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 h, but not 48 h, before a simulated dive prevents bubble formation and protects rats from severe decompression sickness (DCS) and death. Furthermore, we demonstrated that administration of N(omega)-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 20 h 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 20 h before a dive suppressed bubble formation and prevented death, with no effect at any other time (48, 10, 5 and 0.5 h 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.