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Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition

International Journal of Impotence Research volume 18, pages 258–263 (2006)Cite this article

Abstract

Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum nitrergic nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.

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Abbreviations

ERK:

extracellular signal-regulated kinase

JNK:

c-Jun NH2-terminal kinase

MAPK:

mitogen-activated protein kinase

NANC:

nonadrenergic, noncholinergic

References

  1. Cameron NE, Eaton SEM, Cotter MA, Tesfaye S . Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44: 1973–1988.

    Article  CAS  Google Scholar 

  2. Evans JL, Goldfine ID, Maddux BA, Grodsky GM . Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002; 23: 599–622.

    Article  CAS  Google Scholar 

  3. Purves T, Middlemas A, Agthong S, Jude EB, Boulton AJM, Fernyhough P et al. A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J 2001; 15: 2508–2514.

    Article  CAS  Google Scholar 

  4. Giuliano F, Rampin O . Neural control of erection. Physiol Behav 2004; 83: 189–201.

    Article  CAS  Google Scholar 

  5. Azadzoi KM, de Tejada IS . Diabetes mellitus impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1992; 148: 1587–1591.

    Article  CAS  Google Scholar 

  6. Gocmen C, Secilmis A, Kumcu EK, Ertug PU, Onder S, Dikmen A et al. Effects of vitamin E and sodium selenate on neurogenic and endothelial relaxation of corpus cavernosum in the diabetic mouse. Eur J Pharmacol 2000; 398: 93–98.

    Article  CAS  Google Scholar 

  7. Nangle MR, Cotter MA, Cameron NE . Effects of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice: relationship to cholesterol biosynthesis pathway inhibition and lipid lowering. Diabetes 2003; 52: 2396–2402.

    Article  CAS  Google Scholar 

  8. de Tejada IS, Goldstein I, Azadzoi KM, Krane RJ, Cohen RA . Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025–1030.

    Article  Google Scholar 

  9. Price SA, Agthong S, Middlemas AB, Tomlinson DR . Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase. Diabetes 2004; 53: 1851–1856.

    Article  CAS  Google Scholar 

  10. Sweitzer SM, Medicherla S, Almirez R, Dugar S, Chakravarty S, Shumilla JA et al. Antinociceptive action of a p38α MAPK inhibitor, SD-282, in a diabetic neuropathy model. Pain 2004; 109: 409–419.

    Article  CAS  Google Scholar 

  11. McGinn S, Saad S, Poronnik P, Pollock CA . High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase. Am J Physiol 2003; 285: E708–E717.

    CAS  Google Scholar 

  12. Azuma N, Akasaka N, Kito H, Ikeda M, Gahtan V, Sasajima T et al. Role of p38 MAP kinase in endothelial cell alignment induced by fluid shear stress. Am J Physiol 2001; 280: H189–H197.

    CAS  Google Scholar 

  13. De Dios A, Shih C, Lopez de Uralde B, Sanchez C, del Prado M, Martin Cabrejas LM et al. Design of potent and selective 2-aminobenzimidazole-based p38α MAP kinase inhibitors with excellent in vivo efficacy. J Med Chem 2005; 48: 2270–2273.

    Article  CAS  Google Scholar 

  14. Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S et al. Amelioration of accelerated diabetic mesangila expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 2000; 14: 439–447.

    Article  CAS  Google Scholar 

  15. Nangle MR, Cotter MA, Cameron NE . Protein kinase C beta inhibition and aorta and corpus cavernosum function in streptozotocin-diabetic mice. Eur J Pharmacol 2003; 475: 99–106.

    Article  CAS  Google Scholar 

  16. Johnstone MT, Creager BSN, Scales KM, Cusco JA, Lee BK, Creager MA . Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88: 2510–2516.

    Article  CAS  Google Scholar 

  17. McVeigh SE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 771–776.

    CAS  Google Scholar 

  18. Keegan A, Cotter MA, Cameron NE . Effects of diabetes and treatment with the antioxidant, α-lipoic acid, on endothelial and neurogenic functions of corpus cavernosum in rats. Diabetologia 1999; 42: 343–350.

