In contrast, Mosseri et al. showed http://www.selleckchem.com/products/pazopanib.html that PK C might be a mediator of 5 FU induced vasoconstriction. PK C requires Ca2 and phospholipid for its activation. Di acylglycerol considerably Inhibitors,Modulators,Libraries increases the affinity of PK C for Ca2, and thereby fully activates PK C without a net increase in the Ca2 concentration. DAG is formed from phosphatidylinositol 4,5 bisphosphate cleavage, but neomycin, a competitive inhibitor of the phosphodiesterase that cleaves PIP2, did not alter the 5 FU induced vasoconstriction. That denotes that PK C might not be activated through cleavage of PIP2 and DAG formation, but rather through an unknown mechanism, or directly from 5 FU. Furthermore, there was no evidence for any modulation of 5 FU induced vasoconstriction by membrane receptor blockers or activators of the cyclooxy genase pathway.

Noteworthy is that no effect of the Ca2 antagonists, verapamil Inhibitors,Modulators,Libraries and diltiazem, which are often used to treat vasospasm, were seen. The Inhibitors,Modulators,Libraries high plasma levels of endothelin 1 observed by Thyss et al. in 5 FU treated patients, and especially in patients experiencing 5 FU induced cardiotoxicity, may support the hypothesis of 5 FU induced vasocon striction. Endothelin 1 is a potent vasoconstrictor pro duced by endothelial cells, cardiomyocytes and cardiac fibroblasts, but it is also produced in several noncar diac tissues such as the lungs. Endothelin 1 is known to have a regulatory role in coronary vascular resistance and myocardial capillary blood flow in cor onary artery diseases. Hypoxia, ischemia or shear stress are stimuli that induce the synthesis and secretion of endothelin 1 in vascular endothelial cells.

Endothelin 1 is synthesized from the precursor pep tide big endothelin. A trend towards increased big endothelin levels in the plasma of 5 FU treated patients was found by Salepci et al, but this trend was not confined to patients who developed vasoconstrictions. Inhibitors,Modulators,Libraries As endothelin 1 and some big endothelin 1 are secreted mainly towards the adjacent smooth muscle layer of blood vessel wall, only smaller amounts of the peptides reach the lumen of the vessel and contribute to the plasma levels. Hence, it is possible that the raised endothelin 1 in plasma may come from cellular sources other than the endothelial cells. To further elucidate the role of endothelins in 5 FU induced cardiotoxicity, the cellular source of endothelin 1 and the contribution of endothelin 1 to vasomotor tone during 5 FU infusion should be studied.

5 FU induced changes in rheological factors and cardiotoxicity Reversible transformation of RBCs into echinocytic shapes, increased membrane fluidity of RBCs Inhibitors,Modulators,Libraries and altered metabolism in terms of a rapid depletion of pO2, produc tion of 2,3 BPG and decreased ATP levels diminish the ability of RBCs to transfer oxygen to the heart. However, cisplatin BI 6727 induced almost similar changes in RBC morphology and membrane fluidity.