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1 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway2 Department of Cardiology, St Olavs Hospital, Trondheim, Norway3 Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Abstract |
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-nitro-L-arginine methyl ester, a non-selective inhibitor of NO synthase (NOS), turns a dive from safe to unsafe in sedentary but not exercised rats. Therefore based upon previous data an attractive hypothesis is that it may be possible to use either exercise or NO-releasing agents before a dive to inhibit bubble formation and thus protect against DCS. Consequently, the aims of the present study were to determine whether protection against bubble formation in ‘diving’ rats was provided by (1) chronic and acute administration of a NO-releasing agent and (2) exercise less than 20 h prior to the dive. NO given for 5 days and then 20h prior to a dive to 700 kPa lasting 45 min breathing air significantly reduced bubble formation and prevented death. The same effect was seen if NO was given only 30 min before the dive. Exercise 20h before a dive surpressed bubble formation and prevented death, with no effect at any other time (48, 10, 5 and 0.5h prior to the dive). Pre-dive activities have not been considered to influence the growth of bubbles and thus the risk of serious DCS. The present novel findings of a protective effect against bubble formation and death by appropriately timed exercise and an NO-releasing agent may form the basis of a new approach to preventing serious decompression sickness.
(Received 19 September 2003;
accepted after revision 13 January 2004;
first published online 14 January 2004)
Corresponding author U. Wisløff: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway. Email: ulrik.wisloff{at}medisin.ntnu.no
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Introduction |
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Recently we have shown that a single bout of exercise 20h, but not 48h, before a simulated dive prevents bubble formation and protects rats from severe DCS and death (Wisløff & Brubakk, 2001). Furthermore, we demonstrated that administration of N-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NO synthase (NOS), turns a dive from safe to unsafe in sedentary but not exercised rats (Wisløff et al. 2003). Therefore, both acute exercise and NOS affect bubble formation, but they may not be linked. We speculate that both exercise and NOS hinder bubble formation via alteration in vascular endothelial properties since pre-existing gas nuclei are probably attached to the endothelium, where they grow into bubbles that are dislodged into the blood stream (Harvey et al. 1944; Harvey, 1951).
Therefore based upon previous data (Wisløff & Brubakk, 2001; Wisløff et al. 2003), an attractive hypothesis is that it may be possible to use either exercise or NO-releasing agents before a dive to inhibit bubble formation and thus protect against DCS.
However, the correct timing of this type of intervention is not clear, as the benefit of exercise is pronounced at 20 but not 48h post exercise (Wisløff & Brubakk, 2001; Wisløff et al. 2003). As we believe exercise may deplete (wash away) the bubble precursors, it should take 10–100h to regenerate a depleted nuclei population (Yount & Strauss, 1982). Thus, exercise closer than 20h prior to the dive should also protect against bubble formation. Consequently, the aims of the present study were to determine whether protection against bubble formation in diving rats was provided by (1) chronic and acute administration of a NO-releasing agent and (2) exercise less than 20h prior to the dive.
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Methods |
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A total of 84 adult female 310 ± 7g Sprague-Dawley rats (Møllegaards, Denmark) were maintained six in each cage with light controlled on a 12h dark–12h light cycle. Temperature was 21 ± 2°C and humidity 50 ± 4%. Animals were fed a pellet rodent diet ad libitum and had free access to water. The rats were assigned into seven groups, as described in Table 1. Rats in groups I–V were used in experiments to determine the duration of the exercise-induced benefit against bubble formation and death. Exercise was performed 48h, 20h, 10h, 5h, and 30 min prior to the simulated dive in groups I–V, respectively. In groups VI–VII we determined the effect of administration of a NO-releasing agent (isosorbid mononitrate, Roche, Switzerland, 65 mg kg-1) for 5 days (the last time 20h before the dive) and immediately (30 min) prior to the dive on bubble formation and survival. The isosorbid mononitrate was dissolved in water and administrated to the rats by gastric intubation. Control rats received water by gastric intubation.
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and exercise protocol
Nine days before group assignment, oxygen uptake and respiratory exchange ratio were measured during treadmill running as previously described in detail (Wisløff & Brubakk, 2001). In brief, interval running (1.5h total duration) alternating between 8 min at 85–90% of 
and 2 min at 50–60%. After the exercise session, each rat was rewarded with 0.5 g chocolate (Crispo, Nidar Bergene, Norway). Sedentary rats were given the same reward.
Dive protocol and bubble analysis
Pairs of rats (experimental and control) were compressed at a rate of 200kPa min-1 to a pressure of 700kPa, maintained for 45 min breathing air and decompressed to the surface (100kPa) at a rate of 50kPa min-1. Immediately after surfacing the animals were anaesthetized with Midazolam (Dormicum ‘Roche’)–fentanyl–fluanison (Hypnorm) (0.1 ml (100 g)-1S.C.), and the right ventricle was insonated using a GE Vingmed Vivid 5 ultrasonic scanner, with a 10 MHz transducer as previously described in detail (Wisløff & Brubakk, 2001; Wisløff et al. 2003). Images were graded according to a previously described method (Eftedal & Brubakk, 1997) with the observer unaware of the group allocation of the rat. A pilot study showed that rats surviving 60 min were apparently unaffected by the protocol and lived normally thereafter; thus survival times up to 60 min were recorded were. Surviving rats were killed by decapitation.
The experimental procedures conformed to the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes, and the protocol was approved by the Norwegian Council for Animal Research.
