Isoeugenodilol: A vasorelaxant α/β-adrenoceptor blocker with antioxidant activity

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 bradycardia 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 β₁/β₂-adrenoceptor competitive antagonist. The apparent pA₂ 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 pA₂ 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 [³H]CGP-12177 binding to rat ventricle and lung tissues and [³H]prazosin binding to brain membranes. The ranking order of inhibition for [₃H]CGP-12177 binding on β-adrenoceptor was propranolol > labetalol > isoeugenodilol, and that for [₃H]prazosin binding to α-adrenoceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibited lipid peroxidation induced by Fe²⁺ and ascorbic acid with IC₅₀ 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 Ca²⁺ channel, receptor-mediated Ca²⁺ mobilization and by K⁺ channel opening, and to have additional potentially antioxidant effects. (C) 2000 Wiley-Liss, Inc.