Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entryblocker, with ancillary beta(2)-agonist activity

Intravenous injection of ferulidilol (0.5, 1.0, 1.5 mg kg(-1)) produced dos e-dependent hypotensive and bradycardia responses in pentobarbital-anesthet ized Wistar rats. Ferulidilol competitively antagonized (-)isoprenaline-ind uced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The parallel shift to the right of the concentration-response curve of (-)isoprenaline suggested that ferulidilol was a beta-adrenoceptor antagonist. The apparent pA(2) val ues were 8.04 +/- 0.09 for the right atria, 8.03 +/- 0.15 for the left atri a, and 7.51 +/- 0.06 for the trachea, respectively. Ferulidilol was more po tent than labetalol. In thoracic aorta experiments, ferulidilol also produc ed a competitive antagonism of norepinephrine- and CaCl2-induced contractio n with pA(2) and pKCa(-1) values of 7.05 +/- 0.03 and 6.04 +/- 0.05, respec tively. Ferulidilol produced cumulative relaxation responses on isolated tr acheal strips from reserpine-treated guinea pigs. The effects were competit ively antagonized by ICI 118,551 (10(-8)-10(-6) M), a relatively selective beta(2)-adrenoceptor antagonist. The results implied that ferulidilol had p artial beta(2)-agonist activity. In the radioligand binding assay, ferulidi lol produced dose-dependent inhibition of [H-3]CGP-12177 binding to rat ven tricle and lung membranes with K-i values of 3.40 and 17.94 nM, respectivel y. In addition, ferulidilol also antagonized [H-3]prazosin and [H-3]nitrend ipine binding to rat brain membrane with K-i values of 32.48 and 305.01 nM, respectively. These results further confirmed the alpha/beta and calcium e ntry blocking activities of ferulidilol described in functional studies. Fu rthermore, ferulidilol (10(-8)-10(-5) M] inhibited lipid peroxidation induc ed by Fe2+ and ascorbic acid, indicating that it possesses the antioxidant activity inherent in ferulic acid. Our results demonstrate that ferulidilol is a new generation alpha/beta-adrenoceptor blocker with ancillary calcium entry blockade, partial beta(2)-agonist activities and additional antioxid ant effects. Drug Dev. Res. 47:77-89, 1999. (C) 1999 Wiley-Liss, Inc.