Investigation of the role of central cyclooxygenase and lipoxygenase pathways in cardiovascular effects of nesfatin-1

In this study, it was aimed to demonstrate the effects of exogenously intracerebroventricular (ICV) injected nesfatin-1 on cardiovascular parameters, and in this effect, the mediation of central cyclooxygenase (COX) thromboxane A2 (TXA2), prostaglandin (PG) E, D, F2α signaling pathways and lipoxygenase (LOX) pathway by using hemodynamic and microdialysis studies. The experiments were performed on male Sprague Dawley rats (n=91). All of the surgical operations were done under sevoflurane anaesthesia (%2-4 / %100 O2). Left femoral arteries of the rats were catheterized with PE 50 catheters containing heparinized saline (100U/ml heparin in 0.9% saline) to monitored cardiovascular parameters. Hand-made guide cannulas were fixed to the skulls of the rats according to the predetermined coordinates to inject the drugs ICV. The drugs were injected ICV by hand-made injection cannulas connected with Hamilton injectors inserted in the guide cannulas. Microdialysis probes were placed in posterior hypothalamus (PH) to determine extracellular total PG levels, and dialysate samples were collected from PH. In the first experimental group, it was investigated the effects of different doses of nesfatin-1 (100, 200 and 400 pmol) on the mean blood pressure and heart rate. Nesfatin-1, dose-dependently, caused pressor effects on the blood pressure, also bradycardic and tachycardic phases on the heart rate responses in the rats. On the second step of the experiment, it was revealed that 200 pmol dose of nesfatin-1 increased extracellular total PG levels in PH, in accordance with the results of the microdialysis study. To the determination of the central COX, TXA2, PGE, PGD, PGF2α and LOX mediation in nesfatin-1-induced cardiovascular effects, non-selective COX inhibitor ibuprofen (250 µg), TXA2 synthase inhibitor furegrelate (250 µg), PGE and PGD receptors antagonist AH6809 (10 µg), PGF2α receptor antagonist PGF2α dimethylamine (10 µg), non-selective LOX inhibitor NDGA (250 µg), in addition saline and DMSO (as control) pretreatments were administrated 5 min before nesfatin-1 (200 pmol) treatment, in the last experimental group. Ibuprofen completely, whereas furegrelate, AH6809, PGF2α dimethylamine and NDGA partially blocked nesfatin-1-induced cardiovascular effects. In conclusion, the data showed that ICV injected nesfatin-1 caused a rise in the blood pressure and cardiovascular responses including bradycardic/tachycardic phases because of an increase in extracellular total PG levels in PH, in normotensive rats. In the present study, it was also revealed that nesfatin-1-induced cardiovascular effects were mediated by COX enzyme pathway completely, TXA2, -PGE, -PGD and -PGF2α and also LOX enzyme pathway partially.