title: Platelet glycoprotein IIb/IIIa receptor inhibitor preserves coronary flow reserve during progressive coronary arteriostenosis in swine.
abstract: Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95+/-2% (ie, nearly complete coronary artery occlusion) at 15+/-4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor-treated groups, resting CBF had decreased by only 21+/-7% at 18+/-3 minutes, 15+/-3% at 18+/-5 minutes, and 15+/-7% at 21+/-4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor-treated group. At a comparable level of resting CBF ( approximately 15% below baseline), the RHR was reduced more in the control (-56+/-9%), heparin-treated (-49+/-9%), and aspirin-treated (-61+/-12) groups (P:<0.05) than in the GP IIb/IIIa inhibitor-treated group (-26+/-6%). When the resting CBF had decreased by approximately 35%, the RHR still was reduced significantly more (P<0.01) in the heparin-treated group (-64+/-9%) than in the GP IIb/IIIa inhibitor-treated group (-21+/-6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14+/-1 mm Hg from the arterial pressure, and the RHR was 20+/-6%. When the distal coronary perfusion pressure was reduced similarly (-14+/-1 mm Hg) in a separate group of GP IIb/IIIa inhibitor-treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130+/-16% (P<0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA. youtang_shen@merck.com
authors.forename: Y T
authors.initials: YT
authors.lastname: Shen
authors.forename: R T
authors.initials: RT
authors.lastname: Wiedmann
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: R J
authors.initials: RJ
authors.lastname: Gould
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000503:physiopathology* / Q000517:prevention & control; D006439:Hemodynamics; D006493:Heparin / Q000494:pharmacology; D023421:Models, Animal; D010477:Perfusion; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011312:Pressure; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001381:Azepines; C120272:L 739758; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D006493:Heparin; D001241:Aspirin