Platelets, neutrophils, and vasoconstriction after arterial injury by angioplasty in pigs: effects of MK-886, a leukotriene biosynthesis inhibitor.
1 Leukotrienes constitute a class of potent bioactive mediators known to play a pivotal role in inflammation. Since their biosynthesis has been shown to be enhanced by platelet-neutrophil interactions, leukotrienes may be involved in these interactions and the arterial response to injury. Therefore, we investigated the effects of the selective leukotriene biosynthesis inhibitor 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (MK-886) on the acute thrombotic and vasomotor responses after arterial injury by angioplasty. 2 Carotid arterial injury was produced by balloon dilatation in control (molecusol vehicle; n=10) and treated (MK-886, 10 mg kg(-1), i.v.; n=9) pigs. The acute thrombotic reaction following deep arterial wall injury was quantified with 51Cr labelled platelets and 111In labelled neutrophils, and the vasomotor response was determined angiographically. 3 Platelet deposition at the site of deep arterial wall injury averaged 56.4+/-11.0x10(6) platelets cm(-2) in the control group, and was significantly reduced to 18.2+/-3.8x10(6) platelets cm(-2) (P<0.005) by treatment with MK-886. Neutrophil deposition was also decreased by MK-886, from 242.8+/-36.8 to 120.9+/-20.3x10(3) neutrophils cm(-2) (P<0.01). MK-886-treated animals had a significant decrease in the postangioplasty vasoconstrictive response at the site of endothelial injury distally, from 37.5+/-3.1% in the control group to 13.5+/-2.5% (P<0.001). 4 The effects of MK-886 were associated with a profound inhibition of ex vivo leukotriene B4 (LTB4) synthesis in blood stimulated by the calcium ionophore A23187 and a significant reduction of neutrophil aggregation in whole blood (P<0.01), whereas neutrophil superoxide anion production, serum thromboxane B2 and platelet aggregation in whole blood were not influenced. 5 The relevant effects of MK-886 are primarily related to inhibition of neutrophil function and suggest an important modulatory role for leukotrienes in the pathophysiological response associated with platelet and neutrophil interactions following arterial injury in vivo.
Provost
P
P
Laboratory of Experimental Pathology, Montreal Heart Institute and the University of Montreal, Quebec, Canada.
Borgeat
P
P
Merhi
Y
Y
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002339:Carotid Arteries / Q000378:metabolism; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects*; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D015289:Leukotrienes / Q000096:biosynthesis* / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood; D014661:Vasoconstriction / Q000502:physiology*; D002722:Chlorobenzenes
D007211:Indoles; D007975:Leukotriene B4; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013481:Superoxides; D013929:Thromboxane B2; C060893:MK-886; D002722:Chlorobenzenes