Streptozocin-diabetes modifies acetylcholine release from mouse phrenic nerve terminal and presynaptic sensitivity to succinylcholine.
Acetylcholine (ACh) release from the motor nerve terminal in the streptozocin-induced diabetic state was studied in mouse phrenic nerve-diaphragm muscle preparations. Electrically evoked release of 3H-ACh from the preparation preloaded with 3H-choline was measured during two consecutive periods of stimulation (S1 and S2). In diabetic mice, the amount of 3H-ACh release during S2 was decreased, and the evoked ACh release declined more steeply with successive stimulation periods than in normal ddY mice. The decrease in release was restored when the presynaptic autoreceptors were stimulated by accumulating ACh under the irreversible inhibition of junctional cholinesterase by methanesulfonyl fluoride. This effect was abolished by the administration of (+)-tubocurarine (5 microM). In diabetic mice, the biphasic (acceleration and suppression) effect by succinylcholine on evoked ACh release was caused at 3- to 10-fold lower concentrations than in normal mice. The degree of enhancement of resting 3H-overflow by succinylcholine (10 and 30 microM) was greater in the diabetic state. These results indicated that in the diabetic state, the decrease in evoked ACh release interferes with its presynaptic action on inducing further release (positive feedback modulation) via the presynaptic nicotinic ACh receptor (n-AChR). The presynaptic hypersensitivity to succinylcholine may be due to the augmentation of presynaptic n-AChR sensitivity caused by the reduction of evoked ACh release in the diabetic state.
Kimura
I
I
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
Okazaki
M
M
Kimura
M
M
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism*; D011863:Radioimmunoassay; D011950:Receptors, Cholinergic / Q000187:drug effects; D012132:Respiratory Muscles / Q000294:innervation / Q000378:metabolism; D013390:Succinylcholine / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects*
D002800:Cholinesterase Inhibitors; D011950:Receptors, Cholinergic; D013390:Succinylcholine; D002794:Choline; D000109:Acetylcholine