Comparison of cardiorenal and emetic effects of dopamine prodrugs docarpamine (TA-870) and levodopa in dogs.
Positive inotropic and renal vasodilatory effects of a novel dopamine prodrug, docarpamine, [N-(N-acetyl-L-methionyl)-3,4-bis(ethoxycarbonyl)dopamine; TA-870] and those of levodopa were compared in anesthetized dogs, and emetic effects of the two drugs were compared in conscious dogs. Intraduodenal administrations of docarpamine and levodopa at 20 mg/kg produced similar increases in cardiac contractility. The maximal increases in the left ventricular dP/dtmax after docarpamine and levodopa were 36.6 +/- 14.2 and 39.2 +/- 12.1%, respectively. The two drugs also produced similar decreases in renal vascular resistance (21.2 +/- 2.2 and 13.6 +/- 3.4%, respectively) and increases in renal blood flow (27.9 +/- 3.2 and 17.9 +/- 5.2%, respectively), however, the duration of renal vasodilation after docarpamine was longer than that of levodopa. Oral administration of the two drugs in conscious dogs produced vomiting. The ED50 value of the emetic effect for docarpamine was greater than 160 mg/kg, and that for levodopa was 11.0 mg/kg. The emesis was inhibited by pretreatment with a DA2 antagonist, domperidone. In conclusion, docarpamine and levodopa produced similar cardiorenal effects, but the emetic effect of docarpamine was much weaker than that of levodopa. Docarpamine can be used as a selective dopamine prodrug for the peripheral circulation.
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
S
S
Nishiyama
K
K
Kanno
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I
Yamaguchi
D000818:Animals; D004285:Dogs; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D004639:Emetics / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects; D017448:Receptors, Dopamine D2
D015259:Dopamine Agents; D004639:Emetics; D011355:Prodrugs; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D007980:Levodopa; C052143:docarpamine; D004298:Dopamine