Gintonin facilitates catecholamine secretion from the perfused adrenal medulla

The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M₁ receptor antagonist), Ki14625 (10 µM, an LPA₁/₃ receptor antagonist), amiloride (1 mM, an inhibitor of Na⁺/Ca²⁺ exchanger), a nicardipine (1 µM, a voltage-dependent Ca²⁺ channel blocker), TMB-8 (1 µM, an intracellular Ca²⁺ antagonist), and perfusion of Ca²⁺-free Krebs solution with 5mM EGTA (a Ca²⁺chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor). Interestingly, LPA (0.3~3 µM, an LPA receptor agonist) also dose-dependently enhanced the CA secretion from the adrenal medulla, but this facilitatory effect of LPA was greatly inhibited in the presence of Ki 14625 (10 µM). Moreover, acetylcholine (AC)-evoked CA secretion was greatly potentiated during the perfusion of gintonin (3 µg/ml). Taken together, these results demonstrate the first evidence that gintonin increases the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. This facilitatory effect of gintonin seems to be associated with activation of LPA- and cholinergic-receptors, which are relevant to the cytoplasmic Ca²⁺ increase by stimulation of the Ca²⁺ influx as well as by the inhibition of Ca²⁺ uptake into the cytoplasmic Ca²⁺ stores, without the increased nitric oxide (NO). Based on these results, it is thought that gintonin, one of ginseng components, can elevate the CA secretion from adrenal medulla by regulating the Ca²⁺ mobilization for exocytosis, suggesting facilitation of cardiovascular system. Also, these findings show that gintonin might be at least one of ginseng-induced hypertensive components.

Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of Ca(2+)-Activated Potassium Channel Currents

The calcium-activated K+ (BKCa) channel is one of the potassium-selective ion channels that are present in the nervous and vascular systems. Ca2+ is the main regulator of BKCa channel activation. The BKCa channel contains two high affinity Ca2+ binding sites, namely, regulators of K+ conductance, RCK1 and the Ca2+ bowl. Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is one of the neurolipids. LPA affects diverse cellular functions on many cell types through G protein-coupled LPA receptor subtypes. The activation of LPA receptors induces transient elevation of intracellular Ca2+ levels through diverse G proteins such as Galphaq/11, Galphai, Galpha12/13, and Galphas and the related signal transduction pathway. In the present study, we examined LPA effects on BKCa channel activity expressed in Xenopus oocytes, which are known to endogenously express the LPA receptor. Treatment with LPA induced a large outward current in a reversible and concentration-dependent manner. However, repeated treatment with LPA induced a rapid desensitization, and the LPA receptor antagonist Ki16425 blocked LPA action. LPA-mediated BKCa channel activation was also attenuated by the PLC inhibitor U-73122, IP3 inhibitor 2-APB, Ca2+ chelator BAPTA, or PKC inhibitor calphostin. In addition, mutations in RCK1 and RCK2 also attenuated LPA-mediated BKCa channel activation. The present study indicates that LPA-mediated activation of the BKCa channel is achieved through the PLC, IP3, Ca2+, and PKC pathway and that LPA-mediated activation of the BKCa channel could be one of the biological effects of LPA in the nervous and vascular systems.

Expression of endothelial differemtiation gene receptors in human pancreatic cancer / 中华胰腺病杂志

ObjectiveTo evaluate the expression of endothelial differentiation gene/lysophosphatidic acid (LPA) receptors (Edg/LPA) and its clinical significance in human pancreatic cancer.MethodsFifty cases of pancreatic cancer and adjacent normal tissues were collected,and Real-time PCR,Western blot and immunohistochemistry was used to determine the expression of Edg-2/LPA1,Edg-4/LPA2 and Edg-7/LPA3 receptors mRNA and protein,and its relationship with clinicopathological parameters was analyzed.Results The expressions of Edg-2/LPA1,Edg-4/LPA2,Edg-7/LPA3 receptor mRNA were (0.142 ± 0.042 ) ％,(0.471 ±0.064)％,(0.231 ±0.043)％ in pancreatic cancer,and the corresponding values were (0.132 ±0.029)％,(0.027 ±0.015)％,(0.163 ±0.046)％ in adjacent normal tissues.The expressions of Edg-4/LPA2 receptor mRNA in pancreatic cancer were significantly lower than that in adjacent normal tissues ( P ＜0.05 ).The expressions of Edg-4/LPA2 receptor protein in pancreatic cancer were significantly lower than that in adjacent normal tissues ( P ＜ 0.05 ).The expressions of three types of Edg /LPA receptor mRNA in pancreatic cancer were parallel to serum CA19-9 levels.The expressions of Edg-4/LPA2 receptor mRNA were associated with tumor size,differentiation degree,and invasive ability and metastasis.While the expressions of Edg-2/LPA1,Edg-7/LPA3 receptor mRNA was associated with invasive ability and metastasis only.ConclusionsEdg-4/LPA2 receptor is highly expressed in pancreatic cancer,which suggesting the malignant biological behavior of pancreatic cancer.