Mechanisms Involved in the Antiplatelet Activity of Ketamine in Human Platelets

Abstract

The aim of this study was to systematically examine the inhibitory mechanisms of ketamine in platelet aggregation. In this study, ketamine concentration-dependently (100–350 µM) inhibited platelet aggregation both in washed human platelet suspensions and platelet-rich plasma stimulated by agonists. Ketamine inhibited phosphoinositide breakdown and intracellular Ca²⁺ mobilization in human platelets stimulated by collagen. Ketamine (200 and 350 µM) significantly inhibited thromboxane (Tx) A₂formation stimulated by collagen. Moreover, ketamine (200 and 350 µM) increased the fluorescence of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a platelet protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by phorbol-12,13-dibutyrate (100 nM). This phosphorylation was markedly inhibited by ketamine (350 µM). These results indicate that the antiplatelet activity of ketamine may be involved in the following pathways. Ketamine may change platelet membrane fluidity, with a resultant influence on activation of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and phosphorylation of P47, thereby leading to inhibition of intracellular Ca²⁺ mobilization and TxA₂ formation, ultimately resulting in inhibition of platelet aggregation.

Lack of inhibitory effect of acetylsalicylic acid and meloxicam on whole blood platelet aggregation in cats

“…Regardless, the anticipated effect of diazepam would be inhibition of platelet aggregation, which was not demonstrated in this study. This would also apply to the potential effect of ketamine, which may inhibit platelet aggregation in people, but which has shown no overall effect in aggregation parameters or bleeding times in pigs …”

Effects of intravenous anesthetics on the phosphorylation of cAMP response element‑binding protein in hippocampal slices of adult mice

“…These results suggest that PKC is responsible for the anesthetic-induced decrease in CREB phosphorylation at Ser133, while its activation had no effect. The phosphorylation of platelet protein P47, which is a marker of PKC activation, is markedly inhibited by ketamine (350 µM) or midazolam (15 and 30 µM) (29,30), and there is little direct evidence on the effect of intravenous anesthetics on PKC.…”

Cell Dehydration as a Mechanism of Ketamine Analgesic and Anesthetic Effects

“…Kinetic curve of dose-dependent [ 3 H]-ouabain binding with neuronal membrane functionally active proteins consisted of two saturated and one linear component. It turned out that only the last component of curve was connected with Na + /K + pump activity [21]. From this point of view in the last series of experiments the possible mechanism of ketamine anesthetic dose (0.125 mg/g) and influence on dose-dependent ouabain-induced cell hydration in brain tissues (cortex, subcortex, cerebellum) were studied for finding out whether this process is accompanied by corresponding change of membrane functionally active proteins' number.…”

“…The ketamine depressing effect on variety of receptors is well established: nicotinic [8,9], muscarinic [10] and opioid ones [10][11][12], as well as on voltage sensitive Na + [9,13], K + [13][14][15] and Ca 2+ channels [16] of nerve cell membrane in peripheral and central nervous system. At present it is known that ketamine influence is not limited only by nervous system but it has also relaxing effect on smooth and heart muscles [17][18][19][20] and other tissues [21]. However, the nature of cellular mechanism underlying in the ground of above mentioned multisided effects of ketamine on different tissues is not clear yet.…”