After cardiac transplantation, the denervated donor atria and ventricles demonstrate increased sensitivity to infusions of sympathomimetic amines. Recently, supersensitivity of the canine sinus and atrioventricular (AV) nodes to acetylcholine has also been demonstrated after parasympathetic denervation. Acetylcholine and the endogenous nucleoside adenosine exert similar electrophysiological effects in both the sinus and AV nodes, and share a common transduction process. We, therefore, hypothesized that after orthotopic cardiac transplantation, the donor (denervated) sinus node would demonstrate greater sensitivity to exogenous adenosine than the recipient (innervated) sinus node. The effects of incremental doses of intravenous adenosine (37-112 micrograms/kg) on changes in sinus cycle length (SCL) (delta SCLmax%), changes in PR interval (delta PRmax%), time to peak effect (sec), and duration of electrophysiological effects (sec) were prospectively measured in 28 orthotopic cardiac transplant patients and nine control subjects. The baseline SCL was 795 +/- 71 msec for the control subjects, 891 +/- 43 msec for the recipient atria, and 700 +/- 18 msec for the donor atria (p less than 0.05, donor vs. recipient). The delta SCLmax% for each dose of adenosine was similar in the innervated control and recipient atria. In contrast, the donor sinus node demonstrated a threefold to fourfold increased response to adenosine as compared with the recipient sinus node and a threefold to sixfold increased response as compared with control subjects. Similarly, the donor AV node demonstrated a threefold to fivefold increase in PR interval as compared with control subjects. The duration of sinus node slowing in the denervated atria was threefold to fivefold longer than in the recipient and control atria (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)