Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia.
Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia.
Eur J Pharmacol. 2019 Oct 15;861:172593. doi: 10.1016/j.ejphar.2019.172593. Epub 2019 Aug 8.
We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 μg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.
我们专注于环磷酰胺诱导的出血性膀胱炎（100mg/kg/天，连续 3 天腹腔内给药）作为特定的一氧化氮系统紊乱，并探讨治疗的可能性。我们证明，它可以通过随后给予一氧化氮合酶底物 L-精氨酸（100mg/kg/天，腹腔内给药）来减轻，可以通过一氧化氮合酶抑制剂 L-NAME（5mg/kg/天，腹腔内给药）来加重，所有这些都受到稳定的胃十五肽 BPC 157（10μg/kg/天，10ng/kg/天，腹腔内或口服，在饮用水中）的影响。通常情况下，环磷酰胺剂量和时间依赖性地诱导严重的出血性膀胱炎病变，肉眼病变和相应的尿路上皮坏死、膀胱水肿、侵蚀、出血、炎症和溃疡，显微镜下观察。膀胱湿重显著增加。功能上，在第一次环磷酰胺给药后，漏点压力就会增加。直到第二次环磷酰胺给药，L-精氨酸一直减轻常规环磷酰胺诱导的严重出血性膀胱炎病变，无论是肉眼还是显微镜下，但没有功能上的改善。当与 L-精氨酸联合使用时，L-NAME 加重这些病变并消除了 L-精氨酸的有益作用。环磷酰胺给药后，无论剂量或方案如何，给予 BPC 157 均显著减轻所有环磷酰胺病变，肉眼和显微镜下。膀胱湿重的增加一直被减轻。功能上，漏点压力增加恢复到正常大鼠的水平。在单独或联合使用 L-NAME 或 L-精氨酸的大鼠中，也观察到了类似的发现。因此，基于 L-NAME 的给药以及 L-精氨酸的给药，以及它们的相互作用和 BPC 157 应用的拮抗作用，这些病变与一氧化氮有关。同样，我们揭示了新的治疗可能性，强调了稳定的胃十五肽 BPC 157 和 L-精氨酸，与接受环磷酰胺诱导膀胱炎的大鼠中的 L-NAME 相比。
