Effects of combined thromboxane synthetase inhibition/thromboxane receptor antagonism in two models of sudden cardiac death in the canine: limited role for thromboxane.
The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.
Kitzen
J M
JM
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
Chi
L G
LG
Uprichard
A C
AC
Lucchesi
B R
BR
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control; D003094:Collagen / Q000494:pharmacology; D003327:Coronary Disease / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D003645:Death, Sudden / Q000209:etiology; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000502:physiology; D017482:Receptors, Thromboxane; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000502:physiology*
D001095:Arachidonic Acids; D010421:Pentanoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D003094:Collagen; D013930:Thromboxane-A Synthase; C060219:ridogrel