Effects of Antiaggregant and Antiinflammatory Doses of Aspirin on Coronary Hemodynamics and Myocardial Reactive Hyperemia in Conscious Dogs

Abstract

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.

Investigation of mechanisms that mediate reactive hyperaemia in guinea‐pig hearts: role of KATP channels, adenosine, nitric oxide and prostaglandins

“…The mechanisms underlying reactive hyperaemia have been investigated in recent years, with evidence of a role for NO ( Pohl et al ., 1994 ; Gryglewski et al ., 1996 ; Gattullo et al ., 1999 ; Andrieu et al ., 1999 ), prostaglandins ( Messina et al ., 1977 ; Carlsson et al ., 1987 ; Woditsch & Shror, 1992 ; Engelke et al ., 1996 ), adenosine ( Saito et al ., 1981 ; Wei et al ., 1988 ; 1989 ), and K ATP channels ( Daut et al ., 1990 ; Aversano et al ., 1991 ; Lee et al ., 1992 ) mediated vasodilatation. Other studies have shown that K + ATP channels together with prostaglandins ( Viau et al ., 1997 ), adenosine ( Duncker et al ., 1995 ) and NO ( Shinoda et al ., 1997 ) are involved and all act together in mediating the response ( Shinoda et al ., 1997 ; Ishibashi et al ., 1998 ; Kingsbury et al ., 2000 ).…”

“…The mechanisms underlying reactive hyperaemia have been investigated in recent years, with evidence of a role for NO (Pohl et al, 1994;Gryglewski et al, 1996;Gattullo et al, 1999;Andrieu et al, 1999), prostaglandins (Messina et al, 1977;Carlsson et al, 1987;Woditsch & Shror, 1992;Engelke et al, 1996), adenosine (Saito et al, 1981;Wei et al, 1988;1989), and K ATP channels (Daut et al, 1990;Aversano et al, 1991; a b Figure 5 Peak reactive hyperaemic¯ow response (a) and¯ow debt repayment (b) in the presence and absence of glibenclamide. Glibenclamide had a large eect on the peak hyperaemic¯ow response (a).…”