EUGENOLOL - AN EUGENOL-DERIVED BETA-ADRENOCEPTOR BLOCK WITH PARTIAL BETA(2)-AGONIST AND CALCIUM MOBILIZATION INHIBITION ASSOCIATED VASORELAXANT ACTIVITIES

The beta-adrenoceptor blocking, vasorelaxant and hypotensive activitie s of eugenolol (1-(isopropylamino )-3-[(4-allyl-2-methoxy-) phenoxy]-2 -propanol) were investigated under in vivo and in vitro conditions. In pentobarbital anesthetized rats, eugenolol (0.1, 0.5, 1.0 mg/kg, i.v. ) produced a dose-dependent hypotensive and bradycardia response. Euge nolol also inhibited the tachycardia effects induced by (-)isoproteren ol, bur did not block arterial presser responses induced by phenylephr ine. In isolated guinea pig tissues, eugenolol competitively antagoniz ed the (-) isoproterenol-induced positive inotropic and chronotropic e ffects and tracheal relaxation responses. The apparent pA(2) values fo r eugenolol on right atria, left atria and trachea were 8.23 +/- 0.04, 8.36 +/- 0.13 and 8.18 +/- 0.12, respectively. On tracheal strips of reserpinized guinea pig, cumulative doses of eugenolol (10(-10)-10(-7) M) produced dose-dependent relaxant responses. Preincubating the prep aration with ICI 118,551 (10(-8), 10(-7), 10(-6) M) Shifted the eugeno lol concentration-relaxation curve significantly to a region of higher concentrations. Binding characteristics of eugenolol and propranolol were evaluated in [H-3]dihydroalprenolol, binding to pig ventricular m embranes. The K+ values of eugenolol and propranolol were 18.1 +/- 3.2 and 3.8 +/- 0.5 nM, respectively. In guinea pig isolated thoracic aor ta, eugenolol relaxed more potently the contractions induced by phenyl ephrine than those by high K+. The vasorelaxant effect of eugenolol on phenylephrine- or high K+-induced contraction was not attenuated by T EA or Bay K 8644 pretreatment. Furthermore, eugenolol pretreatment had a greater inhibitory effect on phenylephrine induced phasic contracti on than on tonic contraction. These results indicate that eugenolol ex hibits non-selective beta-blocking and vasorelaxant activity by inhibi ting Ca2+ channels, receptor-mediated Ca2+ mobilization and by its par tial beta(2)-agonist activity. Drug Dev. Res. 40:239-250, 1997. (C) 19 97 Wiley-Liss, Inc.