To evaluate the effect of hypoxemia on cardiac release of neuropeptide Y-like immunoreactivity (NPY-LI) and norepinephrine (NE), arterial and coronary sinus blood was sampled and coronary sinus blood flow was measured by thermodilution in nine healthy volunteers at rest and during supine cycle ergometer exercise while they breathed air and 12% O2, which reduced arterial O2 saturation to approximately 68%. Five subjects started to exercise for 30 min breathing air and continued for 30 min breathing 12% O2; four subjects breathed 12% O2 and air in the reverse order. The load was adjusted to give the same heart rate during O2 and air breathing. No significant cardiac net release of NPY-LI or NE was seen at rest. Exercise induced release of NPY-LI and NE. The net release of NPY-LI was 0.7 +/- 0.4 pmol/min during air breathing (average 12 and 30 min) and 2.8 +/- 0.6 pmol/min during 12% O2 breathing. The difference was not influenced by the order of the breathing periods. The NE coronary sinus-arterial difference was not significantly different between 12% O2 and air breathing, whereas the net release was significantly larger during 12% O2 breathing (0.6 +/- 0.1 vs. 0.4 +/- 0.1 nmol/min). Thus, NPY is released with NE from the heart during exercise. Arterial hypoxemia seems to be an additional stimulus of preferential NPY release.