Anpirtoline hydrochloride

Serotonin receptor 1B (5HTR1B) traditionally exhibits anti‐proliferative activity in osteoblasts. We examined the expression and function of 5HTR1B in the COS canine osteosarcoma cell line and normal canine osteoblasts. Equal levels of 5HTR1B gene and protein expression were found between normal and malignant osteoblasts. Treatment with serotonin enhanced viability of osteosarcoma cells but not normal osteoblasts. Challenge with the 5HTR1B agonist anpirtoline caused no change in cell viability. Rather incubation with the specific receptor antagonist SB224289 caused reduction in osteoblast viability, with this effect more substantial in osteosarcoma cells. Investigation of this inhibitory activity showed 5HTR1B antagonism induces apoptosis in malignant cells. Evaluation of phosphorylated levels of CREB and ERK, transcriptional regulators associated with serotonin receptor signalling in osteoblasts, revealed aberrant 5HTR1B signalling in COS. Our results confirm the presence of 5HTR1B in a canine osteosarcoma cell line and highlight this receptor as a possible novel therapeutic target.

Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine (10~100 µM) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine (30 µM), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-HT_2A receptor inhibitor, indicating that ketamine facilitated the activation of 5-HT_2A receptors. Anpirtoline and BW723C86, selective agonists of 5-HT_1B and 5-HT_2B receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-HT_2A receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-HT_2A receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine.