Eugenodilol, derived from natural
eugenol, was first investigated with in vivo and in vitro models. In our in vivo study,
eugenodilol (0.5, 1.0, and 1.5 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardic responses in
pentobarbital-anesthetized Wistar rats.
Eugenodilol also inhibited the
tachycardia and arterial pressor effects induced by (-)
isoproterenol and
phenylephrine, respectively. In our in vitro study,
eugenodilol competitively antagonized (-)
isoproterenol-induced positive inotropic and chronotropic effects and tracheal-relaxation responses on isolated guinea pig tissues in a concentration-dependent manner. The apparent pA2 values were 7.88+/-0.12 for right atria, 7.52+/-0.05 for left atria, and 7.33+/-0.15 for trachea, indicating that
eugenodilol was a nonselective beta-
adrenoceptor blocker. In thoracic aorta experiments, the apparent pA2 values of alpha-
adrenoceptor blockade were 7.05+/-0.25 and 6.87+/-0.08 for
eugenodilol and
labetalol, respectively. In addition,
eugenodilol produced cumulative relaxation responses on isolated guinea pig tracheal strips. The effects were competitively antagonized by
ICI 118,551 (10(-8)-10(-6) M), a relatively selective beta2-adrenoceptor antagonist. In the radioligand-binding assay, the Ki values of [3H]
CGP-12177 binding to rat ventricle and lung membranes were 9.72 and 48.29 nM, respectively, and the value of [3H]
prazosin binding to rat brain membrane was 38.72 nM. These results further confirmed the alpha/beta-
adrenoceptors-blocking activities of
eugenodilol reported in the functional studies. We conclude that
eugenodilol is a novel third-generation beta-
adrenoceptor blocker with ancillary blocking activity at alpha-
adrenoceptors and weak
sympathomimetic activity at beta2-adrenoceptors.