Miguel-Martínez Alejandro D, Linares-Bedolla Juan, Villanueva-Castillo Belinda, Haanes Kristian A, MaassenVanDenBrink Antoinette, Villalón Carlos M
Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas Coapa, Deleg. Tlalpan, Ciudad de Mexico C.P. 14330, Mexico.
Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital-Rigshospitalet, Nordstjernevej 42, DK-2600 Glostrup, Denmark.
Pharmaceuticals (Basel). 2023 Mar 22;16(3):475. doi: 10.3390/ph16030475.
Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X receptors, and adenosine 5'-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPβS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPβS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T-T segment. This inhibition by ADPβS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y) or MRS2211 (3000 µg/kg; P2Y), but not by PSB0739 (300 µg/kg; P2Y), MRS2211 (1000 µg/kg; P2Y) or the K blocker glibenclamide (20 mg/kg). In set 2, ADPβS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPβS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K channels, involves P2Y and probably P2Y, but not P2Y receptors.
降钙素基因相关肽（CGRP）是一种从血管周围感觉神经释放的内源性神经肽，具有强大的血管舒张作用。有趣的是，三磷酸腺苷（ATP）通过激活突触前P2X受体刺激CGRP释放，而5'-O-2-硫代二磷酸腺苷（ADPβS），一种稳定的二磷酸腺苷（ADP）类似物，通过内皮P2Y受体产生血管舒张/血管减压反应。由于ADP在血管减压感觉CGRP能驱动的突触前调节中的作用以及相关受体尚不清楚，本研究调查了ADPβS是否抑制这种CGRP能驱动。因此，对132只雄性Wistar大鼠进行脊髓损毁，随后分为两组。在第一组中，ADPβS（5.6和10μg/kg·min）通过电刺激脊髓T-T节段抑制血管减压CGRP能反应。静脉注射嘌呤能拮抗剂MRS2500（300μg/kg；P2Y）或MRS2211（3000μg/kg；P2Y）后，ADPβS（5.6μg/kg·min）的这种抑制作用被逆转，但PSB0739（300μg/kg；P2Y）、MRS2211（1000μg/kg；P2Y）或钾通道阻滞剂格列本脲（20mg/kg）则不能逆转。在第二组中，ADPβS（5.6μg/kg·min）未能改变对外源性α-CGRP的血管减压反应。这些结果表明，ADPβS抑制血管周围感觉神经中CGRP的释放。这种抑制作用显然与ATP敏感性钾通道的激活无关，涉及P2Y，可能还有P2Y，但不涉及P2Y受体。
