Beneficial effect of the novel thromboxane A2 receptor antagonist sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate on collagen-induced coronary ischemia in guinea-pigs.
The effect of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl) ethylidene]-6,11-dihydrodibenz[b,e] oxepine-2-carboxylate monohydrate, CAS 127166-41-0), a novel thromboxane A2 (TxA2) receptor antagonist, on collagen-induced coronary ischemia was studied in guinea-pigs. Under pentobarbital anaesthesia, intravenous injection (i.v.) of collagen (1 mg/kg) induced abnormal ECG changes such as ST-T changes, elevation of T-wave arrhythmia and cardiac arrest in severe cases. The changes of ECG (leads I, II and III) were recorded for 10 min following collagen injection. KW-3635 (25-50 mg/kg p.o.) remarkably improved the collagen-induced ischemic ECG changes. The effect of KW-3635 was more potent than those of daltroban, isbogrel and ticlopidine. Neither nifedipine nor propranolol had any effect. The plasma thromboxane B2 level in the KW-3635-treated animals was lower in comparison with those in both the control and daltroban-treated animals. These results suggest that TxA2 may play a role in this model of coronary ischemia and that KW-3635 is effective in the treatment of ischemic heart disease.
Kawakage
M
M
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Shirakura
S
S
Karasawa
A
A
Takeda
M
M
Miki
I
I
Ishii
A
A
Kubo
K
K
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001562:Benzimidazoles / Q000627:therapeutic use*; D001584:Benzoxepins / Q000627:therapeutic use*; D003094:Collagen; D003327:Coronary Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006323:Heart Arrest / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D009543:Nifedipine / Q000627:therapeutic use; D010648:Phenylacetates / Q000494:pharmacology; D011433:Propranolol / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000097:blood; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000627:therapeutic use
D001562:Benzimidazoles; D001584:Benzoxepins; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; D013449:Sulfonamides; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; D003094:Collagen; D011433:Propranolol; D009543:Nifedipine; D013988:Ticlopidine; C051762:daltroban; C065729:KW 3635