ABSTRACT
PURPOSE: We investigated whether presynaptic facilitatory M1 and/or inhibitory M2 muscarinic receptors contributed to pancuronium- and cisatracurium-induced tetanic fade. METHODS: Phrenic nerve-diaphragm muscle preparations of rats were indirectly stimulated with tetanic frequency (75 +/- 3.3 Hz; mean +/- SD). Doses of pancuronium, cisatracurium, hexamethonium, and d-tubocurarine for producing approximately 25% fade were determined. The effects of pirenzepine and methoctramine, blockers of presynaptic M1 and M2 receptors, respectively, on the tetanic fade were investigated. RESULTS: The concentrations required for approximately 25% fade were 413 microM for hexamethonium (26.8 +/- 2.4% 4% fade), 55 nM for d-tubocurarine (28.7 +/- 2.55% fade), 0.32 microM for pancuronium (25.4 +/- 2.2% fade), and 0.32 microM for cisatracurium (24.7 +/- 0.8% fade). Pirenzepine or methoctramine alone did not produce the fade. Methoctramine, 1 microM, attenuated the fade induced by hexamethonium (to 16.0 +/- 2.5% fade), d-tubocurarine (to 6.0 +/- 1.6 fade), pancuronium (to 8.0 +/- 4.0% fade), and cisatracurium (to 11.0 +/- 3.3% fade). 10 nM pirenzepine attenuated only the fades produced by pancuronium (to 5.0 +/- 0.11% fade) and cisatracurium (to 13.3 +/- 5.3% fade). Cisatracurium (0.32 microM) showed antiacetylcholinesterase activity (in plasma, 14.2 +/- 1.6%; 6%; in erythrocyt 17.2 +/- 2.66%) similar to that of pancuronium (0.32 microM). The selective A1 receptor blocker, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 2.5 nM), also attenuated the fades induced by pancuronium and cisatracurium. CONCLUSION: The tetanic fades produced by pancuronium and cisatracurium depend on the activation of presynaptic inhibitory M2 receptors; these agents also have anticholinesterase activities. The fades induced by these agents also depend on the activation of presynaptic inhibitory A1 receptors through the activation of stimulatory M1 receptors by acetylcholine.
Subject(s)
Atracurium/analogs & derivatives , Muscle Contraction/drug effects , Neuromuscular Nondepolarizing Agents/pharmacology , Pancuronium/pharmacology , Receptor, Adenosine A1/drug effects , Receptor, Muscarinic M1/drug effects , Receptor, Muscarinic M2/drug effects , Animals , Atracurium/pharmacology , Diamines/pharmacology , Electric Stimulation , Hexamethonium/pharmacology , In Vitro Techniques , Male , Muscarinic Antagonists/pharmacology , Muscle, Skeletal/drug effects , Muscle, Skeletal/innervation , Nicotinic Antagonists/pharmacology , Phrenic Nerve/drug effects , Pirenzepine/pharmacology , Rats , Rats, Wistar , Xanthines/pharmacologyABSTRACT
In endothelium-intact rat aortic ring preparations pre-contracted with norepinephrine or KCl, NG-nitro L-arginine (L-NOARG, 0.1 mM) and 1H-[1,2,4] oxidiazolo [4,3-a] quinoxalin-1-one (ODQ, 10 microM) antagonized the reduction of the vascular tone induced by stevioside, but this antagonism did not occur when the experiment was performed with endothelium-denuded aortic rings. The data indicates that the vasodilatation produced by stevioside is dependent on nitric oxide synthase and guanylate cyclase activities when the endothelium is not damaged.
