Effect of OKY-1581, a thromboxane synthetase inhibitor, on coronary thrombosis in the conscious dog

OKY-1581, a new thromboxane synthetase inhibitor, was studied in a conscious canine model of coronary thrombosis. After thoracotomy with placement of a left circumflex coronary artery flow probe and implantation of an electrode into the circumflex artery, animals were assigned randomly to the following groups: 0.9% NaCl vehicle control or OKY-1581 1 mg/kg every 4 h intravenously for 24 h. During the drug treatment period, a 50 [mu]A anodal current was passed through the circumflex electrode, and venous blood was obtained for platelet aggregation studies. As compared to control animals, the OKY-1581 treated animals developed a greater mean coronary flow at the end of the treatment period, smaller thrombi by wet weight, smaller infarcts, and fewer ventricular arrhythmias. Ex vivo platelet aggregation studies revealed significant inhibition of aggregation to standard aggregating agents for the drug treated group only. OKY-1581 is an effective antitbrombotic agent which maintains coronary flow after a thrombogenic stimulus, presumably via blockade of the synthesis of thromboxane by blood platelets.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24663/1/0000076.pd

The effect of diltiazem on coronary thrombosis in the conscious canine

The effect of diltiazem vs. saline was studied in a conscious canine model of coronary thrombosis. Diltiazem given as a 0.75 mg/kg loading dose intravenously followed by 0.4 mg/kg intravenously every 4 h for 24 h had no significant effect on thrombus wet weight, left ventricular infarct size, frequency of ventricular arrhythmias or ex vivo platelet aggregation. The search for antithrombotic agents using in vitro or ex vivo platelet aggregation studies should include concomitant in vivo thrombosis studies using therapeutic dosages of the drug in question.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24078/1/0000331.pd

Ibuprofen-mediated infarct size reduction: Effects on regional myocardial function in canine myocardial infarction

Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine model of myocardial infarction during 90 minute left circumflex coronary artery occlusion in 25 anesthetized dogs randomly assigned to intravenous ibuprofen infusion (n = 13, 5.36 mg/kg/h beginning 1 hour before occlusion) or vehicle solution as control (n = 12) and in 15 conscious, unsedated dogs 48 and 72 hours after 90 minute circumflex artery occlusion followed by reperfusion (ibuprofen, 5.36 mg/kg/h by intravenous infusion over 7 hours beginning 1 hour before occlusion, n = 7; or vehicle solution infusion as control, n = 8).Miniature subendocardial sonomicrometer crystal pairs were used to calculate left ventricular regional end-diastolic segment length, end-systolic segment length, and regional percent systolic shortening. Infarct size was estimated in 72 hour animals by a postmortem dual perfusion technique using triphenyltetrazolium histochemical dye and Evan's blue dye for determination of infarct area, risk area, and area not at risk. Ibuprofen treatment significantly reduced infarct size expressed as percent of risk area (mean +/- standard deviation of 44.6 +/- 18 versus 64.4 +/- 16% for control dogs, p Thus, ibuprofen does not improve normal, marginal, or ischemic zone regional myocardial function during acute ischemia or 48 or 72 hours after myocardial reperfusion despite a significant reduction of infarct size.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23860/1/0000099.pd

Electrical induction of coronary artery thrombosis in the ambulatory canine: A model for evaluation of anti-thrombotic agents

A simple technique for the reliable induction of coronary artery thrombosis in a conscious dog by delivery of low amperage electric current to the intimal surface of the artery is described. Ibuprofen, an agent known to inhibit platelet function and prostaglandin synthesis is evaluated in this model. Comparison of myocardial infarct size, thrombus weight, arrhythmia development and scanning electron micrographs of drug treated and control animals indicate that Ibuprofen is capable of protecting against the deleterious effects of coronary artery thrombosis produced by this technique. This method holds considerable potential as an in vivo model of coronary artery thrombosis and one in which evaluation of anti-thrombotic agents is possible.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23289/1/0000226.pd

The beneficial effects of nafazatrom (BAYg6575) on experimental coronary thrombosis

An in vivo model of coronary artery thrombosis in the conscious dog was used to evaluate the potential antithrombotic effect of nafazatrom (BAYg6575). A silver wire electrode was implanted in the left circumflex coronary artery (LCX) and was used at a later time to deliver a 50 uA anodal current for 24 hours to the intimal surface of the vessel. The resulting injury to the endothelium was accompanied by the adhesion, aggregation, and subsequent formation of an occlusive thrombus in the LCX of vehicle-treated dogs. Nafazatrom was given as an intravenous dose of 1 mg/kg for 48 hours, before anodal stimulation of the coronary artery was initiated, and was repeated every 6 hours during anodal stimulation for a total treatment period of 72 hours. As compared to vehicle-treated control dogs, the dogs treated with nafazatrom had smaller thrombi, preservation of coronary blood flow, a lesser degree of ischemic injury in the myocardial region subserved by the LCX, and less frequent premature ventricular complexes during the final 12 hours of the study period. Concomitant ex vivo platelet aggregation studies revealed significant inhibition of platelet aggregation in response to collagen and adenosine diphosphate in drug-treated dogs. The results of these investigations provide evidence that nafazatrom prevents in vivo development of occlusive coronary artery thrombi in response to disruption of the endothelial surface of the vessel.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24863/1/0000290.pd

The effect of dietary supplementation of fish oil on experimental myocardial infarction

The effect of altering the abundance of precursors and inhibitors of prostaglandin formation by dietary supplements of fish oil was investigated in dogs with experimentally induced myocardial infarction. Prior to induction, 10 male mongrel dogs were fed standard dog chow supplemented with 25% of the total calories as menhaden oil for 36 to 45 days. The fatty acid composition of the lipids in plasma and platelets changed to reflect the increased intake of polyunsaturated fatty acids of the n-3 type. Thrombosis and subsequent infarction was induced by electrical stimulation of the left circumflex coronary artery of ambulatory dogs that were monitored by telemetry. Upon stimulation of control animals, the frequency of ectopic beats rose from less than 10% at the beginning to about 80% after 19 hours. In contrast, the oil-fed dogs maintained a more normal ECG pattern, showing less than 30% ectopic beats after 19 hours. In these animals, the size of infarction (measured by formazan formation) was 3% of the left ventricle compared to 25% in the control animals. The results suggest that dietary supplementation with fish oil may be beneficial in reducing myocardial damage associated with coronary artery thrombosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23104/1/0000024.pd