| Summary: | 碩士 === 高雄醫學大學 === 醫學研究所 === 88 === ABSTRACT
KMUP 880602 : N - { 4 - [ 2 - hydroxy - 3 - ( 2 - methoxy - 1 - oxyethylamino benzene ) propoxy ] - 3 - methoxybenzyl } ethamide, and KMUP 880708 ：N - { 4 - [ 2 - hydroxy - 3 - ( 2 - methoxy - 1 - oxyethylamino benzene ) propoxy ] - 3 - methoxybenzyl } hexanamide are new b-adrenoceptor blockers synthesized from vanilloid. The pharmacological properties of KMUP 880602 and KMUP 880708 were evaluated both in in vivo, in vitro and radioligand binding studies. In pentobarbital-anesthetized Wistar rats, KMUP 880602 and KMUP 880708 (0.1, 0.5, 1.0, and 2.0 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardia responses. KMUP 880602 and KMUP 880708 markedly inhibited both the tachycardia effects induced by (-) isoproterenol and arterial pressor responses induced by phenylephrine. These findings clearly suggested that KMUP 880602 and KMUP 880708 possessed a- and b-adrenoceptor blocking activities. In the isolated guinea-pig right atria, left atria and tracheal strips, KMUP 880602 and KMUP 880708 competitively antagonized the (-)isoproterenol-induced positive chronotropic effects, inotropic effects and tracheal relaxant effects in a concentration-dependent manner. The parallel shift to the right of the concentration-response curves of (-) isoproterenol suggested that KMUP 880602 and KMUP 880708 are b1/b2-adrenoceptor competitive antagonists. The apparent pA2 values for KMUP 880602 and KMUP 880708 were 7.24 ± 0.08, 7.82 ± 0.06 in the right atria, 7.42 ± 0.07, 7.51 ± 0.13 in the left atria and 6.24 ± 0.06, 6.31 ± 0.07 in the trachea, respectively. In tracheal strips of reserpinized guinea-pigs, the relaxant effects of KMUP 880602 and KMUP 880708 on carbachol-induced tracheal contractions were attenuated by pretreated with glibenclamide, TEA, charybotoxin and apamin, implying the involvement of K+ channel opening. Besides, tracheal smooth muscles pretreated with Nw-nitro-L-arginine methyl ester (L-NAME) and indomethacin could inhibit the relaxant effects of KMUP 880602 and KMUP 880708 in carbachol-induced contractions, implying involvement of endothelium-derived NO and prostaglandins. Pretreated with methylene blue could inhibit the relaxant effects of KMUP 880602 and KMUP 880708 in carbachol-induced contraction, implying the involvement of soluble guanylyl cyclase (sGC). Pretreated with ICI 118,551 could inhibit the relaxant effects of KMUP 880602 and KMUP 880708 in carbachol-induced contraction, implying the involvement of adrenerceptor b2 receptor. KMUP 880708 was found to constrict guinea-pig tracheal strips in a dose-dependent manner. The constriction of KMUP 880708 in tracheal strips was inhibited by pretreatment with capsazepine. The actions of KMUP 880602 and KMUP 880708 in tracheal strips pre-constricted by carbachol were more strength pre-constricted by high- and low-K+ solution. In thoracic aorta experiments, KMUP 880602 and KMUP 880708 competitively antagonized the norepinephrine-induced vasocontractions in concentration-dependent manner. The parallel shift to the right of the concentration-response curves of norepinephrine suggested that KMUP 880602 and KMUP 880708 were competitive a-adrenoceptor antagonist; the estimated pA2 values for KMUP 880602 and KMUP 880708 were 7.64 ± 0.18, 7.92 ± 0.52, respectively. In isolated rat thoracic aorta, KMUP 880602 and KMUP 880708 relaxed the phenylephrine-induced contractions more potently than high K+-induced contractions. The vasorelaxant effects of KMUP 880602 and KMUP 880708 on phenylephrine-induced contractions were attenuated by pretreated with TEA, glibenclamide, charybotoxin and apamin, implying the involvement of K+ channel opening. Besides, pretreated with L-NAME and indomethacin could inhibit the vasorelaxant effects of KMUP 880602 and KMUP 880708 in phenylephrine-induced contractions, implying involvement of endothelium-derived NO and prostaglandins. Pretreated with methylene blue could inhibit the relaxant effects of KMUP 880602 and KMUP 880708 in phenylephrine-induced contraction, implying the involvement of sGC. On the other hand, KMUP 880602 and KMUP 880708 inhibited phenypephrine-induced biphsic contraction; affected the fast twitch phase more significantly than the slow tonic phase. Furthermore, the binding characteristics of KMUP 880602 and KMUP 880708 were evaluated in [3H]CGP-12177 binding to rat ventricle and lung tissues and [3H]prazosin binding to brain membranes. The ranking orders of inhibition for [3H]CGP-12177 binding on b-adrenoceptor were propranolol >> labetalol > KMUP 880708 > KMUP 880602, and that for [3H]prazosin binding of a-adrenoceptor were KMUP 880708 > KMUP 880602 > labetalol. These results indicated that KMUP 880602 and KMUP 880708 are a/b-adrenoceptor antagonists with vasorelaxant and tracheal relaxant activities. KMUP 880602 and KMUP 880708-induced vasorelaxation and tracheal relaxation may involve with L-arginine NO、stimulation of sGC、arachidonic acid cyclooxygenase pathways and potassium channel opening.
|
|---|
