Absence of exacerbation of myocardial stunning in anesthetized dogs treated with KAD-1229, a novel hypoglycemic agent.
The effect of (+)-momocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate]dihydrate (KAD-1229), a novel hypoglycemic agent with a chemical structure different from that of the sulfonylureas, on myocardial stunning was assessed in anesthetized dogs by comparison with that of glibenclamide, a sulfonylurea. Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery. In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [(3)H]glibenclamide binding to the myocardium, but KAD-1229 did not. These results suggest that the difference in binding properties of KAD-1229 and glibenclamide toward cardiac sulfonylurea receptors is one of the causes of their different effects on myocardial stunning. It is likely that KAD-1229 is highly specific for pancreatic sulfonylurea receptors and is speculated to be a safer hypoglycemic agent than, at least, glibenclamide.
Ichikawa
K
K
Pharmacology Research R&D, Kissei Pharmaceutical Co., Ltd., Hotaka, Nagano, Japan. kiyoshi_ichikawa@pharm.kissei.co.jp
Maruyama
K
K
Murakami
M
M
Tsuji
A
A
Yamato
T
T
Kusama
H
H
Kojima
M
M
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001667:Binding, Competitive; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000187:drug effects; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D007211:Indoles; D054833:Isoindoles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C087255:mitiglinide; D005905:Glyburide