Characterization of the vasoinhibitory actions of KT2-230, a new benzothiazepine vasodilator derivative on isolated rabbit vascular smooth muscles: an alpha-adrenergic- and serotonergic-receptor antagonist.
1. Pharmacological properties of KT2-230 (benzothiazepine derivative), a newly synthesized vasorelaxing agent, were studied. 2. In the anesthetized dogs, KT2-230 increased the femoral and vertebral blood flow without effect on systemic blood pressure. 3. In rabbit aorta, KT2-230, methysergide and phentolamine inhibited contractile responses to 5-hydroxytryptamine. 4. The response to norepinephrine was also inhibited by KT2-230 and phentolamine. Responses to histamine were not affected by KT2-230. 5. Responses to KCl and Ca2+ in K+ depolarized aorta in Ca2(+)-free medium were inhibited by a high concentration of KT2-230. 6. In rabbit iliac artery, KT2-230 inhibited the response to caffeine in Ca2(+)-free medium. 7. KT2-230 decreased total La3(+)-resistant Ca2(+)-binding at high affinity sites. 8. These results indicate that KT2-230 inhibits alpha 1-adrenoceptors and 5-HT-receptors and at high concentrations it inhibits slow Ca2(+)-channels. KT2-230 may inhibit the Ca2(+) release from caffeine- and agonist-sensitive Ca2+ stores.
Department of Pharmacology, University of Hawaii, School of Medicine, Honolulu 96822.
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Shibata
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Satake
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RK
Hester
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Mochizuki
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Kosakai
N
N
Ueyama
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Wakabayashi
D000317:Adrenergic alpha-Antagonists; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002132:Calcium Radioisotopes; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D013841:Thiazepines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D002132:Calcium Radioisotopes; D012702:Serotonin Antagonists; D013841:Thiazepines; D014665:Vasodilator Agents; C070246:KT2 230; D012701:Serotonin; D002110:Caffeine; D011189:Potassium Chloride; D007811:Lanthanum; D006632:Histamine; D002118:Calcium; D009638:Norepinephrine