A novel orally active dopamine prodrug TA-870. III. Positive inotropic effect and cardiorenal selectivity in anesthetized dogs.
The effect of TA-870, a novel dopamine prodrug, on the cardiovascular system was studied in anesthetized open- and closed-chest dogs. Intraduodenal administration of less than or equal to 12 mg/kg TA-870 to anesthetized dogs increased left ventricular (LV) dP/dtmax and dP/dt/Pmax. Furthermore, at a lower dose of TA-870 (2 mg/kg), renal vascular resistance (RVR) decreased and renal blood flow (RBF) increased. Similarly, total peripheral resistance (TPR) decreased and cardiac output (CO) increased at less than 4 mg/kg. In an intravenous cumulative dose-response study of TA-870, the plasma-free-dopamine concentration was elevated depending on the dose of TA-870. Renal vasodilation occurred at a low plasma-free-dopamine concentration, whereas a positive inotropic action required higher plasma-free-dopamine. However, the dose-response curve for LVdP/dt/Pmax was steeper than that for RBF or CO. Heart rate was less affected than LVdP/dt/Pmax in open-chest dogs and decreased in closed-chest dogs. Propranolol strongly inhibited the effect of TA-870 on LVdP/dt/Pmax. It also inhibited the effects of TA-870 on TPR and CO to a lesser extent, and the remaining effects were almost completely inhibited by an additional treatment with the dopamine blocker, RS-sulpiride. In conclusion, TA-870 increased myocardial contractility and output by the enteral route, and the latter effect was produced at lower doses with the help of peripheral vasodilation due to the activation of dopamine receptors.
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Japan.
S
S
Nishiyama
I
I
Yamaguchi
Y
Y
Akimoto
M
M
Yoshikawa
H
H
Nakajima
D000758:Anesthesia; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects*; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009928:Organ Specificity; D011355:Prodrugs; D011433:Propranolol / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013268:Stimulation, Chemical; D013469:Sulpiride / Q000494:pharmacology
D011355:Prodrugs; D013469:Sulpiride; D011433:Propranolol; C052143:docarpamine; D004298:Dopamine