∼10% following vitamin C supplementation in the hyperoxic study ( P > 0.05). Elevations in intracranial blood velocities 30 min after surfacing from diving were reduced in the vitamin C study compared with the placebo trial ( P < 0.05). O2 breathing had no postintervention effects on intracranial velocities ( P > 0.05). Prophylactic ingestion of vitamin C effectively abrogated peripheral vascular dysfunction following exposure to 60% O2 but did not abolish the postdive decrease in FMD. Transient elevations of intracranial velocities postdive were reduced by vitamin C. These findings highlight the differential influence of vitamin C on peripheral and cerebral circulations following scuba diving, which are only partly mediated via hyperoxia.

Ascorbic acid supplementation diminishes microparticle elevations and neutrophil activation following SCUBA diving.

Predicated on evidence that diving-related microparticle generation is an oxidative stress response, this study investigated the role that oxygen plays in augmenting production of annexin V-positive microparticles associated with open-water SCUBA diving and whether elevations can be abrogated by ascorbic acid. Following a cross-over study design, 14 male subjects ingested placebo and 2-3 wk later ascorbic acid (2 g) daily for 6 days prior to performing either a 47-min dive to 18 m of sea water while breathing air (∼222 kPa N2/59 kPa O2) or breathing a mixture of 60% O2/balance N2 from a tight-fitting face mask at atmospheric pressure for 47 min (∼40 kPa N2/59 kPa O2). Within 30 min after the 18-m dive in the placebo group, neutrophil activation, and platelet-neutrophil interactions occurred, and the total number of microparticles, as well as subgroups bearing CD66b, CD41, CD31, CD142 proteins or nitrotyrosine, increased approximately twofold. No significant elevations occurred among divers after ingesting ascorbic acid, nor were elevations identified in either group after breathing 60% O2. Ascorbic acid had no significant effect on post-dive intravascular bubble production quantified by transthoracic echocardiography. We conclude that high-pressure nitrogen plays a key role in neutrophil and microparticle-associated changes with diving and that responses can be abrogated by dietary ascorbic acid supplementation.

Observation of increased venous gas emboli after wet dives compared to dry dives.

INTRODUCTION: Testing of decompression procedures has been performed both in the dry and during immersion, assuming that the results can be directly compared. To test this, the aim of the present paper was to compare the number of venous gas bubbles observed following a short, deep and a shallow, long air dive performed dry in a hyperbaric chamber and following actual dives in open water. METHODS: Fourteen experienced male divers participated in the study; seven performed dry and wet dives to 24 metres' sea water (msw) for 70 minutes; seven divers performed dry and wet dives to 54 msw for 20 minutes. Decompression followed a Bühlmann decompression procedure. Immediately following the dive, pulmonary artery bubble formation was monitored for two hours. The results were graded according to the method of Eftedal and Brubakk. RESULTS: All divers completed the dive protocol, none of them showed any signs of decompression sickness. During the observation period, following the shallow dives, the bubbles increased from 0.1 bubbles per cm ² after the dry dive to 1.4 bubbles per cm ² after the wet dive. Following the deep dives, the bubbles increased from 0.1 bubbles per cm ² in the dry dive to 2.4 bubbles per cm ² in the wet dive. Both results are highly significant (P = 0.0001 or less). CONCLUSIONS: The study has shown that diving in water produces significantly more gas bubble formation than dry diving. The number of venous gas bubbles observed after decompression in water according to a rather conservative procedure, indicates that accepted standard decompression procedures nevertheless induce considerable decompression stress. We suggest that decompression procedures should aim at keeping venous bubble formation as low as possible.

Antioxidant pretreatment and reduced arterial endothelial dysfunction after diving.

INTRODUCTION: We have recently shown that a single air dive leads to acute arterial vasodilation and impairment of endothelium-dependent vasodilatation in humans. Additionally we have found that predive antioxidants at the upper recommended daily allowance partially prevented some of the negative effects of the dive. In this study we prospectively evaluated the effect of long-term antioxidants at a lower RDA dose on arterial endothelial function. METHODS: Eight professional male divers performed an open sea air dive to 30 msw. Brachial artery flow-mediated dilation (FMD) was assessed before and after diving. RESULTS: The first dive, without antioxidants, caused significant brachial arterial diameter increase from 3.85 +/- 0.55 to 4.04 +/- 0.5 mm and a significant reduction of FMD from 7.6 +/- 2.7 to 2.8 +/- 2.1%. The second dive, with antioxidants, showed unchanged arterial diameter and significant reduction of FMD from 8.11 +/- 2.4 to 6.8 +/- 1.4%. The FMD reduction was significantly less with antioxidants. Vascular smooth muscle function, assessed by nitroglycerine (endothelium-independent dilation), was unaffected by diving. DISCUSSION: This study shows that long-term antioxidant treatment at a lower RDA dose ending 3-4 h before a dive reduces the endothelial dysfunction in divers. Since the scuba dive was of a similar depth and duration to those practiced by numerous recreational divers, this study raises the possibility of routine predive supplementation with antioxidants.

Exogenous nitric oxide and bubble formation in divers.

PURPOSE: Prevention of bubble formation is a central goal in standard decompression procedures. Previously we have shown that exercise 20-24 h prior to a dive reduces bubble formation and increases survival in rats exposed to a simulated dive. Furthermore, we have demonstrated that nitric oxide (NO) may be involved in this protection; blocking the production of NO increases bubble formation while giving rats a long-lasting NO donor 20 h and immediately prior to a dive reduces bubble formation. This study determined whether a short-lasting NO donor, nitroglycerine, reduced bubble formation after standard dives and decompression in man. METHODS: A total of 16 experienced divers were randomly assigned into two groups. One group performed two dives to 30 m of seawater (msw) for 30 min breathing air, and performed exercise at an intensity corresponding to 30% of maximal oxygen uptake during the bottom time. The second group performed two simulated dives to 18 msw for 80 min breathing air in a hyperbaric chamber, and remained sedentary during the bottom period. The first dive for each diver served as the control dive, whereas the divers received 0.4 mg of nitroglycerine by oral spray 30 min before the second dive. Following the dive, gas bubbles in the pulmonary artery were recorded using ultrasound. RESULTS: The open-water dive resulted in significantly more gas bubbles than the dry dive (0.87 +/- 1.3 vs 0.12 +/- 0.23 bubbles per square centimeter). Nitroglycerine reduced bubble formation significantly in both dives from 0.87 +/- 1.3 to 0.32 +/- 0.7 in the in-water dive and from 0.12 +/- 0.23 to 0.03 +/- 0.03 bubbles per square centimeter in the chamber dive. CONCLUSION: The present study demonstrates that intake of a short-lasting NO donor reduces bubble formation following decompression after different dives.