A highly selective beta1-adrenergic blocker with partial beta2-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.) produced dose-dependent bradycardia responses in pentobarbital-anesthetized Wistar rats, whereas it had no significant effects on the blood pressure. Ferulinolol markedly inhibited the tachycardia effects induced by (-)isoproterenol but did not show any blocking effect on the arterial pressor responses induced by (-)phenylephrine. These findings clearly suggested that ferulinolol had a beta-adrenergic blocking activity; nevertheless, it did not involve an alpha-adrenergic blocking action. In isolated guinea pig tissues, ferulinolol competitively antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that ferulinolol was a beta-adrenoceptor-competitive antagonist. The apparent pA2 values for ferulinolol on right atria, left atria, and trachea were 7.62 +/- 0.05, 7.54 +/- 0.01, and 6.28 +/- 0.11, respectively. Ferulinolol was more potent on the atria than on tracheal tissues, demonstrating that it possessed beta1-adrenoceptor selectivity. The intrinsic sympathomimetic activity (ISA) of ferulinolol and propranolol were determined on isolated atria and trachea from reserpine-treated guinea pig. Propranolol caused significantly negative inotropic and chronotropic effects at > or =1 microM, whereas ferulinolol possessed fewer cardiodepressant activities than propranolol. In reserpine-treated tracheal strips, ferulinolol produced dose-dependent relaxant responses, but propranolol was without effectiveness. Preincubating the preparations with ICI 118,551 (0.1, 1.0, and 10 nM), a beta2-adrenoceptor antagonist, significantly shifted the concentration-relaxation curves of ferulinolol to a region of higher concentrations. These results implied that ferulinolol had a partial beta2-agonist activity. Further, binding characteristics of ferulinolol and various beta-adrenoceptor antagonists were evaluated in [3H]CGP-12177 binding to rat ventricular or lung membranes. The Ki values of ferulinolol, 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 membranes. In conclusion, ferulinolol was found to be a highly selective beta1-adrenoceptor antagonist with partial beta2-agonist activity but was devoid of alpha-adrenoceptor blocking action.
Wu
B N
BN
Department of Pharmacology, Kaohsiung Medical College, Taiwan, Republic of China.
Huang
Y C
YC
Wu
H M
HM
Hong
S J
SJ
Chiang
L C
LC
Chen
I J
IJ
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D003373:Coumaric Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010946:Plants, Medicinal / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000959:Antihypertensive Agents; D003373:Coumaric Acids; D019275:Radiopharmaceuticals; C112517:ferulinolol; C004999:ferulic acid