Modifications Produced by Indomethacin and <i>L</i>-NAME in the Effect of Ultralow-Dose Aspirin on Platelet Activity in Portal Hypertension

Abstract

In our previous study, we demonstrated the effect of ultralow-dose aspirin (ULDA) on platelet activity and bleeding in rats with portal hypertension (PHT) produced by portal vein ligation (PVL). This paper reports modifications in this effect caused by blocking NO production by nitro arginine methyl ester (NAME) and cyclooxygenase (COX) activity with indomethacin. PVL rats and sham-operated controls were treated with placebo, indomethacin or NAME and 30 min thereafter with placebo or ULDA treatment. Platelet activity was studied by a model of in vivo laser-induced thrombus production in the mesenteric circulation, induced hemorrhage time (IHT) and platelet aggregation ex vivo induced by adenosine diphosphate in an aggregometer. The PVL group receiving placebo showed a decreased platelet activity with prolonged IHT, an effect that was reversed by ULDA. Indomethacin induced a decreased platelet activity in the control rats and a prolonged IHT. In PHT with ULDA, in vivo platelet activity was enhanced but the normalization of IHT observed in rats without indomethacin was blunted. The addition of NAME normalized the diminished in vivo platelet aggregation and increased the IHT observed in PVL animals. These changes decreased the effect of ULDA in both sham-operated and PVL animals. The effect of indomethacin was more clearly modified by ULDA than the effect of NAME, thus suggesting that modifications in the COX pathway might alter the effect of ULDA. The simultaneous administration of indomethacin and ULDA could inhibit its beneficial effect on bleeding in rats with PHT.

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

“…The results found in this study corroborate the previously described effects of ULDA in portal hypertensive rats, normalizing number of emboli, duration of embolisation and the IHT [6,9] . In rats with portal hypertension, an increase in 6-keto PGF1α was observed, probably due to the known increased PGI2 production described for the mesenteric vascular bed in this animal model [3] .…”

“…Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] . Previous papers have shown the potentially beneficial effect of ULDA in portal hypertensive animals normalizing altered platelet activity and induced hemorrhagic time [6] . Further experiments were performed to clarify if this effect was mediated mostly by a cyclooxigenase (COX) pathway or by modifying NO synthesis, the two aspirin mechanisms of action [7] , although a previous study with a different model suggested that ULDA could decrease PGI2 synthesis [8] .…”

Confirmation of biological effects of high dilutions. Effects of submolecular concentrations of histamine and 1-, 3- and 4-methylhistamines on human basophil activation

“…Similar results have been obtained in other models, such as the effect of highly diluted aspirin on thrombus formation in laser irradiated rat capillaries [4].…”

Paradoxical Thrombotic Effects of Aspirin: Experimental Study on 1000 Animals

“…COX 1 and COX 2 simultaneous inhibition produced an antithrombotic effect similar to that observed after only COX 1 selective inhibition. With the same model, a previous study showed an antithrombotic effect with indomethacin, a non/selective COX inhibitor, similar to that observed with both selective inhibitors [22]. Similar antithrombotic results were also obtained in a different model by Hong T in their study of blood flow in canine coronary arteries.…”