In-vitro smooth muscle relaxant activity of a series of vecuronium analogues in the rat aorta.
The ability of a series of 17-ester analogues of vecuronium to elicit a direct relaxant effect on vascular smooth muscle has been studied using rat isolated aortic rings contracted with 40 mM KCl. The IC50 for inhibition of KCl-induced contractions increased with increasing size of the 17-ester substituent, such that vecuronium (17 beta-acetate) was the least potent with an IC50 of around 50 microM and Org-9827 (17 alpha-pivalate) was the most potent with an IC50 of around 5 microM. In addition, for the weaker-acting compounds, the 17 alpha-esters were more potent than their corresponding 17 beta-esters, although this difference was lost as the size of the 17-ester substituent increased. From the results obtained here, it is concluded that the hypotensive activity of some of the newer neuromuscular blocking steroids seen in cats, pigs and dogs in-vivo is probably, at least in part, a consequence of a direct relaxant effect of the compound on vascular smooth muscle through inhibition of voltage-activated, L-type, calcium channels. This may have both advantageous and disadvantageous clinical consequences when using large doses of one of the newer vecuronium analogues with a low relative neuromuscular-blocking potency.
Fiddes
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S
Department of Physiology and Pharmacology, University of Strathelyde, Glasgow, UK.
Prior
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C
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014673:Vecuronium Bromide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D015220:Calcium Channels; D010656:Phenylephrine; D011189:Potassium Chloride; D014673:Vecuronium Bromide; D002118:Calcium