Statistics
Data are expressed as mean ±S.D., or as median and range. Non-parametric tests were employed due to the limited number of rats in each group. A Mann-Whitney U test was used to evaluate differences in bubble formation, whereas the Gehan generalized Wilcoxon test was used to evaluate differences in survival time between groups. P < 0.05 was considered as statistically significant. Group size and statistical power were estimated using nQuery Advisor software (version 3.0, Statistical Solutions Ltd, Cork, Ireland). Based on cautious estimates from a previous study (Wisløff & Brubakk, 2001) six rats in each group would permit us to detect a 15% difference between groups in bubble grade and survival time (P= 0.01, power = 0.80).
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Results |
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Discussion |
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To better elucidate the role of NO in the exercise-induced protection against bubble formation, further studies should include rats that normally produce a lot of nitrogen bubbles and (1) determine the effect of exercise 20h prior to a dive in L-NAME-treated rats, and (2) determine the effect of exercise close to the dive in rats receiving a NO donor prior to the exercise bout.
The present data clearly show that the mechanism of exercise-induced protection requires a time lag of 10–20h to be fully activated, while a time lag of 20–48 h negates the protective effect. It is known that short-term high-intensity exercise (about 90% of 
) can induce hypervolaemia (Gillen et al. 1991; Richardson et al. 1996), and the responses of aldosterone, angiotensin–renin and atrial natriuretic peptide (among others) all have significant consequences that last 24–48h (Richardson et al. 1996). An increase in plasma volume could increase the functionally active capillary bed and the rate of plasma exchange through the muscle bed, which might increase the rate of nitrogen elimination. Interestingly, it is known that volume expansion decreases the severity of DCS (Merton et al. 1983). Thus, the well-known volume expansion developed a day after intense exercise may induce the observed exercise-related protection against bubble formation.
Conclusion
Efforts to prevent of DCS have traditionally focused upon the reduction of nitrogen supersaturation in the tissues. It is, however, well documented that the presence of nuclei is probably needed for bubbles to form at the level of supersaturation encountered in human diving (Vann, 1989). The idea that removal of nuclei may prevent DCS is not new. Vann et al. (1980) showed that exposure to significantly higher pressures before a dive, which presumably crushed the nuclei, significantly reduced the incidence of DCS. However until now, no practical way of removing nuclei has been suggested.
Pre-dive activities have not been considered to influence the growth of bubbles and thus the risk of serious DCS. The present novel findings of appropriately timed exercise and the use of a NO-releasing agent may form the basis for a new approach to prevention of serious decompression sickness.
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References |
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Dervay JP, Powell MR, Butler B & Fife CE (2002). The effect of exercise and rest duration on the generation of venous gas bubbles at altitude. Aviat Space Environ Med 73, 22–27.[Medline]
Eftedal O & Brubakk A (1997). Agreement between trained and untrained observers in grading intravascular bubble signals in ultrasonic images. Undersea Hyperbar Med 24, 293–299.
Francis T & Gorman D (1993). Pathogenesis of the decompression disorders. In The Physiology and Medicine of Diving, ed. Elliot DH & Bennett PB, pp. 454–480.W.B. Saunders, London.
Gillen CM, Lee R, Mack GW, Tomaselli CM, Nishiyasu T & Nadel ER (1991). Plasma volume expansion in humans after a single intense exercise protocol. J Appl Physiol 71, 1914–1920.
Harvey EN (1951). Physical factors in bubble formation. In Decompression Sickness, ed. Fulton JF, pp. 90–114. W.B. Saunders, Philadelphia and London.
Harvey EN, McElroy WD, Whiteley AH, Warren GH & Pease DC (1944). Bubble formation in animals. III. An analysis of gas tension and hydrostatic pressure in cats. J Cell Comp Physiol 24, 117–132.[CrossRef]
McDonough PM & Hemmingsen EA (1985a). A direct test for the survival of gaseous nuclei in vivo. Aviat Space Environ Med 56, 54–56.[Medline]
McDonough PM & Hemmingsen EA (1985b). Swimming movements initiate bubble formation in fish decompressed from elevated gas pressures. Comp Biochem Physiol A 81, 209–212.[Medline]
Merton DA, Fife WP & Gross DR (1983). An evaluation of plasma volume expanders in the treatment of decompression sickness. Aviat Space Environ Med 54, 218–222.[Medline]
Richardson RS, Verstraete D, Johnson SC, Luetkemeier MJ & Stray-Gundersen J (1996). Evidence of a secondary hypervolemia in trained man following acute high intensity exercise. Int J Sports Med 17, 243–247.[Medline]
Roberts CK, Barnard RJ, Jasman A & Balon TW (1999). Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol 277, E390–E394.[Medline]
Vann RD (1989). Exercise and circulation in the formation and growth of bubbles. In Supersaturation and Bubble Formation in Fluid and Organisms, ed. Brubakk AO, Hemmingsen BB & Saunders G, pp. 235–258.Tapir, Trondheim.
Vann RD, Grimstad J & Nielsen CH (1980). Evidence for gas nuclei in decompressed rats. Undersea Biomed Res 7, 107–112.[Medline]
Wisløff U & Brubakk A (2001). Aerobic endurance training reduces bubble formation and increases survival in rats exposed to hyperbaric pressure. J Physiol 537, 607–611.
Wisløff U, Richardson RS & Brubakk AO (2003). NOS inhibition increases bubble formation and reduces survival in sedentary but not exercised rats. J Physiol 546, 577–582.
Yount D & Strauss R (1982). On the evolution, generation and regeneration of gas cavitation nuclei. J Acoust Soc AM 65, 1431–1439.
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Acknowledgements |
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