Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entry blocker,with ancillary β2‐agonist activity

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 K_i 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 K_i 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.