Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase beta.
Corpus cavernosum smooth muscle (CCSM) from rabbits made diabetic for 6 months as a result of alloxan injection exhibited increased sensitivity (3vs 9 nM EC(50)) and generated 20-50% greater force to endothelin-1 (ET-1) compared to CCSM from normal rabbits. In contrast, the force produced by the CCSM in response to KCl and phenylephrine was not significantly altered in diabetic CCSM. The increased ET-1 sensitivity is associated with a two to three-fold upregulation of ET receptor A at both mRNA and protein levels in diabetic CCSM. ET-1-induced CCSM contraction is largely dependent upon Rho-kinase (ROK), since it is almost completely blocked by Y-27632 (a highly selective ROK inhibitor). Furthermore, expression of ROKbeta isoform is selectively upregulated in CCSM from diabetic rabbits. Thus, an increased CCSM tone, modulated by sensitization of the endothelin-mediated contractile pathway via ROK, may be a key component of the molecular mechanism of diabetes-induced erectile dysfunction.
Chang
S
S
Division of Urology, University of Pennsylvania, Philadelphia 19104, USA.
Hypolite
J A
JA
Changolkar
A
A
Wein
A J
AJ
Chacko
S
S
DiSanto
M E
ME
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D007172:Erectile Dysfunction / Q000378:metabolism* / Q000503:physiopathology; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000201:enzymology*; D010413:Penis / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019332:Endothelin-1; D047908:Intracellular Signaling Peptides and Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein