Stable pentadecapeptide therapy counteracts gentamicin-induced nephrotoxicity via nitric oxide-system modulation: evidence from a triple nitric oxide-agent approach in rats.

In rats, stable gastric pentadecapeptide (BPC 157) therapy may resolve severe gentamicin nephrotoxicity (100 mg/kg ip/daily through 8 days) and the nitric oxide (NO)-system relation. We applied BPC 157 (10 µg/kg, 10 ng/kg, in drinking water or daily intraperitoneally) along with a triple NO-agent approach. Triple NO-agent approach captures NO-system, as a whole, simultaneously the inhibition (N(G)-nitro-L-arginine methylester (L-NAME) 5 mg/kg ip/daily), the overstimulation (L-arginine, 100 mg/kg ip/daily), and the immobilization (L-NAME + L-arginine/daily). BPC 157 therapy counteracted gentamicin nephrotoxicity clinical presentation (i.e., close to normal), serum urea, and creatinine (i.e., values close to normal preserved), maintained diuresis (polyuria/oliguria completely avoided), and no renal mass increase. Finally, fully preserved normal tubular epithelium cells and nephron presentation were present in the microscopy. Counteracted were in kidney gentamicin-increased malondialdehyde (MDA)-levels, and gentamicin-decreased NO-, and superoxide dismutase (SOD)-levels. NO-agents exhibited the opposite (worsening/attenuation) relations: L-arginine (a further increase of urea and creatinine serum values, polyuria, oliguria) vs. L-NAME relations (decrease of the increased urea and creatinine serum values, delayed polyuria, avoided oliguria, less tubular necrosis). These opposite points, combined (L-NAME + L-arginine), resulted in even stronger lesions, and more pronounced oliguria occurred, indicating the annihilation of the beneficial effect of L-NAME when it was combined with L-arginine. BPC 157 regimens (peroral or intraperitoneal) overwhelmed these NO-agents' effects. Thereby, in general, a triple NO-agent approach can reveal all essential gentamicin points of the NO-system (attenuation (L-NAME)/worsening (L-arginine)), revealing the full spectrum of the NO-system functions. Combined with the BPC 157 application, the triple NO-agent approach shows BPC 157's full efficacy in maintaining and/or reestablishing NO-system effects and functions, and kidney integrity in the gentamicin-rats.