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Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase β

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.

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References

  1. McMahon CG . Erectile dysfunction. Med J Aust 2000; 173: 492–497.

    CAS  PubMed  Google Scholar 

  2. Merrick GS et al. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53: 1112–1116.

    Article  CAS  Google Scholar 

  3. Porst H . IC351 (tadalafil, Cialis): update on clinical experience. Int J Impot Res 2002; 14: S57–S63.

    Article  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Goldstein I et al. Vardenafil, a new highly selective PDE5 inhibitor, improves erectile function in patients with diabetes mellitus. Diabetes 2001; 50: A114.

    Google Scholar 

  6. Krane RJ, Goldstein I, Saenz IdT . Impotence. N Engl J Med 1989; 321: 1648–1659.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. Hopfner RL, Gopalakrishnan V . Endothelin: emerging role in diabetic vascular complications. Diabetologia 1999; 42: 1383–1394.

    Article  CAS  Google Scholar 

  9. Yanagisawa M et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.

    Article  CAS  Google Scholar 

  10. Luscher TF, Barton M . Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000; 102: 2434–2440.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Google Scholar 

  13. Saenz IdT et al. Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H1078–H1085.

    Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Sakamoto A et al. Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem Biophys Res Commun 1991; 178: 656–663.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Sumner MJ et al. Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol 1992; 107: 858–860.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. Sullivan ME et al. Down-regulation of endothelin-B receptor sites in cavernosal tissue of hypercholesterolaemic rabbits. Br J Urol 1998; 81: 128–134.

    Article  CAS  Google Scholar 

  22. Sakurada S et al. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am J Phys 2001; 281: C571–C578.

    Article  CAS  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. Adelstein RS, Eisenberg E . Regulation and kinetics of the actin–myosin–ATP interaction. Annu Rev Biochem 1980; 49: 921–956.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. DiSanto ME et al. Expression of myosin isoforms in smooth muscle cells in the corpus cavernosum penis. Am J Physiol 1998; 275: C976–C987.

    Article  CAS  Google Scholar 

  30. Chang S et al. Expression of myosin light chain kinase and Rho-associated kinase in corpus cavernosum smooth muscle. Biophys J 2000; 78: 139.

    Article  CAS  Google Scholar 

  31. Olsen UB, Weis J . Rat gastric relaxation induced by stimulation of endothelin-1 selective receptors. Regul Pept 1992; 39: 113–119.

    Article  CAS  Google Scholar 

  32. Sarman B et al. Circulating plasma endothelin-1, plasma lipids and complications in Type 1 diabetes mellitus. Diabetes Nutr Metab 2000; 13: 142–148.

    CAS  PubMed  Google Scholar 

  33. Morganti A et al. Plasma endothelin levels: a meaningless number?. J Cardiovasc Pharmacol 2000; 35: S21–S23.

    Article  CAS  Google Scholar 

  34. Frelin C, Guedin D . Why are circulating concentrations of endothelin-1 so low? Cardiovasc Res 1994; 28: 1613–1622.

    Article  CAS  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. 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.

    CAS  Google Scholar 

  38. 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.

    Article  CAS  Google Scholar 

  39. Mills TM et al. Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation. J Appl Physiol 2001; 91: 1269–1273.

    Article  CAS  Google Scholar 

  40. Kimura K et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996; 273: 245–248.

    Article  CAS  Google Scholar 

  41. Amano M et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271: 20246–20249.

    Article  CAS  Google Scholar 

  42. Khan MA et al. Normal and pathological erectile function: the potential clinical role of endothelin-1 antagonists. Curr Drug Targets 2000; 1: 247–260.

    Article  CAS  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. Yang D et al. The role of endothelin antagonism for the preservation of erectile function in diabetic rats. J Urol 2001; 165: 230.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants DK55529 and DK55042 from the National Institutes of Health.

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Correspondence to M E DiSanto.

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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

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