A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects

E. Vízi, Z. Tuba, S. Mahó, F. F. Foldes, O. Nagano, M. Dóda, S. Takagi, I. A. Chaudhry, A. J. Saubermann, H. Nagashima

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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[α-hydroxy-17β-acetyloxy-2β-(1,4-dioxa-8-azaspiro[4,5] dec-8-yl)-5α-androstane-16β-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. Conclusion: 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.

Original languageEnglish
Pages (from-to)291-300
Number of pages10
JournalActa Anaesthesiologica Scandinavica
Volume47
Issue number3
DOIs
Publication statusPublished - Mar 2003

Fingerprint

Neuromuscular Nondepolarizing Agents
Muscles
Guinea Pigs
Muscle Contraction
Electric Stimulation
Cats
Muscarinic M3 Receptors
Muscarinic M2 Receptors
Blood Pressure
Oxotremorine
Neuromuscular Blocking Agents
Phrenic Nerve
Neuromuscular Blockade
Muscarinic Antagonists
Anesthesiology
Laboratory Animals
Sciatic Nerve
Bromides
Atropine
Ileum

Keywords

  • Antivagal effects
  • Cardiovascular side-effect
  • M- and M-muscarinic receptor antagonism
  • Neuromuscular relaxants
  • Norepinephrine release

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects. / Vízi, E.; Tuba, Z.; Mahó, S.; Foldes, F. F.; Nagano, O.; Dóda, M.; Takagi, S.; Chaudhry, I. A.; Saubermann, A. J.; Nagashima, H.

In: Acta Anaesthesiologica Scandinavica, Vol. 47, No. 3, 03.2003, p. 291-300.

Research output: Contribution to journalArticle

Vízi, E, Tuba, Z, Mahó, S, Foldes, FF, Nagano, O, Dóda, M, Takagi, S, Chaudhry, IA, Saubermann, AJ & Nagashima, H 2003, 'A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects', Acta Anaesthesiologica Scandinavica, vol. 47, no. 3, pp. 291-300. https://doi.org/10.1034/j.1399-6576.2003.00033.x
Vízi, E. ; Tuba, Z. ; Mahó, S. ; Foldes, F. F. ; Nagano, O. ; Dóda, M. ; Takagi, S. ; Chaudhry, I. A. ; Saubermann, A. J. ; Nagashima, H. / A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects. In: Acta Anaesthesiologica Scandinavica. 2003 ; Vol. 47, No. 3. pp. 291-300.
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AU - Tuba, Z.

AU - Mahó, S.

AU - Foldes, F. F.

AU - Nagano, O.

AU - Dóda, M.

AU - Takagi, S.

AU - Chaudhry, I. A.

AU - Saubermann, A. J.

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N2 - 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[α-hydroxy-17β-acetyloxy-2β-(1,4-dioxa-8-azaspiro[4,5] dec-8-yl)-5α-androstane-16β-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. Conclusion: 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.

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