UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA(1).
Environmental Science and Health Institute, Dublin Institute of Technology, Grangegorman, Dublin 7, Ireland.
Eur J Pharm Biopharm. 2018 Jul;128:179-187. doi: 10.1016/j.ejpb.2018.04.021. Epub 2018 Apr 20.
The tripeptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), inhibit angiotensin-converting enzyme (ACE) resulting in lowered blood pressure. Our hypothesis was that the medium chain fatty acid permeation enhancer, sodium caprate (C), may prevent the decrease in permeability of the tripeptides when PepT1 is inhibited by glycyl-sarcosine (Gly-Sar), a situation that may occur in the presence of food hydrolysates. Using Caco-2 monolayers and isolated rat jejunal tissue, the apparent permeability coefficients (P) of [H]-IPP and [H]-LKP were assessed in the presence of Gly-Sar with and without C. Gly-Sar decreased the P of both tripeptides across monolayers and isolated jejunal tissue, but C restored it. C likely increased the paracellular permeability of the tripeptides, as indicated by immunofluorescence changes in tight junction proteins in Caco-2 monolayers accompanied by a concentration-dependent decrease in transepithelial electrical resistance (TEER). [H]-IPP and [H]-LKP were orally-gavaged to normal rats with Gly-Sar, C, or with a mixture. Plasma levels of both peptides were reduced by Gly-Sar to less than half that of the levels detected in its absence, but were restored when C was co-administered. In spontaneously hypertensive rats (SHRs), unlabelled IPP and LKP lowered blood pressure when delivered either by i.v. or oral routes. Oral gavage of Gly-Sar reduced the hypotensive action of peptides in SHRs, but the effect was restored in the presence of C. In conclusion, there was a reduction in the hypotensive effects of IPP and LKP in SHRs when intestinal PepT1 was inhibited by Gly-Sar, but C may circumvent this by enhancing paracellular permeability.
三肽，异亮氨酸-脯氨酸-脯氨酸（IPP）和亮氨酸-赖氨酸-脯氨酸（LKP），抑制血管紧张素转化酶（ACE），导致血压降低。我们的假设是，中链脂肪酸渗透增强剂癸酸钠（C）可能会防止三肽的通透性在 PepT1 被甘氨酰-肌氨酸（Gly-Sar）抑制时降低，这种情况可能在存在食物水解物时发生。使用 Caco-2 单层和分离的大鼠空肠组织，在存在 Gly-Sar 时评估了[H]-IPP 和[H]-LKP 的表观渗透系数（P），并在有和没有 C 的情况下进行了评估。Gly-Sar 降低了这两种三肽在单层和分离的空肠组织中的 P，但 C 恢复了它。C 可能增加了三肽的细胞旁通透性，这表现为 Caco-2 单层中紧密连接蛋白的免疫荧光变化，并伴有跨上皮电阻（TEER）的浓度依赖性降低。[H]-IPP 和[H]-LKP 被灌胃给予正常大鼠，并用 Gly-Sar、C 或混合物处理。用 Gly-Sar 处理后，两种肽的血浆水平均降低至其不存在时检测到的水平的一半以下，但当同时给予 C 时则恢复。在自发性高血压大鼠（SHR）中，未标记的 IPP 和 LKP 经静脉或口服给药均可降低血压。口服给予 Gly-Sar 降低了 SHR 中肽的降压作用，但在存在 C 的情况下，这种作用得到恢复。总之，当肠道 PepT1 被 Gly-Sar 抑制时，IPP 和 LKP 的降压作用在 SHR 中降低，但 C 可能通过增强细胞旁通透性来规避这种作用。
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