A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects.
BACKGROUND
In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non-depolarizing muscle relaxant without cardiovascular side-effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non-depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants.


METHODS
Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i). in vitro isolated phrenic nerve-hemidiaphragm preparation of mice, rats and guinea pigs and (ii). in vivo sciatic nerve-anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine-induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence.


RESULTS
One of more than 120 newly synthesized non-depolarizing muscle relaxants compounds, 1-3[alpha-hydroxy-17beta-acetyloxy-2beta-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5alpha-androstane-16beta-il] -1-(2-propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side-effects. Pharmacodynamic studies show that SZ1677 is a non-depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED90. This compound, unlike many other muscle relaxants, does not have atropine-like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1677 compares favorably with all presently available short-acting muscle relaxants, including rapacuronium.


CONCLUSIONS
In experiments, SZ1677 proved to be a short-acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side-effects.
Vizi
E S
ES
Department of Pharmacology, Institute of Experimental Medicine, Budapest, Hungary. esvizi@koki.hu
Tuba
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Mahó
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Foldes
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Nagano
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Dóda
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Takagi
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Chaudhry
I A
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Saubermann
A J
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Nagashima
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D000731:Androstanes / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018727:Muscarinic Antagonists; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects; D003473:Neuromuscular Nondepolarizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010791:Phrenic Nerve / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects; D012584:Sciatic Nerve / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
C458501:1-(3-hydroxy-17-acetyloxy)-2-(1.4-dioxa-8-azaspiro-(4,5)-dec-8-yl)-(5alpha-androstane-16-yl)-1-(2-propenyl) pyrrolidine; D000731:Androstanes; D018727:Muscarinic Antagonists; D003473:Neuromuscular Nondepolarizing Agents; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D009638:Norepinephrine