Effects of wortmannin on alpha-1/alpha-2 adrenergic receptor-mediated contractile responses in rabbit vascular tissues.
The inhibitory effect of wortmannin (WO), a fungus-derived protein kinase inhibitor, was assessed on contractile responses elicited by phenylephrine-induced alpha 1-(alpha 1 R) and UK 14304-induced alpha 2-adrenergic receptor (alpha 2R) stimulation in the rabbit aorta and saphenous vein, respectively. In agonist dose-response studies, WO caused a noncompetitive inhibition of both alpha 1R and alpha 2R responses, but was more potent against alpha 2R. Maximally effective single-dose responses at both receptors were less sensitive to WO. The initial alpha 1R contractile response, associated with intracellular Ca2+ release and myosin light chain kinase activation, was relatively insensitive to WO, while the Ca2+ influx-dependent tonic contraction was more sensitive. Contractions induced by high K+ buffer were relatively insensitive to WO in both the aorta and saphenous vein. These results indicate that WO inhibits receptor-initiated Ca2+ influx-dependent contractile responses such as those caused by alpha 2R stimulation and the sustained phase of alpha 1R stimulation more readily than Ca2+ release-dependent responses.
Waen-Safranchik
V I
VI
Department of Pharmaceutical Sciences, Northeastern University, Boston, Mass. 02115.
Deth
R C
RC
D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D012501:Saphenous Vein; D000077191:Wortmannin
D000730:Androstadienes; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D010656:Phenylephrine; D000068438:Brimonidine Tartrate; D011189:Potassium Chloride; D002118:Calcium; D000077191:Wortmannin