Abstract
Corpus cavernosum smooth muscle (CCSM) from rabbits made diabetic for 6 months as a result of alloxan injection exhibited increased sensitivity (3vs 9 nM EC50) 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 ROKβ 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 8 print issues and online access
$259.00 per year
only $32.38 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McMahon CG . Erectile dysfunction. Med J Aust 2000; 173: 492–497.
Merrick GS et al. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53: 1112–1116.
Porst H . IC351 (tadalafil, Cialis): update on clinical experience. Int J Impot Res 2002; 14: S57–S63.
Porst H et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res 2001; 13: 192–199.
Goldstein I et al. Vardenafil, a new highly selective PDE5 inhibitor, improves erectile function in patients with diabetes mellitus. Diabetes 2001; 50: A114.
Krane RJ, Goldstein I, Saenz IdT . Impotence. N Engl J Med 1989; 321: 1648–1659.
Fedele D et al. Erectile dysfunction in type 1 and type 2 diabetics in Italy. On behalf of Gruppo Italiano Studio Deficit Erettile nei Diabetici. Int J Epidemiol 2000; 29: 524–531.
Hopfner RL, Gopalakrishnan V . Endothelin: emerging role in diabetic vascular complications. Diabetologia 1999; 42: 1383–1394.
Yanagisawa M et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.
Luscher TF, Barton M . Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000; 102: 2434–2440.
Firth JD, Ratcliffe PJ . Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest 1992; 90: 1023–1031.
Usuki S, Kondoh K, Kubo T . Plasma endothelin and LH-RH, LH, FSH, prolactin, progesterone, 17alpha-hydroxyprogesterone, estrone, 17beta-estradiol, delta4-androstenedione, testosterone, active renin, angiotensin-II and ANP levels in blood and LH, estrone and 17beta-estradiol and pregnanediol levels in urine of normal cycling women. J Cardiovasc Pharmacol 2000; 36: S21–S427.
Saenz IdT et al. Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H1078–H1085.
Christ GJ, Lerner SE, Kim DC, Melman A . Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips. J Urol 1995; 153: 1998–2003.
Sakamoto A et al. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun 1991; 178: 656–663.
Nakamuta M et al. Cloning and sequence analysis of a cDNA encoding human non-selective type of endothelin receptor. Biochem Biophys Res Commun 1991; 177: 34–39.
Matsuda H et al. Involvement of cyclo-oxygenase-generated vasodilating eicosanoid(s) in addition to nitric oxide in endothelin-1-induced endothelium-dependent vasorelaxation in guinea pig aorta. Heart Vessels 1993; 8: 121–127.
Sumner MJ et al. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol 1992; 107: 858–860.
Bell CR et al. The density and distribution of endothelin 1 and endothelin receptor subtypes in normal and diabetic rat corpus cavernosum. Br J Urol 1995; 76: 203–207.
Sullivan ME et al. Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential relevance to the pathogenesis of erectile dysfunction. J Urol 1997; 158: 1966–1972.
Sullivan ME et al. Down-regulation of endothelin-B receptor sites in cavernosal tissue of hypercholesterolaemic rabbits. Br J Urol 1998; 81: 128–134.
Sakurada S et al. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am J Phys 2001; 281: C571–C578.
Kawada N, Seki S, Kuroki T, Kaneda K . ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. Biochem Biophys Res Commun 1999; 266: 296–300.
Adelstein RS, Eisenberg E . Regulation and kinetics of the actin–myosin–ATP interaction. Annu Rev Biochem 1980; 49: 921–956.
Leung T, Chen XQ, Manser E, Lim L . The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 1996; 16: 5313–5327.
Matsui T et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996; 15: 2208–2216.
Chang S et al. Enhanced force generation by corpus cavernosum smooth muscle in rabbits with partial bladder outlet obstruction. J Urol 2002; 167: 2636–2644.
DiSanto ME, Cox RH, Wang Z, Chacko S . NH2-terminal-inserted myosin II heavy chain is expressed in smooth muscle of small muscular arteries. Am J Physiol 1997; 272: C1532–C1542.
DiSanto ME et al. Expression of myosin isoforms in smooth muscle cells in the corpus cavernosum penis. Am J Physiol 1998; 275: C976–C987.
Chang S et al. Expression of myosin light chain kinase and Rho-associated kinase in corpus cavernosum smooth muscle. Biophys J 2000; 78: 139.
Olsen UB, Weis J . Rat gastric relaxation induced by stimulation of endothelin-1 selective receptors. Regul Pept 1992; 39: 113–119.
Sarman B et al. Circulating plasma endothelin-1, plasma lipids and complications in Type 1 diabetes mellitus. Diabetes Nutr Metab 2000; 13: 142–148.
Morganti A et al. Plasma endothelin levels: a meaningless number?. J Cardiovasc Pharmacol 2000; 35: S21–S23.
Frelin C, Guedin D . Why are circulating concentrations of endothelin-1 so low? Cardiovasc Res 1994; 28: 1613–1622.
Mazzoni MR et al. Suc-[Glu9,Ala11,15]-endothelin-1 (8-21), IRL 1620, identifies two populations of ET(B) receptors in guinea-pig bronchus. Br J Pharmacol 1999; 127: 1406–1414.
Zuccarello M, Boccaletti R, Rapoport RM . Does blockade of endothelinB1-receptor activation increase endothelinB2/endothelinA receptor-mediated constriction in the rabbit basilar artery? J Cardiovasc Pharmacol 1999; 33: 679–684.
Shyamala V, Moulthrop TH, Stratton-Thomas J, Tekamp-Olson P . Two distinct human endothelin B receptors generated by alternative splicing from a single gene. Cellular Mol Biol Res 1994; 40: 285–296.
Nishiyama M et al. Pharmacological heterogeneity of both endothelin ETA- and ETB-receptors in the human saphenous vein. Jpn J Pharmacol 1995; 69: 391–398.
Mills TM et al. Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation. J Appl Physiol 2001; 91: 1269–1273.
Kimura K et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996; 273: 245–248.
Amano M et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271: 20246–20249.
Khan MA et al. Normal and pathological erectile function: the potential clinical role of endothelin-1 antagonists. Curr Drug Targets 2000; 1: 247–260.
Kim NN et al. Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction. J Androl 2002; 23: 76–83.
Yang D et al. The role of endothelin antagonism for the preservation of erectile function in diabetic rats. J Urol 2001; 165: 230.
Acknowledgements
This work was supported by Grants DK55529 and DK55042 from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chang, S., Hypolite, J., Changolkar, A. et al. Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase β. Int J Impot Res 15, 53–62 (2003). https://doi.org/10.1038/sj.ijir.3900947
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ijir.3900947
Keywords
This article is cited by
-
The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study
BMC Urology (2018)
-
Elevated plasma aldosterone is an independent risk factor for erectile dysfunction in men
World Journal of Urology (2016)
-
The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review
Journal of Inflammation (2015)
-
Possibility of inhibition of calcium-activated chloride channel rescuing erectile failures in diabetes
International Journal of Impotence Research (2014)
-
The use of PDE-5 Inhibitors in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia
Current Urology Reports (2013)