Effects of Paracetamol on NOS, COX, and CYP Activity and on Oxidative Stress in Healthy Male Subjects, Rat Hepatocytes, and Recombinant NOS
Figure 8
Simplified scheme showing the proposed contribution of three major enzymatic pathways to the vasoconstriction, vasodilatation, and aggregation in the vasculature without (a) and with (b) administration of paracetamol (acetaminophen) in health and disease. In platelets, arachidonic acid (AA) is converted by COX-1 to the vasoconstrictor and aggregator TxA2. In endothelial cells, AA is converted by COX-2 to PGI2, and L-Arg is oxidized by NOS to ∙NO; PGI2 and ∙NO are both vasodilatators and antiaggregators. AA is converted by CYP epoxygenases (CYP) to the vasodilatators epoxyeicosatrienoic acids (EETs). (a) In the absence of COX inhibitors including paracetamol and in health, production of TxA2, PGI2, ∙NO, and EETs guarantees a balance between vasoconstriction/aggregation and vasodilatation/antiaggregation. (b) Paracetamol and other COX inhibitors shift this balance in favour of COX-dependent vasoconstriction/aggregation. In response to this shift, ∙NO and EETs formation is increased in order to compensate the imbalance. In health, this compensation succeeds and blood pressure and platelet aggregation do not change. In endothelium dysfunction-related diseases, such as coronary artery disease (CAD), this compensation is insufficient and leads to moderate increase in blood pressure [9]. –, +, and ≈ mean inhibition, activation, and no remarkable change, respectively. The thickness of the arrows is quantitative but not true to scale measure of the contribution of the individual pathways and paracetamol.
