Abstract

Adenosine 3',5'-monophosphate (cAMP) phosphodiesterase of rat pineal gland shows characteristic high- and low-K_m activities for cAMP. Treatment with l-isoproterenol (5 mg/kg intraperitoneally) increased the activity of the low-K_m phosphodiesterase of pineal by 40% within 1 hr, and the activity returned to normal within 5 hr. The gain of activity was accompanied by a change in V_max. Prior treatment of rats with dl-propranolol blocked the increase in phosphodiesterase activity while treatment with phentolamine did not, demonstrating modulation of enzyme activity through a beta adrenergic receptor. Activity was apparently induced at postsynaptic sites, as phosphodiesterase could still be increased by l-isoproterenol treatment after bilateral superior cervical ganglionectomy. Treatment of rats with cycloheximide prevented the response to l-isoproterenol, indicating that protein synthesis was required. Treatment with aminophylline, a phosphodiesterase inhibitor, produced a small but significant increase in the enzyme activity. Aminophylline in combination with a dose of l-isoproterenol below the threshold for phosphodiesterase activation resulted in greater activity than with aminophylline alone. These results suggest a direct relationship between cAMP concentrations and the increase in phosphodiesterase activity. Tolerance to repeated doses of beta receptor agonists might be explained by this mechanism.