Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Microvasc Res. 2023 Jul;148:104516. doi: 10.1016/j.mvr.2023.104516. Epub 2023 Mar 6.
Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT-5-HT), with 5-HT predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca levels ([Ca]) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT is the predominant 5-HT receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca] and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.
5-羟色胺（5-HT；血清素）对微血管反应的控制较为复杂，可能取决于血管床类型和 5-HT 受体。5-HT 受体包括七个家族（5-HT1-5-HT7），其中 5-HT 主要介导肾血管收缩。环氧化酶（COX）和平滑肌细胞内 Ca 水平 ([Ca]) 已被认为与 5-HT 诱导的血管反应有关。尽管 5-HT 受体表达和循环 5-HT 水平已知依赖于出生后年龄，但 5-HT 对新生儿肾微血管功能的控制尚不清楚。在本研究中，我们证明 5-HT 可短暂刺激中国仓鼠卵巢细胞中瞬时表达的 TRPV4。5-HT 是新鲜分离的新生猪肾微血管平滑肌细胞（SMC）中主要的 5-HT 受体亚型。TRPV4 选择性阻断剂 HC-067047（HC）可减弱 SMC 中 5-HT 诱导的阳离子电流。HC 还抑制 5-HT 诱导的肾微血管 [Ca]增加和收缩。内肾动脉内输注 5-HT 对全身血液动力学几乎没有影响，但降低了猪的肾血流量（RBF）和增加了肾血管阻力（RVR）。肾小球滤过率（GFR）的经皮测量表明，5-HT 肾输注降低了 GFR。HC 和 5-HT 受体拮抗剂利坦色林减弱了 5-HT 对 RBF、RVR 和 GFR 的作用。此外，与对照组相比，5-HT 处理仔猪的血清和尿液 COX-1 和 COX-2 水平没有变化。这些数据表明，5-HT 通过激活肾微血管 SMC TRPV4 通道损害了新生猪的肾功能，而与 COX 产生无关。
