Endovanilloids are potential activators of the trigeminovascular nocisensor complex.

BACKGROUND: In the dura mater encephali a significant population of trigeminal afferents coexpress the nociceptive ion channel transient receptor potential vanilloid type 1 (TRPV1) receptor and calcitonin gene-related peptide (CGRP). Release of CGRP serves the central transmission of sensory information, initiates local tissue reactions and may also sensitize the nociceptive pathway. To reveal the possible activation of meningeal TRPV1 receptors by endogenously synthetized agonists, the effects of arachidonylethanolamide (anandamide) and N-arachidonoyl-dopamine (NADA) were studied on dural vascular reactions and meningeal CGRP release. METHODS: Changes in meningeal blood flow were measured with laser Doppler flowmetry in a rat open cranial window preparation following local dural applications of anandamide and NADA. The release of CGRP evoked by endovanilloids was measured with ELISA in an in vitro dura mater preparation. RESULTS: Topical application of NADA induced a significant dose-dependent increase in meningeal blood flow that was markedly inhibited by pretreatments with the TRPV1 antagonist capsazepine, the CGRP antagonist CGRP8-37, or by prior systemic capsaicin desensitization. Administration of anandamide resulted in minor increases in meningeal blood flow that was turned into vasoconstriction at the higher concentration. In the in vitro dura mater preparation NADA evoked a significant increase in CGRP release. Cannabinoid CB1 receptors of CGRP releasing nerve fibers seem to counteract the TRPV1 agonistic effect of anandamide in a dose-dependent fashion, a result which is confirmed by the facilitating effect of CB1 receptor inhibition on CGRP release and its reversing effect on the blood flow. CONCLUSIONS: The present findings demonstrate that endovanilloids are potential activators of meningeal TRPV1 receptors and, consequently the trigeminovascular nocisensor complex that may play a significant role in the pathophysiology of headaches. The results also suggest that prejunctional CB1 receptors may modulate meningeal vascular responses.

Enhanced methylglyoxal formation in the erythrocytes of hemodialyzed patients.

Methylglyoxal (MG) contributes significantly to the carbonyl stress in uremia; however, the reason for its increased concentration is not clear. Thus, the present study was aimed to investigate the formation and degradation of MG in the erythrocytes of hemodialyzed (HD) patients with end-stage renal disease. In 22 nondiabetic patients on long-term HD, erythrocyte MG and d-lactate levels, glyoxalase activities, and whole blood reduced glutathione content were determined. The data were compared with those from 22 healthy controls. Erythrocyte MG and d-lactate production were also investigated in vitro under normoglycemic (5 mmol/L) and hyperglycemic (50 mmol/L) conditions. The erythrocyte MG levels were elevated (P < .001) in the HD patients. The blood reduced glutathione content and glyoxalase I activity were similar to the control levels, but the glyoxalase II activity was significantly (P < .005) increased. In the normoglycemic in vitro model, production of both MG (P < .001) and d-lactate (P < .002) was significantly enhanced in the HD erythrocytes relative to the controls. During hyperglycemia, the MG formation and degradation rates were further increased (P < .001). The present study demonstrated an increased formation of MG in the erythrocytes of HD patients. This seemed to be related to a glucose metabolism disturbance of the cells. The degradation system of MG was also activated; still, it was not able to counteract the high rate of MG formation. The alterations and imbalance of these metabolic processes may contribute to the carbonyl overload and stress in the HD patients.