2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Myocardial-Infarction

Topics: Angina Pectoris; Aspirin; Coronary Disease; Epoprostenol; Humans; Hypertension; Methacrylates; Myocardial Infarction; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase; Thromboxanes; Urokinase-Type Plasminogen Activator

The effect of KW-3049, (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride on myocardial infarction in rats was examined, in comparison with some other drugs. Extension of myocardial infarction was assessed by separately determining the tissue creatine kinase (CK) activity of left ventricular free wall (LVFW) and that of interventricular septum. Loss of CK activity was limited to LVFW until 6 h after the ligation of the left main coronary artery, while 24 h after the ligation, it extended to the septum. Therefore, the effects of drugs were examined mainly in rats following 6 h of coronary artery ligation. Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.), given 1 h before coronary artery ligation, significantly reduced the loss of CK activity of LVFW by 45.3 and 39.7%, respectively. Also, posttreatment with KW-3049 at 30 micrograms/kg (i.p.), given 10 min after the ligation, significantly reduced the loss of CK activity by 30.6%. On the other hand, nifedipine (3, 10 mg/kg, p.o.), propranolol (100 mg/kg, p.o.), OKY-1581 (100 mg/kg, p.o.) and BM 13.177 (100 mg/kg, p.o.), each of which was given 1 h before coronary ligation, did not significantly reduce the loss of CK activity. Coronary artery ligation for 6 h significantly decreased the myocardial contents of adenosine triphosphate (ATP) and creatine phosphate (CP). Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.) reduced the decrease in ATP and CP. These results suggest that KW-3049 possesses a superior cardioprotective effect in comparison with the other drugs examined. The possible implications for the protection by KW-3049 are discussed.

Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Coronary Circulation; Creatine Kinase; Ligation; Male; Methacrylates; Myocardial Infarction; Myocardium; Nifedipine; Phosphates; Phosphocreatine; Propranolol; Rats; Rats, Inbred Strains; Sulfonamides

Serial changes in thromboxane B2, a stable catabolite of thromboxane A2, were measured by radioimmunoassay in peripheral plasma of 55 patients with acute myocardial infarction. Twenty two of 31 patients who were admitted within 6 hr after the onset of acute myocardial infarction, exhibited high thromboxane B2 levels (greater than 300 pg/ml plasma) during the first 24 hr, whereas thromboxane B2 levels of 9 patients never exceeded 300 pg/ml during that period. The former cases were associated with a higher frequency of transmural myocardial infarction, accompanying higher cumulative creatine kinase release (1173 +/- 134 mIU/ml, mean +/- SEM), as compared with the latter cases (393 +/- 104 mIU/ml, P less than 0.001). To evaluate the efficacy of selective thromboxane A2 blockade on diminution of propagating acute myocardial infarction, another group of patients (24 cases) showing transmural myocardial infarction were subjected to therapeutic examination employing OKY-1581, a potent thromboxane A2 synthetase inhibitor. Eleven randomly selected patients were treated with an infusion of OKY-1581 (initiated within 6 hr after onset, 2-3 micrograms/kg per min) for 48 hr, while 13 patient served as controls. The treated patients exhibited a precipitous decrease in thromboxane B2 levels, as compared with the controls, returning to the normal range within 12 hr. The creatine kinase release in the treated patients was markedly reduced (978 +/- 97 mIU/ml) as compared with that in the control patients (1295 +/- 95 mIU/ml, P less than 0.05). These results indicate that a marked increase in thromboxane B2 levels is seen during the early phase of transmural myocardial infarction, and that OKY-1581-induced reduction of thromboxane B2 levels is effective in diminishing creatine kinase release. We suggest that an excessive generation of thromboxane A2 is associated with the evolution of transmural myocardial infarction.

Topics: Acrylates; Creatine Kinase; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Prognosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: Adult; Angina, Unstable; Anticoagulants; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Perfusion; Stroke Volume; Thiophenes; Thromboxane A2; Thromboxane B2; Ticlopidine; Tomography, Emission-Computed; Urokinase-Type Plasminogen Activator

The in vivo effectiveness of the thromboxane synthetase inhibitor OKY-1581 was tested in normal and infarcted canine myocardium. A rapid in vitro assay was developed which permits an accurate assessment of the status of the tissue thromboxane synthetase at the time of sacrifice. Reperfused infarcts were created by two hours of coronary artery occlusion followed by release of occlusion and three days of recovery. OKY-1581 was infused at 100 micrograms/kg/min for 15 minutes, a dose previously found to cause an 85% inhibition of canine platelet thromboxane synthetase in vivo. The heart was rapidly excised and transmural tissue plugs of infarcted and normal areas were obtained. These were incubated for 5 minutes with prostaglandin endoperoxide (PGH2) in phosphate buffer. Thromboxane production was inhibited from 16 +/- 1 ng TxB2 per tissue plug to 5 +/- 1 in normal myocardium and from 27 +/- 5 to 6 +/- 1 in infarcted areas of myocardium. Control incubations showed no further inhibition with the in vitro addition of 20 micrograms/ml OKY-1581, confirming the completeness of in vivo inhibition. Thus significant inhibition of thromboxane synthetase by intravenous OKY-1581 occurs even in a reperfused zone of infarction.

Topics: Acrylates; Animals; Dogs; Male; Methacrylates; Myocardial Infarction; Oxidoreductases; Prostaglandins H; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Adult; Angina Pectoris; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Physical Exertion; Platelet Aggregation; Reference Values; Thromboxane B2; Thromboxane-A Synthase