Intrapericardial procaine has been used by several groups to block cardiac afferent nerves to study effects of cardiogenic reflexes. In eight conscious rabbits, procaine (17–113 mg ipc; median 32) blocked cardiac efferents. Procaine (17–113 mg ipc; median 39) abolished the reflex depressor effects of the cardiac C-fiber excitant 1-phenylbiguanide (PBG), and in four of eight rabbits prevented the hypotensive phase 2 of acute central hypovolemia, which has been attributed to a signal from the heart. However, in three of the rabbits respiratory incoordination and blood gas abnormalities developed. In another study of four rabbits, procaine (165–335 mg ipc; median 235) invariably caused phrenic nerve blockade and underventilation. In three rabbits, after intrapericardial (250 mg) or subcutaneous (50 mg) procaine, plasma procaine levels rose to 9.4 and 4.8 micrograms/ml, respectively. During intravenous infusion of procaine, the PBG chemoreflex was abolished at plasma levels > 3.1 micrograms/ml, and phase 2 of acute hypovolemia at levels > or = 4.3 micrograms/ml. There is a narrow margin between a dose of intrapericardial procaine that blocks cardiac nerves and one that can produce confounding effects from phrenic nerve blockade or absorption into the bloodstream.