BIPHASIC CHANGES IN THE DENSITY OF MUSCARINIC AND BETA-ADRENERGIC RECEPTORS IN CARDIAC ATRIA OF RATS TREATED WITH DIISOPROPYLFLUOROPHOSPHATE

Chronic treatment with organophosphate inhibitors of cholinesterases i s known to bring about down-regulation of muscarinic acetylcholine rec eptors in the heart while its effect on the functionally antagonistic beta-adrenergic receptors is not known. We describe experiments in whi ch rats were exposed to daily injections of diisopropylflurophosphate (DFP) and the density of muscarinic and beta-adrenergic binding sites in their cardiac atria was measured according to the binding of (H-3)q uinuclidinyl benzilate ((H-3)QNB) and mino-2-hydroxypropoxy)-(5,7-H-3) benzimidazol-2-one ((H-3)CGP 12177) as subtype non-specific muscarinic and beta-adrenergic ligands, respectively. Biphasic course of changes was discovered with both ligands. With the dosage scheme applied, the density of beta-adrenoceptors was augmented 24 h after the first dose of DFP and decreased to about one half of control values after 5 days of treatment with DFP. The density of muscarinic receptors was augmen ted after two days of treatment with DFP and decreased to about one ha lf of control values after 5 days of treatment. Comparatively small ch anges in the heart rate were observed during the treatment; they refle cted changes in the muscarinic and beta-adrenergic receptor density. T he finding of DFP-induced changes in the binding of (H-3)CGP 12177 sug gests that the mechanisms responsible for the control of the density o f muscarinic and beta-adrenergic receptors in the heart cells are inte rconnected but potential roles of other factors involved in in vivo ex periments deserve further analysis. The transient increase in the dens ity of muscarinic receptors after two days of DFP treatment appears re lated to published data on transient stimulation by cholinergic agonis ts of the transcription of mRNAs for muscarinic receptors.