Platelet function thrombus formation Vessel tone blood pressure

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PG- endoperoxides

Inhibition

Figure 2.28 Arachidonic acid metabolism via COX-1 and COX-2 in the cardiovascular system. Note the possible exchange of PG-endoperoxide precursors between platelets, vessel wall, and inflammatory cells (for further explanation, see the text).

PGI2 PGE2

have a similar effect (Section 4.1.1). The clinical significance of an interaction between aspirin and reversible COX inhibitors is not proven. However, the possible interaction of aspirin with vascular PGI2 and platelet TXA2 is of considerable interest.

At this point, it should be noted that inhibition of PGI2 generation is not necessarily equivalent to inhibition of PGI2 function. PGI2 acts via specific G-protein-coupled receptors at the cell membrane that are subject to agonist-induced (down)regula-tion in number and affinity. Unfortunately, there are only very few studies addressing the issue in prostacyclin receptors. Bioassay data suggest that inhibition of tissue-derived prostaglandin synthesis is generally associated with an enhanced sensitivity ofthe target tissue. This has also been shown for inhibition of platelet aggregation by prostacy-clin after aspirin treatment [298]. The opposite is seen in situations ofextensive endogenous prosta-cyclin production, for example, ischemia-induced prostacyclin formation in acute myocardial infarction. This is associated with a marked reduction in prostacyclin receptor number and sensitivity [299, 300].

Aspirin and Other Endothelium-Derived Antiplatelet Factors Prostacyclin is not the only endothelium-derived product that inhibits platelet function. Two others are the endothelial cell ADPase (CD39)[301] and nitric oxide. Although the cleavage of ADP by the ADPase activity of the 5'-nucleotidase is not changed or only modestly reduced [302], the

Weksler and colleagues have studied the inhibition of vascular PGI2 in vessel segments ex vivo and platelet TXA2 formation in serum in patients with angiograph-ically documented coronary artery disease, undergoing elective aortocoronary bypass surgery.

Aspirin caused a dose-dependent inhibition of thromboxane formation in serum and PGI2 generation in specimens ofthe aorta and saphenous vein. A single dose of 325 mg completely prevented thromboxane generation but reduced PGI2 formation for significantly less amounts. No significant reduction of prostacyclin generation was seen at lower doses. There was no difference in perioperative blood loss at 325 mg aspirin as compared to untreated controls.

The conclusion was that low-dose aspirin can largely inhibit platelet aggregation and thromboxane formation but is much less effective on vascular prostacyclin production in arterial and venous endothelium in these patients (Figure 2.29) [296, 297].

Aspirin (mg) Aspirin (mg) Aspirin (mg)

Aspirin (mg) Aspirin (mg) Aspirin (mg)

Figure 2.29 Dose-dependent inhibition of thromboxane and PGI2 formation in serum and vessel specimens of patients with ischemic heart disease undergoing elective aortocoronary bypass surgery. All patients received single-dose aspirin at the dose indicated. There was no significant inhibition of PGI2 formation by up to 80 mg aspirin and only about 75% reduction at 325 mg but a nearly complete prevention of thromboxane formation at these doses (modified after [296]).

endothelial generation and action of NO might be significantly enhanced by aspirin. Taubert et al. [188] have shown that aspirin acetylates eNOS protein, an effect independent of COX inhibition or inhibition of superoxide-mediated NO degradation (Section 2.2.2). Aspirin treatment of patients at advanced stages of atherosclerosis or hypercholes-terolemia improves the reduced endothelium-

dependent relaxation. No such effect was seen in healthy subjects [303, 304] (Figure 2.30).

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