Effect of the K+ efflux stimulating vasodilator BRL 34915 on 86Rb+ efflux and spontaneous activity in guinea‐pig portal vein

Abstract

1 The effect of BRL 34915 on ⁸⁶Rb⁺ efflux and myogenic activity was studied simultaneously in guinea-pig portal vein. ⁸⁶Rb⁺ was used as a tracer ion for K⁺. 2 BRL 34915 inhibited myogenic activity with an IC₅₀ value of 12 ± 2 nm by reducing primarily the frequency of spontaneous contractions. Washout of the substance was followed by hyperreactivity of the vessel. 3 ⁸⁶Rb⁺ efflux was slightly reduced by concentrations of BRL 34915 below 100 nm; above 300 nm efflux was increased in a concentration-dependent manner. 4 Above 10 μm BRL 34915, a slow desensitization of the effect on flux was observed during the 10 min application period of the agonist. 5 The Ca²⁺ entry blocker, isradipine (PN 200-110, 200–500 nm) did not modify BRL 34915-stimulated ⁸⁶Rb⁺ efflux at any BRL 34915 concentration tested, indicating that the influx of extracellular Ca²⁺ through dihydropyridine-sensitive Ca²⁺ channels is not necessary for this effect. However, by abolishing spontaneous activity, it allowed the ⁸⁶Rb⁺ efflux promoting effect of BRL 34915 to be observed at a concentration of 60 nm. 6 The K⁺ channel blockers tetraethylammonium and 3,4 diaminopyridine inhibited the BRL 34915-induced ⁸⁶Rb⁺ efflux with IC₅₀ values of 13 and 3 mm, respectively. 7 Cell permeable derivatives of cyclic AMP and cyclic GMP had no major effect on BRL 34915-induced ⁸⁶Rb⁺ flux, indicating that cyclic nucleotide-induced phosphorylation does not play an important modulatory role here. 8 In conclusion, there is an at least 5 fold difference between the concentrations of BRL 34915 necessary to inhibit myogenic activity and those needed to stimulate ⁸⁶Rb⁺ efflux. This may be explained by a primary effect of BRL 34915 on the pacemaker cells of the portal vein.