Pharmacological and pharmacokinetic characteristics of YM435, a novel dopamine DA1-receptor agonist, in anaesthetized dogs.
Time-course of plasma concentration of unchanged drug of the dopamine DA1-receptor agonist (-)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4- tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs. Continuous intravenous infusion of YM435 (0.1-3 micrograms kg-1 min-1) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P < 0.0001) and between the former and the reduction in blood pressure (r = 0.93, P < 0.0001). The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.
Yatsu
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, Ibaraki, Japan. yatsu@yamanouchi.co.jp
Miyamoto
I
I
Kaneko-Takanuki
F
F
Watanabe
T
T
Takenaka
T
T
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D044005:Tetrahydroisoquinolines; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D007546:Isoquinolines; D017447:Receptors, Dopamine D1; D044005:Tetrahydroisoquinolines; D014665:Vasodilator Agents; C098593:dopamine D1A receptor; C073504:zelandopam