Effect of thromboxane and serotonin receptor antagonists on intracoronary platelet deposition in dogs with experimentally stenosed coronary arteries.
We have reported previously that thromboxane A2 (TXA2) and serotonin (5-HT, 5-hydroxytryptamine) are important mediators of cyclic flow variations (CFVs) in a canine model of coronary artery stenosis and endothelial injury. The present study tested the hypothesis that a TXA2 receptor antagonist is more effective in reducing intracoronary platelet deposition at sites of endothelial injury and severe stenosis than a 5-HT2 receptor antagonist. CFVs developed after placing a plastic constrictor around the left anterior descending coronary artery (LAD) in 51 of 56 dogs. Autologous platelets labeled with 111In were injected in 48 animals. Ten control dogs (group 1A) were killed after CFVs were observed for 1 hour at the nadir of coronary blood flow. Five dogs (group 1B) did not develop CFVs after placement of the constrictor. CFVs were abolished with SQ 28668 (2.75 +/- 0.36 mg/kg, group 2) and SQ 29548 (0.45 +/- 0.1 mg/kg, group 3), two different TXA2 and PGH2 receptor antagonists, in eight of 10 and six of seven dogs, respectively. In eight of 10 dogs (group 4), CFVs were abolished with ketanserin (0.66 +/- 0.12 mg/kg), a 5-HT2 receptor antagonist. In group 2, 3, and 4 dogs, the respective drugs were given so that the minimal dose required to abolished CFVs was administered. In six of six dogs (group 5), a higher dose of ketanserin (i.e., 1.5 mg/kg) was used to abolish CFVs. At death, intracoronary platelet deposition was evaluated by calculating the LAD platelet accumulation ratio (111In activity in the LAD/111In activity in the circumflex coronary artery) in 43 dogs and, in 22 dogs, by microscopic examination of the LAD. A marked LAD platelet accumulation ratio was found in group 1A dogs at the stenotic site and in segments immediately distal to it. The LAD platelet accumulation ratio was significantly reduced by both the low and the high doses of ketanserin compared with group 1A dogs (p less than 0.001). However, the two TXA2 receptor antagonists further reduced the LAD platelet accumulation ratio compared with ketanserin-treated animals (p less than 0.01). Microscopic examination confirmed these findings. We conclude that SQ 28668 and SQ 29548, two different TXA2 receptor antagonists, reduce residual intracoronary platelet deposition associated with CFVs in this canine model more effectively than ketanserin, a 5-HT2 receptor antagonist.
Golino
P
P
Department of Internal Medicine, University of Texas Health Science Center, Dallas 75235-9047.
Buja
L M
LM
Ashton
J H
JH
Kulkarni
P
P
Taylor
A
A
Willerson
J T
JT
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003327:Coronary Disease / Q000473:pathology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology*; D004285:Dogs; D005231:Fatty Acids, Unsaturated; D005260:Female; D006439:Hemodynamics; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D010974:Platelet Aggregation; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013928:Thromboxane A2; C050448:SQ 28668; C045749:SQ 29548