Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entry blocker, with ancillary ?2-agonist activity

Abstract

Intravenous injection of ferulidilol (0.5, 1.0, 1.5 mg kg−1) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. Ferulidilol competitively antagonized (-)isoprenaline-induced 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 β-adrenoceptor antagonist. The apparent pA2 values were 8.04 ± 0.09 for the right atria, 8.03 ± 0.15 for the left atria, and 7.51 ± 0.06 for the trachea, respectively. Ferulidilol was more potent than labetalol. In thoracic aorta experiments, ferulidilol also produced a competitive antagonism of norepinephrine- and CaCl2-induced contraction with pA2 and pKCa−1 values of 7.05 ± 0.03 and 6.04 ± 0.05, respectively. Ferulidilol produced cumulative relaxation responses on isolated tracheal strips from reserpine-treated guinea pigs. The effects were competitively antagonized by ICI 118,551 (10−8–10−6 M), a relatively selective β2-adrenoceptor antagonist. The results implied that ferulidilol had partial β2-agonist activity. In the radioligand binding assay, ferulidilol produced dose-dependent inhibition of [3H]CGP-12177 binding to rat ventricle and lung membranes with Ki values of 3.40 and 17.94 nM, respectively. In addition, ferulidilol also antagonized [3H]prazosin and [3H]nitrendipine binding to rat brain membrane with Ki values of 32.48 and 305.01 nM, respectively. These results further confirmed the α/β and calcium entry blocking activities of ferulidilol described in functional studies. Furthermore, ferulidilol (10−8–10−5 M] inhibited lipid peroxidation induced 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 α/β-adrenoceptor blocker with ancillary calcium entry blockade, partial β2-agonist activities and additional antioxidant effects. Drug Dev. Res. 47:77–89, 1999. © 1999 Wiley-Liss, Inc.