Hemodynamic characterization of YM435, a novel dopamine DA1 receptor agonist, in anesthetized dogs.
The cardiovascular effects of YM435, a dopamine DA1 receptor agonist, were compared with those of dopamine in open-chest anesthetized dogs. Intravenous infusion of YM435 (0.1-3 microg/kg/min) increased renal blood flow and cardiac output and reduced renal vascular resistance and total peripheral vascular resistance, with a decrease in mean blood pressure, in a dose-dependent manner, with little change in heart rate. At 1 microg/kg/min i.v., renal blood flow increased by 20 +/- 7%, cardiac output increased by 14 +/- 6%, renal vascular resistance decreased by 22 +/- 4%, total peripheral vascular resistance decreased by 18 +/- 4%, and mean blood pressure decreased by 7 +/- 1%. The striking difference between the cardiovascular effects of YM435 and those of dopamine was that YM435 caused no vasoconstriction or increase in heart rate, even at high doses. The cardiovascular effects of YM435 (1 microg/kg/min i.v.) were almost completely inhibited by treatment with SCH 23390, a selective dopamine DA1 receptor antagonist. Furthermore, intravenous infusion of YM435 (0.1-3 microg/kg/min) dose-dependently reversed the increase in blood pressure and renal vascular resistance induced by angiotensin II or norepinephrine in closed-chest anesthetized dogs. Our results demonstrate that intravenous infusion of YM435 produces dose-dependent renal vasodilating and hypotensive effects by stimulation of dopamine DA1 receptors and suggest that YM435 may be useful for the parenteral treatment of acute elevation of blood pressure.
Yatsu
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company, Tsukuba, Ibaraki, Japan.
Takizawa
K
K
Kasai-Nakagawa
C
C
Uchida
W
W
Tanaka
A
A
Asano
M
M
Honda
K
K
Takenaka
T
T
D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004298:Dopamine / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012079:Renal Circulation / Q000187:drug effects; D044005:Tetrahydroisoquinolines; D014655:Vascular Resistance / Q000187:drug effects
D007546:Isoquinolines; D017447:Receptors, Dopamine D1; D044005:Tetrahydroisoquinolines; C098593:dopamine D1A receptor; D000804:Angiotensin II; C073504:zelandopam; D004298:Dopamine; D009638:Norepinephrine