A Highly Selective β1-Adrenergic Blocker with Partial β2-Agonist Activity Derived from Ferulic Acid, an Active Component of Ligusticum wallichii Franch
| Autor: | Show-Jen Hong, Hsien-Ming Wu, Bin-Nan Wu, Ing-Jun Chen, Lien-Chai Chiang, Yeun-Chih Huang |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Chronotropic medicine.medical_specialty Coumaric Acids Blood Pressure Propranolol Pharmacology Binding Competitive Partial agonist Heart Rate Internal medicine medicine Animals Rats Wistar Adrenergic beta-2 Receptor Agonists Phenylephrine Antihypertensive Agents Metoprolol Plants Medicinal Dose-Response Relationship Drug Chemistry Antagonist Biological activity Atenolol Adrenergic beta-1 Receptor Antagonists Rats Endocrinology Radiopharmaceuticals Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology. 31:750-757 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/00005344-199805000-00014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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