Effects of antiaggregant and antiinflammatory doses of aspirin on coronary hemodynamics and myocardial reactive hyperemia in conscious dogs.
Clinical studies have shown that low doses of aspirin (<300 mg/day) inhibit thromboxane A2 production and platelet aggregation but preserve prostacyclin synthesis. In contrast, high doses of aspirin (>1,000 mg/day) suppress the synthesis of both eicosanoids. Because the consequences of aspirin administration have never been investigated on coronary vasomotor tone in vivo, we investigated the effects of low and high doses of aspirin on systemic and coronary hemodynamics under basal conditions and after myocardial reactive hyperemia in conscious dogs. Dogs were instrumented with a Doppler flow probe and a hydraulic occluder. Coronary blood flow was measured in the conscious state at baseline and during myocardial reactive hyperemia after 10, 20, and 30 s of coronary occlusion. Thromboxane B2 serum concentrations, an index of platelet aggregation, decreased by >90% after long-term i.v. administration of aspirin, 100 mg/day for 7 days (low dose). Neither systemic and coronary hemodynamics nor reactive hyperemia were affected by the drug. After combined administration of this low dose of aspirin and of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NNA, 30 mg/kg/day/7 days), reactive hyperemia decreased to the same extent as when L-NNA was administered alone. After administration of a unique high-dose aspirin (1,000 mg, i.v.), myocardial reactive hyperemia was markedly reduced, and this effect was still observed after previous blockade of NOS and cyclooxygenase by L-NNA and diclofenac, respectively. Thus long-term treatment with a low antiaggregant dose of aspirin does not alter the ability of coronary vessels to dilate during myocardial reactive hyperemia in conscious dogs. In contrast, short-term administration of a high antiinflammatory dose of aspirin severely blunts myocardial reactive hyperemia through a mechanism that is independent of both cyclooxygenase and nitric oxide metabolic pathways.
Département de Pharmacologie, Faculté de Médecine Paris Sud, Le Kremlin Bicêtre, France.
S
S
Andrieu
M
M
Lebret
J
J
Maclouf
F
F
Bévérelli
J F
JF
Giudicelli
A
A
Berdeaux
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D003327:Coronary Disease; D003331:Coronary Vessels / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006940:Hyperemia / Q000473:pathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D020156:Salicylic Acid / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D019335:Nitroarginine; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D020156:Salicylic Acid; D001241:Aspirin; D001920:Bradykinin