Modulation of insulin-like growth factor-I system of the bladder using a somatostatin analogue in chronic spinalized rats.
OBJECTIVE
We have previously reported the possible role of the insulin-like growth factor-I (IGF-I) system of mitogens in the development of detrusor smooth muscle hyperplasia and hypertrophy after spinal cord injury. We evaluated the in vivo effects of the anti-growth factor somatostatin analogue octreotide on the IGF-I system as well as subsequent changes in bladder smooth muscle hypertrophy and function after spinal cord injury in rats.


METHODS
Included in this study were 90 adult female Sprague-Dawley rats weighing 200 to 250 gm. Of the rats 18 served as sham operated controls, while the remaining 72 underwent were spinal cord transection at the level of the T10 vertebra. The spinalized animals were randomly divided into 4 equal groups of 18, of which 1 group served as paraplegic controls. The other 3 groups received octreotide (60 microgram. daily for 4 weeks) delivered via a subcutaneously implanted osmotic pump immediately, 2 and 4 weeks after spinal cord injury. At the end of the experiment (6 to 8 weeks) each group of animals was subdivided into 2 subgroups of 9. In the first group filling cystometrography was done, while in the second subgroup wet bladder weight was estimated and Northern blot analysis was performed.


RESULTS
Mean wet bladder weight plus or minus standard deviation in sham operated and paraplegic controls was 0.11 +/- 0.01 and 0.64 +/- 0.33 gm., respectively (p <0.05). The increase in bladder weight in paraplegic controls was associated with over expression of the IGF-I gene and with marked suppression of IGF binding proteins-3 and 5 compared with sham operated controls. On the other hand, mean wet bladder weight in the animals that received octreotide immediately after spinal cord injury was 0.17 +/- 0.02 gm., which was associated with a dramatic decrease in IGF-I gene expression and increased expression of IGF binding proteins-3 and 5. Mean cystometric bladder capacity in paraplegic controls was 0.48 +/- 0.18 ml. with an associated voiding pressure of 71 +/- 13 cm. water. All paraplegic controls showed detrusor hyperreflexia. In animals that received octreotide immediately after spinal cord injury mean cystometric bladder capacity was 2.49 +/- 1.75 ml. with an associated voiding pressure of 32 +/- 7 cm. water. Detrusor hyperreflexia disappeared in 88.89% of the rats in this group. There were less marked changes in bladder weight (mean 0.24 and 0.29 +/- 0.3 gm.), IGF-I gene expression and its binding proteins and urodynamic parameters when the drug was given 2 and 4 weeks, respectively, after spinal cord injury.


CONCLUSIONS
Modulating the IGF-I system of mitogens in detrusor smooth muscle with consequently decreased bladder hypertrophy and improved urodynamic behavior in spinal cord injured animals using somatostatin analogue could be a possible therapeutic modality in patients with spinal cord injury.
Urology Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada.
A M
AM
Abdel-Karim
M
M
Abdel-Gawad
H
H
Huynh
M M
MM
Elhilali
D000818:Animals; D005260:Female; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D015282:Octreotide / Q000494:pharmacology*; D009929:Organ Size; D010264:Paraplegia / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014563:Urodynamics / Q000187:drug effects
D007334:Insulin-Like Growth Factor I; D015282:Octreotide