IN-VITRO SMOOTH-MUSCLE RELAXANT ACTIVITY OF A SERIES OF VECURONIUM ANALOGS 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 500 mu M and Org-9827 (17 alpha-pivalate) was the most potent with an IC50 of around 5 mu M. 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.