A novel orally active dopamine (DA) prodrug TA-870. IV. Renal vasodilatory and negative chronotropic effects in anesthetized dogs: influence of DA1 and DA2 dopamine receptor selective antagonists.
We investigated the involvement of the activations of dopamine (DA) receptors DA1 and DA2 in the effects of a novel DA prodrug TA-870 in anesthetized dogs and compared the effects with those of DA. Intravenous (i.v.) administration of TA-870 in anesthetized dogs produced a dose-dependent increase in free DA in blood and caused a decrease in renal vascular resistance (RVR) and an increase in renal blood flow (RBF). It also produced a bradycardia at high doses. In phenoxybenzamine-treated anesthetized dogs, the renal vasodilatory action of intrarenally administered TA-870 was less than or equal to that of i.v. TA-870, whereas that of intrarenally administered DA was greater than that of i.v. DA. The renal vasodilatory effects of TA-870 and DA were almost completely inhibited by the DA1 selective antagonist SCH-23390 but were not affected by the DA2 selective antagonist domperidone. In bilaterally vagotomized dogs, both TA-870 and DA at high doses partially reduced the positive chronotropic responses to the right postganglionic cardioaccelerator nerve stimulation; this effect was abolished after treatment with domperidone. In isolated guinea pig right atria, unchanged TA-870 and deethoxycarbonyl metabolite of TA-870, the intermediate from TA-870 to DA, did not affect the spontaneous atrial rate even at high concentrations, whereas DA produced a concentration-dependent increase in the rate. In addition, neither compound showed antagonistic action to the positive chronotropic effect of DA, which was competitively inhibited by propranolol. We conclude that the renal vasodilatory effect of TA-870 results simply from the activation of DA1 receptors by DA.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishiyama
S
S
Biological Research Laboratory, Tanabe Seiyaku Company, Saitama, Japan.
Yoshikawa
M
M
Yamaguchi
I
I
D000758:Anesthesia; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004285:Dogs; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018492:Dopamine Antagonists; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects*; D014665:Vasodilator Agents
D001552:Benzazepines; D018492:Dopamine Antagonists; D011355:Prodrugs; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014665:Vasodilator Agents; D004294:Domperidone; C052143:docarpamine; D004298:Dopamine