Isoeugenodilol: A vasorelaxant alpha/beta-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 pentoba rbital-anesthetized Wistar rats. Isoeugenodilol (0.5 mg kg(-1), i.v.) also markedly inhibited both the tachycardia effects induced by (-) isoprotereno l and arterial presser responses induced by phenylephrine. A single oral ad ministration of isoeugenodilol at doses of 10, 30, and 100 mg kg(-1) dose-d ependently reduced blood pressure, with a decrease in heart rate in conscio us spontaneously hypertensive rats (SHRs). In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, isoeugenodilol competit ively antagonized the (-) isoproterenol-induced positive chronotropic effec ts, inotropic effects, and tracheal relaxation effects in a concentration-d ependent manner. The parallel shift to the right of the concentration-respo nse curve of (-) isoproterenol suggested that isoeugenodilol was a beta (1) /beta (2)-adrenoceptor competitive antagonist. The apparent pA(2) values we re 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 nonselect ive beta -adrenoceptor blocker. In thoracic aorta experiments, isoeugenodil ol also produced a competitive antagonism of norepinephrine-induced contrac tion with a pA(2) value of 7.47 +/- 0.45. In isolated atria of reserpinized rats, cumulative additions of isoeugenodilol and propranolol produced sign ificantly cardiodepressant responses at high concentrations (10(-5) M) and were without intrinsic sympathomimetic activity (ISA). In isolated rat thor acic aorta, isoeugenodilol more potently relaxed the contractions induced b y norepinephrine (3 x 10(-6) M) than those by high K+ (75 mM). The vasorela xant 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, isoeugenodilo l inhibited norepinephrine-induced biphasic contraction; it affected the fa st phase significantly more than the slow phase. Furthermore, the binding c haracteristics of isoeugenodilol and various beta -adrenoceptor antagonists were evaluated in [H-3]CGP-12177 binding to rat ventricle and lung tissues and [H-3]prazosin binding to brain membranes. The ranking order of inhibit ion for [H-3]CGP-12177 binding on beta -adrenoceptor was propranolol > labe talol > isoeugenodilol, and that for [H-3]prazosin binding to alpha -adreno ceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibit ed 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 generati on alpha/beta -adrenoceptor antagonist with vasorelaxant activity by inhibi ting Ca2+ channel, receptor-mediated Ca2+ mobilization and by K+ channel op ening, and to have additional potentially antioxidant effects. Drug Dev. Re s. 51:29-42, 2000. (C) 2000 Wiley-Liss, Inc.