    Article  CAS  Google Scholar 

  19. Nangle MR, Cotter MA, Cameron NE . Effects of the peroxynitrite decomposition catalyst, FeTMPyP, on function of corpus cavernosum from diabetic mice. Eur J Pharmacol 2004; 502: 143–148.

    Article  CAS  Google Scholar 

  20. Thompson CS, Mumtaz FH, Khan MA, Wallis RM, Mikhailidis DP, Morgan RJ et al. The effect of sildenafil on corpus cavernosum smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit. Eur J Pharmacol 2001; 425: 57–64.

    Article  CAS  Google Scholar 

  21. Way KJ, Reid JJ . The effects of diabetes on nitric oxide-mediated responses in rat corpus cavernosum. Eur J Pharmacol 1999; 376: 73–82.

    Article  CAS  Google Scholar 

  22. Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 1999; 103: 185–195.

    Article  CAS  Google Scholar 

  23. van Etten RW, de Koning EJ, Honing ML, Stroes ES, Gaillard CA, Rabelink TJ . Intensive lipid lowering by statin therapy does not improve vascular reactivity in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2002; 22: 799–804.

    Article  CAS  Google Scholar 

  24. Bayraktutan U . Free radicals, diabetes and endothelial dysfunction. Diabetes Obes Metab 2002; 4: 224–238.

    Article  CAS  Google Scholar 

  25. Beckman JS, Koppenol WH . Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol 1996; 271: C1424–C1437.

    Article  CAS  Google Scholar 

  26. Srinivasan S, Bolick DT, Hatley ME, Natarajan R, Reilly KB, Yeh M et al. Glucose regulates interleukin-8 production in aortic endothelial cells through activation of the p38 mitogen-activated protein kinase pathway in diabetes. J Biol Chem 2004; 279: 31930–31936.

    Article  CAS  Google Scholar 

  27. Takaishi H, Taniguchi T, Takahashi A, Ishikawa Y, Yokoyama M . High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem Biophys Res Commun 2003; 305: 122–128.

    Article  CAS  Google Scholar 

  28. Sommer F, Klotz T, Steinritz D, Schmidt A, Addicks K, Engelmann U et al. MAP kinase 1/2 (Erk 1/2) and serine/threonine specific protein kinase Akt/PKB expression and activity in the human corpus cavernosum. Int J Impot Res 2002; 14: 217–225.

    Article  CAS  Google Scholar 

  29. Hoefen RJ, Berk BC . The role of MAP kinases in endothelial activation. Vasc Pharmacol 2002; 38: 271–273.

    Article  CAS  Google Scholar 

  30. Hurt KJ, Musicki B, Palese MA, Crone JK, Becker RE, Moriarity JL et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 2002; 99: 4061–4066.

    Article  CAS  Google Scholar 

  31. Archibald V, Cotter MA, Keegan A, Cameron NE . Contraction and relaxation of aortas from diabetic rats: effects of chronic anti-oxidant and aminoguanidine treatments. Naunyn-Schmeideberg's Arch Pharmacol 1996; 353: 584–591.

    Article  CAS  Google Scholar 

  32. Cai H, Harrison DG . Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840–844.

    Article  CAS  Google Scholar 

  33. Cameron NE, Nangle MR, Gibson TM, Cotter MA . Benfotiamine treatment improves vascular endothelium and nerve function in diabetic rats. Diabetes 2004; 53: A35.

    Google Scholar 

  34. Gibson TM, Cotter MA, Cameron NE . Effects of α-lipoic acid on impaired gastric fundus innervation in diabetic rats. Free Radic Biol Med 2003; 35: 160–168.

    Article  CAS  Google Scholar 

  35. Cellek S, Foxwell NA, Moncada S . Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 2353–2362.

    Article  CAS  Google Scholar 

  36. Cameron NE, Cotter MA . Diabetes causes an early reduction in autonomic ganglion blood flow in rats. J Diabetes Complications 2001; 15: 198–202.

    Article  CAS  Google Scholar 

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  1. Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK

    M R Nangle, M A Cotter & N E Cameron

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  1. M R Nangle
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  2. M A Cotter
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  3. N E Cameron
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Correspondence to N E Cameron.

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Nangle, M., Cotter, M. & Cameron, N. Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition. Int J Impot Res 18, 258–263 (2006). https://doi.org/10.1038/sj.ijir.3901414

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