Mustafa F. Usta (1,2) , Muammer Kendirci (2) , Trinity J Bivalacqua (2) ,
description
Transcript of Mustafa F. Usta (1,2) , Muammer Kendirci (2) , Trinity J Bivalacqua (2) ,
DELAYED ADMINISTRATION OF ALT-711, BUT NOT OF AMINOGUANIDINE IMPROVES
ERECTILE FUNCTION IN STREPTOZOTOCIN DIABETIC RATS: CURATIVE VERSUS
PREVENTIVE MEDICINE
Mustafa F. Usta (1,2), Muammer Kendirci (2), Trinity J Bivalacqua (2),
Serap Gur (2), Neale A Foxwell (3), Wayne J.G. Hellstrom (2) , Selim Cellek (3)
Akdeniz University School of Medicine Department of Urology, Section of Andrology Antalya-TURKEY (1)
Tulane University, School of Medicine Department of Urology, Section of Andrology New Orleans, LA-USA (2)
Wolfson Institute for Biomedical Research University College, London-UK (3)
Common Conditions Associated with Erectile Dysfunction
Diabetes 40%
Vascular Disease30%
Spinal Cord Injury8%
Radical Surgery13%
Endocrine Disorders6%
MultipleSclerosis3%
Zonszein. Urol Clin North Am. 1995
Diabetes and Erectile Dysfunction
*Diabetes affects >15 million individuals in the USA, and prevalence of ED reported to be as high as 50 - 75%.
*Causative factors in diabetic ED are the reduction in NOS nerve fibers, disordered endothelial smooth muscle relaxation, and NO bio-availability.
*Animal models of diabetes exhibit ED with significant decreases in eNOS & nNOS protein and NOS-containing nerve fibers in the dorsal and intracavernosal nerves.
El Sakka AI et al., IJIR 1999Vernet D et al., Endocrinology 1995Akingba A & Burnett AL, Mol Urol 2001Bivalacqua TJ et al., BBRC 2001
*Possible relation between elevated levels of AGE in DM and ED
*AGEs are responsible for the impairment of NO-mediated corpus cavernosal smooth muscle relaxation in DM
*The protective effect of Aminoguanidine (selective AGE inhibitor) on erectile function in diabetic rats
Advanced Glycation End Products (AGE) and ED
Seftel A et al, Urology, 1997Cartledge JJ et al, BJU Int, 2001Usta et al, J Urol, 2003Usta et al, BJU Int 2004
*The result of nonenzymatic glycation of proteins commonly encountered in systemic disease (DM, CRF and ageing)
*The reaction occurs between reduced sugars (aldoses and ketoses) and free amino groups of proteins (Amodori product, Maillard reaction)
*One of the most important primer target for Maillard reaction are long lived proteins such:COLLAGEN, LAMININ
*AGEs decrease eNOS expression in the vascular endothelium, causing to decreased NO production
*After inducing diabetes in rats AGEs occur over a period of weeks (3-5 weeks)
What is AGE?
Singh R et al, Diabetologia 2001Vlasara H, Diabetes Metab Res Rev 2001Cellek S et al, Diabetes 2003
Diabetes mellitus
nNOS depletion
in the axons
AGEsaccumulation
Oxidative stress
Caspase-3 activation
Apoptotic cell death
Nitrergic degeneration
serum AGEs
Reversible phase Irreversible phase
NO
Mitochondrial dysfunction
Nitrergic dysfunction
Axonal transport
defect
PO
INT
OF
NO
RE
TU
RN
Cellek S et al., Diabetes 2003
1. Accumulation of AGEs has been linked to diabetes related ED. Inhibitors of AGEs such as AMG prevents ED in diabetic rats ( If administered immediately). We assessed the effect of late administered AMG on erectile function in diabetic rats.
2. Additionally, we investigated whether late administration of a cross-link breaker ALT-711 (alagebrium) can protect against the development of ED in a diabetic rat model.
SPECIFIC AIMS
Harlan Sprague-Dawley rats (18 to 20 weeks old) were divided into 4 groups:
Group-1: Control (n=10)
Group-2: STZ-diabetic rats (n=10) (Free access to water and standard diet)
Group-3: STZ-diabetic rats treated with ALT-711 (3mg/kg i.p. daily)* (n=12)
Group-4: STZ-diabetic rats treated with AMG (AMG added to drinking water 1g/l per day)* (n=11)
*ALT and AMG treatment started 6 weeks after DM induction
STUDY DESIGN
STUDY PROTOCOL
* Blood glucose level was assessed every two weeks throughout the study period (10mmol/l)
* Assessment of erection:Three months after induction of diabetes an in vivo erectile protocol (Intracavernosal pressure and total ICP measurements in response to cavernosal nerve stimulation) was employed
*AGE (serum):ELISA and fluorometry AGE ( penis): Immunofluorescence nNOS (penis): Western Blotting
RESULTS-1
RESULTS-2
RESULTS-3
RESULTS-4
RESULTS-5
RESULTS-6
* STZ induced diabetes caused ED in rats within 12 weeks. However ALT-711 treatment for the last 6 weeks improved erectile function in diabetic rats which was comparable to non-diabetic control group
* Treatment with AMG for the 6 weeks did not reverse erectile function
* ALT-711 treatment normalized the nNOS levels suggesting that AGEs might be interfering with the axonal transport of nNOS. Therefore our results may also suggest a new mechanism by which AGEs may have a detrimental effect on NO production in the autonomic nervous system
*The effect of ALT-711 on arterial compliance has been assessed in a human study. The results of that study clearly demonstrated that ALT-711 improved total arterial compliance in aged humans with vascular stiffness. ALT-711 may provide a novel therapeutic approach in endothelial dysfunction as well as ED, which are commonly seen with diabetes.
CONCLUSIONS