RESUMO
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.
Assuntos
Endotelinas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Receptores de Endotelina/fisiologia , Vasoconstritores/farmacologia , Venenos de Víboras/farmacologia , Sequência de Aminoácidos , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina , Veias Jugulares/efeitos dos fármacos , Veias Jugulares/metabolismo , Masculino , Dados de Sequência Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Coelhos , Ratos , Ratos Sprague-Dawley , Veia Safena/efeitos dos fármacos , Veia Safena/metabolismoRESUMO
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)
Assuntos
Benzopiranos/farmacologia , Ácido Gálico/análogos & derivados , Músculo Liso Vascular/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Pirróis/farmacologia , Rubídio/metabolismo , Animais , Aorta , Benzopiranos/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Cromakalim , Ácido Gálico/farmacologia , Glibureto/farmacologia , Técnicas In Vitro , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Cloreto de Potássio/farmacologia , Pirróis/antagonistas & inibidores , Ratos , Ratos Sprague-DawleyRESUMO
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.