RELEASE OF ENZYMES FROM A RAT LIVER LYSOSOME FRACTION: INHIBITION BY CATECHOLAMINES AND CYCLIC 3',5'-ADENOSINE MONOPHOSPHATE, STIMULATION BY CHOLINERGIC AGENTS AND CYCLIC 3',5'-GUANOSINE MONOPHOSPHATE

¹ Research Department, Pharmaceutical Division, CIBA-GEIGY Corporation, Ardsley, New York

Adrenergic agents and cyclic 3',5'-adenosine monophosphate inhibited, whereas cholinergic agents and cyclic 3',5'-guanosine monophosphate accelerated, the release of enzymes from rat liver lysosomes in vitro. Norepinephrine, epinephrine and isoproterenol inhibited lysosomal enzyme release; this action appears to be mediated by cyclic 3',5'-adenosine monophosphate. Liver lysosome fractions were shown to contain adenyl cyclase and phosphodiesterase activities. Adenyl cyclase activity was stimulated by catecholamines; this effect was inhibited by propranolol but not by phentolamine. Phosphodiesterase activity was inhibited by theophylline, papaverine and ZnCl₂. Acetylcholine, acetyl--methylcholine and carbamylcholine accelerated lysosomal enzyme release; this action was inhibited by atropine. Cholinergic agents did not affect adenvl cyclase activity but these agents stimulated phosphodiesterase activity, and this effect was also inhibited by atropine. Cyclic 3',5'-guanosine monophosphate accelerated lysosomal enzyme release and stimulated phosphodiesterase activity. Neither effect was influenced by atropine. Thus, it appears that cholinergic agents elicit their action on lysosomes by decreasing cyclic 3',5'-adenosine monophosphate, perhaps via a mechanism involving cyclic 3',5'-guanosine monophosphate. Reduction in norepinephrine and epinephrine levels in vivo with reserpine resulted in enhanced liver lysosome fragility, release of lysosomal enzymes and elevated plasma levels of enzymes. Repeated administration of 3, 4-dihydroxyphenylalanine to reserpine-treated rats restored the integrity of lysosomes. Lysosomes from reserpine-treated rats were more sensitive than lysosomes from untreated controls to the membrane-stabilizing action of catecholamines and cyclic 3',5'-adenosine monophosphate. Treatment of rats with 6-hydroxydopamine also resulted in enhanced liver lysosome fragility. Thus, it appears that catecholamines are important in maintaining the integrity of lysosomes in vivo. The data in this report suggest that the inflammatory process can be regulated by the autonomic nervous system through the actions of neurohormones and cyclic nucleotides on the release of enzymes from lysosomes.

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