Nitrogen dissolves in the blood during dives, but comes out of solution if divers return to normal pressure too rapidly. Nitrogen bubbles cause a range of effects from skin rashes to seizures, coma and death. It is believed that these bubbles form from bubble precursors (gas nuclei). Recently we have shown that a single bout of exercise 20 hours, but not 48 hours, before a simulated dive prevent bubble formation and protect rats from severe decompression sickness (DCS) and death. Furthermore, we demonstrated that administration of N-nitro-L-arginine methyl ester, a nonselective 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 hour prior to the dive. NO given for five days and then 20 hours prior to a dive to 700 kPa lasting 45 minutes breathing air significantly reduced bubble formation and prevented death. The same effect was seen if NO was given only 30 minutes before the dive. Exercise 20 hours before a dive surpressed bubble formation and prevented death, with no effect at any other time (48, 10, 5 and 0.5 hours 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 protective effect against bubble formation and death due to appropriately timed exercise and the NO-releasing agent may form the basis for a new approach to prevent serious decompression sickness.