Pharmacologic profiles of YM934, a novel potassium channel opener.
Pharmacologic profiles of YM934, a newly synthesized 1,4-benzoxazin derivative K channel opener were evaluated in in vitro and in vivo experiments. In isolated rat portal vein, YM934 and a benzopyran derivative K channel opener lemakalim inhibited the frequency of spontaneous rhythmic contractions concentration dependently, with IC50 values of 14 and 38 nM, respectively. These inhibitory effects were competitively antagonized by glibenclamide (an ATP-sensitive K channel blocker; 10(-7)-3 x 10(-6) M). In isolated rabbit aorta, YM934 (10(-8)-10(-6) M) and lemakalim (10(-8)-10(-6) M) relaxed the contractions induced by 20 mM KCl concentration dependently but were ineffective against the contractions induced by 50 mM KCl. YM934 (10(-8)-3 x 10(-6) M) and lemakalim (3 x 10(-8)-10(-5) M), but not the calcium antagonist nifedipine, relaxed the contractions induced by norepinephrine (NE 10(-6) M) or prostaglandin F2 alpha (PGF2 alpha 3 x 10(-6) M) in the aorta. In pentobarbital-anesthetized dogs, YM934 (1-10 micrograms/kg intravenously, i.v.) dose-dependently increased coronary artery blood flow (CBF), and decreased total peripheral resistance (TPR) and mean blood pressure (MBP). YM934 selectively increased CBF, but had little effect on vertebral, carotid, mesenteric, renal and femoral artery BF. These vasodilatory effects of YM934 were antagonized by glibenclamide. YM934 is a potent K channel opener and possesses potent vasodilatory effects, with particularly pronounced effects on the coronary artery. These effects of YM934 may, like lemakalim, be mediated by opening of ATP-sensitive K channels.
Uchida
W
W
Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research, Ibaraki, Japan.
Masuda
N
N
Taguchi
T
T
Shibasaki
K
K
Shirai
Y
Y
Asano
M
M
Matsumoto
Y
Y
Tsuzuki
R
R
Fujikura
T
T
Takenaka
T
T
D000758:Anesthesia; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D048588:Benzoxazines; D019806:Cromakalim; D003497:Cyclic N-Oxides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010078:Oxazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001578:Benzopyrans; D048588:Benzoxazines; D003497:Cyclic N-Oxides; D010078:Oxazines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D009543:Nifedipine; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide