Effect of Chronic Administration of Denopamine (TA-064), a New Positive Inotropic Agent, on Cardiac Response of Rats to Denopamine

Abstract

Effects of chronic administration of denopamine on acute cardiovascular response to denopamine were studied in anesthetized rats. Effects of repeated treatment with isoproterenol was also investigated. The dose of denopamine to increase LV dp/dt _max by 50% of the control (ED50) was 0.77 mg/kg, p.o. Following chronic administration of denopamine once daily at 10 or 20 mg/kg, p.o., for 14 days, the effect of denopamine (i.v.) on LV dp/dt _max was similar to that in the control group. In the 40 mg/kg-group, however, the positive inotropic effect of denopamine (i.v.) was attenuated significantly at lower doses without a decrease in the maximal response and the ED50 was increased 1.8-fold. Chronic treatment with denopamine in the diet at 20 or 40 mg/kg/day for 14 days did not influence the response to the drug. By subcutaneous administration of 50 μg/kg isoproterenol, thrice daily for 3 days, the ED50 of isoproterenol (i.v.) for positive inotropy were increased 6.8-fold. In addition, the maximal response to isoproterenol was depressed to about 70% of that obtained in the control. In the preparation desensitized by isoproterenol (50 μg/kg), the inotropic response to denopamine was attenuated at lower doses, but the maximal response was not altered. In the groups desensitized by the two drugs, the positive chronotropic effect of the drugs (i.v.) tended to decrease and the effects on blood pressure was not changed. By Scatchard analysis, the specific ³H-dihydroalprenolol binding to the cardiac membranes (B_max) was reduced in the 40 mg/kg denopamine (p.o.) group as well as in the isoproterenol-treated groups. In the 10 mg/kg denopamine and 20 mg/kg denopamine groups, however, B_max was not changed. These results suggest that chronic administration of denopamine hardly results in desensitization of its positive inotropy at the effective doses.