Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

Abstract

Abstract.We recently reported endothelium-dependent relaxation caused by nucleotides in the non-human primate cerebral artery. Here, we investigated the endothelium-dependent, nitric oxide-and prostanoid-independent relaxation induced by 2-methylthio-ADP (2MeSADP) in monkey cerebral artery. Mechanical responses of isolated monkey cerebral arteries to the agents were isometrically recorded. In endothelium-intact arterial strips treated with indomethacin plus N G -nitro-L-arginine and partially contracted with prostaglandin F 2α , 2MeSADP (1 nM -10 μM) induced concentration-dependent relaxation that was abolished by removal of endothelium but was not influenced by either carboxy PTIO or 18α-glycyrrhetinic acid. The 2MeSADP-induced relaxation was inhibited by MRS2179 and U73122. The relaxation was markedly suppressed by exposure of the strips to high K + media, but was not affected by glibenclamide. Combination of charybdotoxin plus apamin markedly suppressed the relaxation, whereas iberiotoxin partially attenuated it. Relaxation induced by 2MeSADP was inhibited by arachidonyl trifluoromethyl ketone, ketoconazole, and 14,15-epoxyeicosa-5(Z)-enoic acid. The inhibitors that affected the 2MeSADP-induced relaxation did not influence relaxation caused by sodium nitroprusside or forskolin. These findings indicate that 2MeSADP elicits 'endothelium-derived hyperpolarizing factor (EDHF)-type' relaxation via stimulation of endothelial P2Y 1 receptors in monkey cerebral artery. Furthermore, phospholipase A 2 , cytochrome P450-derived epoxyeicosatrienoic acids and Ca 2+-activated K + channels appear to be involved in the relaxation.

Purinergic Signaling and Blood Vessels in Health and Disease

“…EDHF, in addition to NO, mediates vasodilation of rat middle cerebral arteries via endothelial P2Y 2 receptors by opening an atypical calcium-activated K + channel (You et al, 1999b). In a more recent article (Geddawy et al, 2010), it was shown that 2-MeSADP elicited EDHFtype relaxation via stimulation of endothelial P2Y 1 receptors in monkey cerebral artery. In a comparative study of rat middle cerebral arteries, third-order branches, and penetrating arterioles, it was concluded that the role of NO in purinoceptor-evoked dilations diminishes along the cerebrovascular tree (artery to arterioles), whereas the role of EDHF becomes more prominent (You et al, 1999a).…”

14,15‐epoxyeicosatrienoic acid produced by cytochrome P450s enhances neurite outgrowth of PC12 and rat hippocampal neuronal cells

“…In this study, we detected 14,15‐EET‐ producing P450s (CYP2C11, 2C13, and 2C23) in PC12 cells, and their inhibitor, ketoconazole, abrogated NGF‐enhanced neurite outgrowth, suggesting the contribution of these P450s to neurogenesis. Ketoconazole also inhibit EET‐induced relaxation in monkey cerebral artery . Expression of CYP2C in rat brain has been shown in several reports .…”

Signaling pathways of ATP‐induced PGE2 release in spinal cord astrocytes are EGFR transactivation‐dependent

“…We show here that ATP could stimulate the transactivation of EGFR via P2Y1 receptor, and this pathway is Ca 21 dependent. ATP could stimulate the release of [Ca 21 ] i via P2Y1 receptor, and this result was also repeated by 2MeSADP, which may be a more stable and selective agonist for P2Y1 receptor (Geddawy et al, 2010). But McIlvain et al (2010) reported that 2MeSADP could also stimulate P2Y12 receptor in primary cultured microglia.…”

“…And some researches reported that the synthetic analogue 2-methylthio-ADP (2MeSADP) may be a more stable and selective agonist for P2Y1, which mimics the natural nucleotides Erlinge and Burnstock, 2008;Geddawy et al, 2010). P2Y2 receptor mediates UTP-evoked Ca 21 responses in spinal astrocytes .…”