REPLY BY AUTHORS

134 ACTIVATION OF KALLIKREIN KININ SYSTEM IN INTERSTITIAL CYSTITIS 16. Clements, J. A,: The human kallikrein gene family: A diversity of expression and function. Mol. Cell. Endocr., 99: C1, 1994. 17. Hunt, S. C., Hasstedt, S. J., Wu, L. L. and Williams, R. R.: A gene-environment interaction between inferred kallikrein ge- notype and potassium. Hypertension, 22 161, 1993. 18. Berry, T. D., Hasstedt, S. J., Hunt, S. C., Wu, L. L., Smith, J. B., Ash, K. 0.. Kuida, H. and Williams, R. R.: A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension, 13 3, 1988. EDITORIAL COMMENT The authors investigated whether the kallikrein kinin system is activated in interstitial cystitis by measuring urinary levels of kinin peptides, active and total kallikrein and neutral endopeptidase. They compared these levels to a control group of women with stress in- continence and normal bladder function. They conclude that there is increased bradykinin formation and/or reduced kinin degradation in the bladder wall of subjects with interstitial cystitis, which may affect the pathogenesis of this condition. There are some questions with regard to the rather arbitrary methodology chosen by the investigators. It would seem that all patients have some degree of bladder distention, as they are asked to drink 500 to 1,000 ml. water immediately. Given the average voided volumes, they would all have at least a 100 cc distention from the outset. The bladder distention of 100 ml. is less than the normal voided volume for the majority of patients and controls, and is not truly distention. Perhaps distending to the same pressure or to 80% of the normal awake voided volume in each group would result in a more accurate reflection of the inflammatory mediator contribution of the bladder tissue. The experiment would then be repeated a h r distention with the subject under anesthesia in both groups to 80 cm, water pressure to confirm a difference between patients with interstitial cystitis and controls, and strengthen the conclusions. The important finding would be the level of inflammatory mediators in controls and normals at the usual voided bladder volumes. That information may be accurate for the interstitial cystitis group but it is not determined for the control group and is a potentially important distinction. Philip M. Hanno Division of Reproductiue & Urologic Drug Products Food and Drug Administration Rockville, Maryland REPLY BY AUTHORS We compared patients and controls using an identical protocol. Although 100 ml. water were minimal for bladder distention, the primary function was to flush the bladder as it was important to avoid distention sufficient to cause mucosal hemorrhage. Hemor- rhage would have resulted in activation of plasma kallikrein and caused an artifactual increase in urinary bradykinin peptide levels.

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134 ACTIVATION OF KALLIKREIN KININ SYSTEM IN INTERSTITIAL CYSTITIS

16. Clements, J. A,: The human kallikrein gene family: A diversity of expression and function. Mol. Cell. Endocr., 99: C1, 1994.

17. Hunt, S . C . , Hasstedt, S. J., Wu, L. L. and Williams, R. R.: A gene-environment interaction between inferred kallikrein ge- notype and potassium. Hypertension, 2 2 161, 1993.

18. Berry, T. D., Hasstedt, S. J., Hunt, S. C., Wu, L. L., Smith, J. B., Ash, K. 0.. Kuida, H. and Williams, R. R.: A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension, 1 3 3, 1988.

EDITORIAL COMMENT

The authors investigated whether the kallikrein kinin system is activated in interstitial cystitis by measuring urinary levels of kinin peptides, active and total kallikrein and neutral endopeptidase. They compared these levels to a control group of women with stress in- continence and normal bladder function. They conclude that there is increased bradykinin formation and/or reduced kinin degradation in the bladder wall of subjects with interstitial cystitis, which may affect the pathogenesis of this condition.

There are some questions with regard to the rather arbitrary methodology chosen by the investigators. It would seem that all patients have some degree of bladder distention, as they are asked to drink 500 to 1,000 ml. water immediately. Given the average voided volumes, they would all have a t least a 100 cc distention from the outset. The bladder distention of 100 ml. is less than the normal voided volume for the majority of patients and controls, and is not

truly distention. Perhaps distending to the same pressure or to 80% of the normal awake voided volume in each group would result in a more accurate reflection of the inflammatory mediator contribution of the bladder tissue. The experiment would then be repeated a h r distention with the subject under anesthesia in both groups to 80 cm, water pressure to confirm a difference between patients with interstitial cystitis and controls, and strengthen the conclusions. The important finding would be the level of inflammatory mediators in controls and normals at the usual voided bladder volumes. That information may be accurate for the interstitial cystitis group but it is not determined for the control group and is a potentially important distinction.

Philip M. Hanno Division of Reproductiue & Urologic Drug Products Food and Drug Administration Rockville, Maryland

REPLY BY AUTHORS

We compared patients and controls using an identical protocol. Although 100 ml. water were minimal for bladder distention, the primary function was to flush the bladder as i t was important to avoid distention sufficient to cause mucosal hemorrhage. Hemor- rhage would have resulted in activation of plasma kallikrein and caused an artifactual increase in urinary bradykinin peptide levels.