Isoeugenodilol: A vasorelaxant ?/?-adrenoceptor blocker with antioxidant activity

Autor: Young Tso Lin, Tzu Hsin Yang, Ing Jun Chen, Jwu-Lai Yeh, Jhy Chong Liang, Yeun Chih Huang, Yi Ching Lo, Jiunn Ren Wu
Rok vydání: 2000
Předmět:
Zdroj: Drug Development Research. 51:29-42
ISSN: 1098-2299
0272-4391
DOI: 10.1002/1098-2299(20000901)51:1<29::aid-ddr4>3.0.co;2-2
Popis: Isoeugenodilol, derived from isoeugenol, was investigated under in vivo and in vitro conditions. Isoeugenodilol (0.1, 0.5, 1.0, and 3.0 mg kg -1 , i.v.) produced dose-dependent hypotensive and brady-cardia responses in pentobarbital-anesthetized Wistar rats. Isoeugenodilol (0.5 mg kg -1 , i.v.) also markedly inhibited both the tachycardia effects induced by (-) isoproterenol and arterial pressor responses induced by phenylephrine. A single oral administration of isoeugenodilol at doses of 10, 30, and 100 mg kg -1 dose-dependently reduced blood pressure, with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, isoeugenodilol competitively antagonized the (-) isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-) isoproterenol suggested that isoeugenodilol was a β 1 /β 2 -adrenoceptor competitive antagonist. The apparent pA 2 values were 7.33 ± 0.12 in the right atria, 7.80 ± 0.09 in the left atria, and 7.26 ± 0.11 in the trachea, indicating that isoeugenodilol was a nonselective β-adrenoceptor blocker. In thoracic aorta experiments, isoeugenodilol also produced a competitive antagonism of norepinephrine-induced contraction with a pA 2 value of 7.47 ± 0.45, In isolated atria of reserpinized rats, cumulative additions of isoeugenodilol and propranolol produced significantly cardiodepressant responses at high concentrations (10 -5 M) and were without intrinsic sympathomimetic activity (ISA). In isolated rat thoracic aorta, isoeugenodilol more potently relaxed the contractions induced by norepinephrine (3 x 10 -6 M) than those by high K + (75 mM). The vasorelaxant effects of isoeugenodilol on norepinephrine-induced contractions were attenuated by pretreatment with tetraethylammonium (TEA) and glibenclamide, implying the involvement of K + channel opening. In addition, isoeugenodilol inhibited norepinephrine-induced biphasic contraction; it affected the fast phase significantly more than the slow phase. Furthermore, the binding characteristics of isoeugenodilol and various β-adrenoceptor antagonists were evaluated in [ 3 H]CGP-12177 binding to rat ventricle and lung tissues and [ 3 H]prazosin binding to brain membranes. The ranking order of inhibition for [ 3 H]CGP-12177 binding on β-adrenoceptor was propranolol > labetalol > isoeugenodilol, and that for [ 3 H]prazosin binding to α-adrenoceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibited lipid peroxidation induced by Fe 2+ and ascorbic acid with IC 50 of 0.74 ± 0.03 mM, indicating that it possesses the antioxidant activity inherent in isoeugenol. In conclusion, isoeugenodilol was found to be a new generation α/β-adrenoceptor antagonist with vasorelaxant activity by inhibiting Ca 2+ channel, receptor-mediated Ca 2+ mobilization and by K + channel opening, and to have additional potentially antioxidant effects.
Databáze: OpenAIRE
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