A HIGHLY SELECTIVE BETA(1)-ADRENERGIC BLOCKER WITH PARTIAL BETA(2)-AGONIST ACTIVITY DERIVED FROM FERULIC ACID, AN ACTIVE COMPONENT OF LIGUSTICUM-WALLICHII FRANCH

Short-term injection of ferulinolol (0.1, 0.5, and 1.0 mg/kg, i.v.) pr oduced dose-dependent bradycardia responses in pentobarbital-anestheti zed Wistar rats, whereas it had no significant effects on the: blood p ressure. Ferulinolol markedly inhibited the tachycardia effects induce d by (-)isoproterenol but did not show any blocking effect on the arte rial presser responses induced by (-)phenylephrine. These findings cle arly suggested that ferulinoIol had a beta-adrenergic blocking activit y; nevertheless, it did not involve an alpha-adrenergic blocking actio n. In isolated guinea pig tissues, ferulinolol competitively antagoniz ed (-)isoproterenol-induced positive inotropic and chronotropic effect s of the atria and tracheal relaxation responses. The parallel shift t o the right of the concentration-response curve of (-)isoproterenol su ggested that ferulinolol was a beta-adrenoceptor-competitive antagonis t. The apparent pA(2) Values for ferulinolol on right atria, left atri a, and trachea were 7.62 +/- 0.05, 7.54 +/- 0.01, and 6.28 +/- 0.11, r espectively. Ferulinolol was more potent on the atria than on tracheal tissues, demonstrating that it possessed beta(1)-adrenoceptor selecti vity. The intrinsic sympathomimetic activity (ISA) of ferulinolol and propranolol were determined on isolated atria and trachea from reserpi ne-treated guinea pig. Propranolol caused significantly negative inotr opic and chronotropic effects at greater than or equal to 1 mu M, wher eas ferulinolol possessed fewer cardiodepressant activities than propr anolol. In reserpine-treated tracheal strips, ferulinolol produced dos e-dependent relaxant responses, but propranolol was without effectiven ess . Preincubating the preparations with ICI 118,551 (0.1, 1.0, and 1 0 nM), a beta(2)-adrenoceptor antagonist, significantly shifted the co ncentration-relaxation curves of ferulinolol to a region of higher con centrations. These results implied that ferulinolol had a partial beta (2)-agonist activity. Further, binding characteristics of ferulinolol and various beta-adrenoceptor antagonists were evaluated in [H-3]CGP-1 2177 binding to rat ventricular or lung membranes. The Ki values of fe rulinolol atenolol, metoprolol, and (-)propranolol were 103, 262, 123, and 0.23 nM, respectively, in ventricular membranes, and 2,412, 7,539 , 2,186, and 0.72 nM, respectively, in lung membrane. In conclusion. f erulinolol was found to be a highly selective beta(1)-adrenoceptor ant agonist with partial beta(2)-agonist activity but was devoid of alpha- adrenoceptor blocking action.