THE ROLE OF ADENOSINE IN PROMOTING CARDIAC BETA-ADRENERGIC SUBSENSITIVITY IN AGING HUMANS

The mechanism by which aging decreases the cardiac chronotropic response in human subjects is unknown. We investigated the role of endogenous adenosine in attenuating the chronotropic response to beta-adrenoceptor stimulation due to aging by employing the adenosine receptor antagonist, theophylline. Sixteen healthy elderly (67.1 +/- 1.3 yrs) and sixteen healthy young (26.1 +/- 0.6 yrs) subjects were studied. The bolus dose of isoproterenol necessary to increase the heart rate 25 beats per minute (I-25) was determined by calculating the log dose response curve before and after a 30-min infusion of theophylline (6.5 mg/kg) in each subject. In addition, the effect of theophylline on the orthostatic increase in plasma renin activity (PRA) was determined. The I-25 for the elderly and young groups were 34.55 +/- 6.98 and 10.85 +/- 1.93 ng/kg, respectively (p<.01). After theophylline administration, the difference in I-25 in the two groups was no longer present (13.32 +/- 2.72 vs 7.46 +/- 1.26 ng/kg). The dose ratios (I-25 after theophylline/I-25 before theophylline) in the elderly and young groups were 0.43 +/- 0.06 and 0.82 +/- 0.14, respectively (p<.05). After the administration of theophylline, the orthostatic increase in PRA was enhanced more in the elderly subjects (0.53 +/- 0.23 vs 1.54 +/- 0.35 ng Al/ml/hr; p<.01) than in the young (1.31 +/- 0.23 vs 2.49 +/- 0.53 ng Al/ml/hr; p-value n.s.). Plasma norepinephrine changes after theophylline and postural norepinephrine changes after theophylline were not different in the two age groups. Excessive adenosine production or effect is partly responsible for the cardiac chronotropic resistance to isoproterenol and the diminished postural change in PRA in the elderly.