Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential relevance to the pathogenesis of erectile dysfunction.
OBJECTIVE
Diabetes Mellitus (DM) is a major risk factor for erectile dysfunction in both patients and animal models. The pathogenesis of this dysfunction has not been fully elucidated. However, alterations in the synthesis of a number of vasoactive compounds, such as nitric oxide (NO) and prostacyclin (PGI2), have been reported in various diabetic tissues. The interaction between NO, PGI2 and endothelin-1 (ET-1), a powerful vasoconstrictor and smooth muscle cell mitogen, is thought to be important in maintaining vascular tone and the erectile process. We investigated the density and distribution of ET-1 and endothelin receptor subtypes in cavernosal tissue and assessed any changes brought about by DM in a rabbit model.


METHODS
DM was induced in New Zealand White rabbits using alloxan. Penises were excised from the diabetic rabbits three months (n = 6) and six months (n = 6) after the induction of DM. Low and high resolution autoradiography was performed using radioligands for ET-1, endothelin A (ETA) and endothelin B (ETB) receptors and were analyzed densitometrically. The results were compared with those from six age-matched healthy control rabbits for each group. Immunohistochemical localization of ET-1 immunoreactivity was also performed, together with ultrastructural evaluation of the corpus cavernosum.


RESULTS
ET-1, ETA and ETB receptor binding sites were primarily localized to the smooth muscle cells of the corpus cavernosum and the endothelium lining the cavernosal spaces. A significant increase in ETB receptor binding sites was found only in cavernosal tissue six months after induction of DM, when compared with age-matched healthy controls. These receptor changes were accompanied by ultrastructural changes in the corpus cavernosum indicative of an early, atherosclerosis-like process.


CONCLUSIONS
The autoradiographic and immunohistochemical findings in this study suggest that ET-1 may have a role in the pathophysiology of diabetic ED. This peptide may be released in an autocrine fashion causing cavernosal smooth muscle cell (CSMC) contraction and/or proliferation.
Sullivan
M E
ME
Department of Urology, Royal Free Hampstead NHS Trust and School of Medicine, London, United Kingdom.
Dashwood
M R
MR
Thompson
C S
CS
Muddle
J R
JR
Mikhailidis
D P
DP
Morgan
R J
RJ
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology*; D019332:Endothelin-1 / Q000032:analysis; D007172:Erectile Dysfunction / Q000209:etiology*; D007150:Immunohistochemistry; D008297:Male; D010413:Penis / Q000737:chemistry* / Q000648:ultrastructure; D011817:Rabbits; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000032:analysis* / Q000502:physiology
D001786:Blood Glucose; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D002784:Cholesterol