Purpose: In this prospective clinical study, we aimed to determine whether shockwave lithotripsy (SWL) has any specific effect on plasma as well as urinary nitrite, a stabile metabolite of nitric oxide (NO) and adrenomedullin (AM) concentrations, and to investigate whether these variables can be used as a marker for detecting shockwave-induced impairment of renal tubular and glomerular cells. Material and Methods: A total of 20 patients with renal pelvic or caliceal stones less than or equal to2 cm undergoing anesthesia-free SWL without auxiliary measures and a control group of ten patients without any urological symptoms were included in this study. The plasma and urinary concentrations of nitrite and AM were measured before, 24 h, and 7 days after SWL. Nitrite levels were measured by Griess reaction. Reverse-phase high-performance liquid chromatography (HPLC) was used to determine AM levels. Results: Application of high-energy shock waves (HESW) in our study caused a statistically significant increase in plasma levels of both NO and AM, which reflected an organized response of the kidney to this type of trauma in an attempt to maintain normal renal hemodynamics. Mean plasma nitrite concentration before SWL application was 29.9+/-7.6 mumol/l and this value was found to be 39.02+/-8.45 mumol/l at 24-h follow-up. Comparative evaluation of the plasma concentrations of AM revealed a significant increase at the 24-h examination: 20.51+/-3.0 pmol/ml and 32.54+/-4.3 pmol/l, respectively. On the other hand, comparative evaluation of urinary levels of both nitrite and AM levels before as well as 24 h after SWL application revealed a statistically significant increase related to markers. Conclusion: This first clinical study on plasma-urinary nitrite and AM levels in patients undergoing the SWL procedure indicated that plasma and urine levels of both peptides were increased. Our findings in turn suggested that SWL application to kidneycan stimulate the NO-cGMP signalling pathway to increase NO production in the kidney. Our findings also indicated that the increased levels of NO and AM secretion during renal parenchymal ischemia may be protective enough for renal pathological alterations resulting from SWL-induced renal trauma. We suggest that this increase may be a compensatory response to SWL induced injury.