A novel, orally active dopamine prodrug TA-870. V. Natriuretic and positive inotropic effects in rats: an assessment after chronic administration.
We investigated the acute natriuretic and positive inotropic effects of the dopamine prodrug TA-870 in rats before and after repeated administration for 2 weeks. Single intraduodenal (i.d.) administration of TA-870 (10-250 mg/kg) to saline-loaded anesthetized rats produced a dose-dependent increase in urinary flow and sodium excretion. It also produced a decrease in renal vascular resistance and an increase in renal blood flow. In another series of normal anesthetized rats, TA-870 caused dose-dependent increases in cardiac contractility [left ventricular dP/dtmax (LV dP/dtmax)] at i.d. doses of 10-250 mg/kg. Although the heart rate was also increased, this effect was much smaller than the effect on LV dP/dtmax. SCH-23390 (0.3 mg/kg i.v.), a selective DA1 dopamine receptor antagonist, strongly inhibited the above diuretic, natriuretic, and renal vasodilatory effects of TA-870. The positive inotropic effect of TA-870 was not inhibited by SCH-23390, but the latter effect was inhibited by pretreatment with propranolol (0.5 mg/kg i.v.). After repeated oral administration of TA-870 to rats (250 mg/kg twice a day for greater than 2 weeks), there was no significant differences in the natriuretic and positive inotropic responses to TA-870 between the TA-870-pretreated and control groups indicating a lack of pharmacological tolerance. In conclusion, TA-870, when administered enterally to rats, produced the natriuretic effect via the DA1 dopamine receptor and positive inotropic effects via the beta 1 adrenergic receptor stimulation, and these effects were not attenuated by chronic treatment with TA-870.
Nishiyama
S
S
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Yamaguchi
I
I
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006321:Heart / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D011355:Prodrugs; C052143:docarpamine; D004298:Dopamine