Functional role of endothelin ETA and ETB receptors in venous and arterial smooth muscle.

The functional importance of endothelin ETA and ETB receptors in selected arterial and venous smooth muscle preparations was characterized. Endothelin-1 induced force in the saphenous and jugular veins is normally mediated by endothelin ETB-like receptors. However, desensitization or pharmacological block of these receptors reveals an endothelin ETA receptor population that is of sufficient size to mediate full endothelin-1-evoked force. Block of either endothelin ETA or endothelin ETB receptors alone is insufficient to antagonize endothelin-1-evoked force in saphenous vein. Endothelin-1-induced force in hamster aorta may also be mediated by activation of both endothelin ETA and ETB receptors. However, activation of endothelin ETB-like receptors alone is insufficient to generate a full endothelin-1 response. Sarafotoxin S6c treatment, to desensitize endothelin ETB receptors, failed to affect the responses of rat aorta and rabbit carotid artery to endothelin-1 or endothelin ETA receptor antagonists. These findings indicate that selective endothelin receptor antagonists will vary enormously in their efficacy against endothelin-induced force in different vascular beds.

8-(Diethylamino)-octyl-3,4,5-trimethoxybenzoate inhibits cromakalim-induced 86Rb efflux from the rat aorta.

The effects of 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) on cromakalim-induced 86Rb efflux and vasorelaxation in the rat aorta have been assessed. TMB-8 inhibited cromakalim (10 microM)-induced 86Rb efflux with an IC50 of 0.50 +/- 0.15 microM (n = 4; IC50 for glyburide 0.17 +/- 0.05 microM, n = 4), but it produced minimal antagonism of the cromakalim-induced vasorelaxation (rings precontracted with 30 mM KCl-PSS) at TMB-8 concentrations < or = 3 microM. TMB-8 at 10 microM produced significant inhibition of the cromakalim-induced vasodilation. Inhibition of cromakalim-induced 86Rb efflux produced by TMB-8 was little affected by raising the KCl concentration to 30 mM (inhibition by 0.5 microM TMB-8: 62.9 +/- 6.9 and 52.5 +/- 10.9% in 4.6 and 30 mM KCl, respectively; n = 4 for both). Similarly, the inhibitory effects of glyburide on the cromakalim-induced 86Rb efflux were minimally affected by this maneuver. TMB-8 was approximately equipotent against the increase in 86Rb efflux generated by either 1 or 10 microM cromakalim (IC50: 0.73 +/- 0.11 and 0.65 +/- 0.33 microM, respectively; n = 4 of both). In contrast, the glyburide IC50 was reduced approximately 10-fold by reducing the concentration of cromakalim used from 10 to 1 microM (IC50: 182.5 +/- 4.8 and 19.5 +/- 2.6 nM, respectively; n = 4 for both). We hypothesize that TMB-8 inhibits the potassium channel that is opened by cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin receptor subtype(s) in rabbit jugular vein smooth muscle.

The goal of our study was to characterize pharmacologically the receptor subtype(s) that mediate endothelin-induced force development in the rabbit jugular vein. Endothelin-1 (ET-1), sarafotoxin S6c, and the linear endothelin peptide Ala11,15-ET-1[8-21] evoked approximately monophasic concentration-dependent increases in force development in the rabbit jugular vein (rank order of potency: sarafotoxin S6c > ET-1 > Ala11,15-ET-1[8-21]). Maximally effective concentrations of the relatively ETB-selective (in comparison to ETA) ligands sarafotoxin S6c and Ala11,15-ET-1[8-21] produced significantly less force than a maximally effective ET-1 concentration (79 and 78% of ET-1 max., respectively; p < 0.001 for both). ET-3 produced a relatively shallow concentration-force relationship. Force evoked by ET-1 was minimally affected by the relatively ETA-selective (in comparison with ETB) receptor antagonists BQ-123 and FR139317. These data indicate that the dominant functional ET receptor in rabbit jugular vein smooth muscle is of a non-ETA subtype.