Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa

Journal of Sexual Medicine

Volumn 11, Issue 7, 2014, Pages 1694-1708

  Vignozzi, Linda ^a   Filippi, Sandra ^b   Comeglio, Paolo ^a   Cellai, Ilaria ^a   Morelli, Annamaria ^a   Rastrelli, Giulia ^a   Maneschi, Elena ^a   Mannucci, Edoardo ^b   Maggi, Mario ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

^b UNIVERSITY OF FLORENCE   (Italy)

Author keywords

Adenosine; Erection; Metformin

Indexed keywords

ACETYLCHOLINE; ADENOSINE; ADENOSINE MONOPHOSPHATE DEAMINASE; ADENOSINE MONOPHOSPHATE DEAMINASE 1; ADENOSINE MONOPHOSPHATE DEAMINASE 2; ADENOSINE RECEPTOR; ADENOSINE RECEPTOR 3; ASPARTATE AMINOTRANSFERASE; DEAMINASE; GLUCOSE; METFORMIN; N(G) NITROARGININE METHYL ESTER; NITRIC OXIDE SYNTHASE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; ANTIDIABETIC AGENT; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENZYME INHIBITOR; TESTOSTERONE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CHOLESTEROL BLOOD LEVEL; CONCENTRATION RESPONSE; CONTROLLED STUDY; CORPUS CAVERNOSUM; DRUG MECHANISM; ERECTILE DYSFUNCTION; GLUCOSE BLOOD LEVEL; GLUCOSE TOLERANCE; IC 50; IN VITRO STUDY; IN VIVO STUDY; LIPID DIET; MALE; METABOLIC SYNDROME X; MUSCLE CONTRACTILITY; MUSCLE RELAXATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; DRUG EFFECTS; METABOLISM; PENIS; PENIS ERECTION; RABBIT;

ADENOSINE; AMP DEAMINASE; ANIMALS; DIET, HIGH-FAT; ENZYME INHIBITORS; ERECTILE DYSFUNCTION; HYPOGLYCEMIC AGENTS; MALE; METFORMIN; NG-NITROARGININE METHYL ESTER; NITRIC OXIDE SYNTHASE TYPE III; PENILE ERECTION; PENIS; RABBITS; RECEPTORS, PURINERGIC P1; SIGNAL TRANSDUCTION; TESTOSTERONE;

EID: 84903771830     PISSN: 17436095     EISSN: 17436109     Source Type: Journal    
DOI: 10.1111/jsm.12572     Document Type: Article

References (56)

1. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881-887.
2. Corona G, Rastrelli G, Morelli A, Vignozzi L, Mannucci E, Maggi M. Hypogonadism and metabolic syndrome. J Endocrinol Invest 2011;34:557-567.
3. Corona G, Mannucci E, Schulman C, Petrone L, Mansani R, Cilotti A, Balercia G, Chiarini V, Forti G, Maggi M. Psychobiologic correlates of the metabolic syndrome and associated sexual dysfunction. Eur Urol 2006;50:595-604. discussion 04.
4. Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: A pathological link supporting cardiovascular diseases. Int J Androl 2009;32:587-598.
5. Dunkley AJ, Charles K, Gray LJ, Camosso-Stefinovic J, Davies MJ, Khunti K. Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: Systematic review and mixed treatment comparison meta-analysis. Diabetes Obes Metab 2012;14:616-625.
6. Rotella CM, Monami M, Mannucci E. Metformin beyond diabetes: New life for an old drug. Curr Diabetes Rev 2006;2:307-315.
7. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S; Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: The Diabetes Prevention Program randomized trial. Ann Intern Med 2005;142:611-619.
8. Ramachandran A, Snehalatha C, Yamuna A, Mary S, Ping Z. Cost-effectiveness of the interventions in the primary prevention of diabetes among Asian Indians: Within-trial results of the Indian Diabetes Prevention Programme (IDPP). Diabetes Care 2007;30:2548-2552.
9. Rey-Valzacchi GJ, Costanzo PR, Finger LA, Layus AO, Gueglio GM, Litwak LE, Knoblovits P. Addition of metformin to sildenafil treatment for erectile dysfunction in eugonadal nondiabetic men with insulin resistance. A prospective, randomized, double-blind pilot study. J Androl 2012;33:608-614.
10. Labazi H, Wynne BM, Tostes R, Webb RC. Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction. J Sex Med 2013;10:2154-2164.
11. Kim YW, Park SY, Kim JY, Huh JY, Jeon WS, Yoon CJ, Yun SS, Moon KH. Metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. J Androl 2007;28:555-560.
12. Majithiya JB, Balaraman R. Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats. Life Sci 2006;78:2615-2624.
13. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174.
14. Ouyang J, Parakhia RA, Ochs RS. Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem 2011;286:1-11.
15. Lanaspa MA, Cicerchi C, Garcia G, Li N, Roncal-Jimenez CA, Rivard CJ, Hunter B, Andrès-Hernando A, Ishimoto T, Sànchez-Lozada LG, Thomas J, Hodges RS, Mant CT, Johnson RJ. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS ONE 2012;7:e48801.
16. Phatarpekar PV, Wen J, Xia Y. Role of adenosine signaling in penile erection and erectile disorders. J Sex Med 2010;7:3553-3564.
17. Szentmiklosi AJ, Cseppento A, Harmati G, Nanasi PP. Novel trends in the treatment of cardiovascular disorders: Site- and event-selective adenosinergic drugs. Curr Med Chem 2011;18:1164-1187.
18. Maggi M, Filippi S, Ledda F, Magini A, Forti G. Erectile dysfunction: From biochemical pharmacology to advances in medical therapy. Eur J Endocrinol 2000;143:143-154.
19. Filippi S, Vignozzi L, Morelli A, Chalvamane AK, Sarchielli E, Fibbi B, Saad F, Sadner P, Ruggiano P, Vannelli GB, Mannucci E, Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J Sex Med 2009;6:3274-3288.
20. Morelli A, Comeglio P, Filippi S, Sarchielli E, Vignozzi L, Maneschi E, Cellai I, Gacci M, Lenzi A, Vannelli GB, Maggi M. Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: An experimental study in the rabbit. Prostate 2013;73:428-441.
21. Vignozzi L, Morelli A, Filippi S, Comeglio P, Chavalmane AK, Marchetta M, Toce M, Yehiely-Cohen R, Vannelli GB, Adorini L, Maggi M. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med 2011;8:57-77.
22. Maneschi E, Morelli A, Filippi S, Cellai I, Comeglio P, Mazzanti B, Mello T, Calcagno A, Sarchielli E, Vignozzi L, Saad F, Vector R, Vannelli GB, Maggi M. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J Endocrinol 2012;215:347-362.
23. Morelli A, Comeglio P, Filippi S, Sarchielli E, Cellai I, Vignozzi L, Yehiely-Cohen R, Maneschi E, Gacci M, Carini M, Adorini L, Vannelli GB, Maggi M. Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J Steroid Biochem Mol Biol 2012;132:80-92.
24. Vignozzi L, Morelli A, Sarchielli E, Comeglio P, Filippi S, Cellai I, Maneschi E, Serni S, Gacci M, Carini M, Piccinni MP, Saad F, Adorini L, Vannelli GB, Maggi M. Testosterone protects from metabolic syndrome-associated prostate inflammation: An experimental study in rabbit. J Endocrinol 2012;212:71-84.
25. Morelli A, Sarchielli E, Comeglio P, Filippi S, Vignozzi L, Marini M, Rastrelli G, Maneschi E, Cellai I, Persani L, Adorini L, Vannelli GB, Maggi M. Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits. Mol Cell Endocrinol 2013;382:107-119.
26. Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, Orlando C, Vannelli GB, Aversa A, Natali A, Forti G, Giorgi M, Jannini EA, Ledda F, Maggi M. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 2004;145:2253-2263.
27. Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M, Gacci M, Vignozzi L, Vannelli GB, Carini M, Forti G, Maggi M. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 2007;148:1019-1029.
28. Morelli A, Filippi S, Sandner P, Fibbi B, Chavalmane AK, Silvestrini E, Sarchielli E, Vignozzi L, Gacci M, Carini M, Vannelli GB, Maggi M. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med 2009;6:1594-1608.
29. Morelli A, Filippi S, Comeglio P, Sarchielli E, Chavalmane AK, Vignozzi L, Fibbi B, Silvestrini E, Sadner P, Gacci M, Carini M, Vannelli GB, Maggi M. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med 2010;7:107-120.
30. DeLean A, Munson PJ, Rodbard D. Simultaneous analysis of families of sigmoidal curves: Application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol 1978;235:E97-102.
31. Filippi S, Mancini M, Amerini S, Bartolini M, Natali A, Mancina R, Forti G, Ledda F, Maggi M. Functional adenosine receptors in human corpora cavernosa. Int J Androl 2000;23:210-217.
32. Mantelli L, Amerini S, Ledda F, Forti G, Maggi M. The potent relaxant effect of adenosine in rabbit corpora cavernosa is nitric oxide independent and mediated by A2 receptors. J Androl 1995;16:312-317.
33. Noto T, Inoue H, Mochida H, Kikkawa K. Role of adenosine and P2 receptors in the penile tumescence in anesthetized dogs. Eur J Pharmacol 2001;425:51-55.
34. Faria M, Magalhaes-Cardoso T, Lafuente-de-Carvalho JM, Correia-de-Sa P. Corpus cavernosum from men with vasculogenic impotence is partially resistant to adenosine relaxation due to endothelial A(2B) receptor dysfunction. J Pharmacol Exp Ther 2006;319:405-413.
35. Mi T, Abbasi S, Zhang H, Uray K, Chunn JL, Xia LW, Molina JG, Weisbrodt NW, Kellems RE, Blackburn MR, Xia Y. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest 2008;118:1491-1501.
36. Dai Y, Zhang Y, Phatarpekar P, Mi T, Zhang H, Blackburn MR, Xia Y. Adenosine signaling, priapism and novel therapies. J Sex Med 2009;6(3 suppl):292-301.
37. Shimoni Y, Han X, Severson D, Giles WR. Mediation by nitric oxide of the indirect effects of adenosine on calcium current in rabbit heart pacemaker cells. Br J Pharmacol 1996;119:1463-1469.
38. Martynyuk AE, Kane KA, Cobbe SM, Rankin AC. Nitric oxide mediates the anti-adrenergic effect of adenosine on calcium current in isolated rabbit atrioventricular nodal cells. Pflugers Arch 1996;431:452-457.
39. Tostes RC, Giachini FR, Carneiro FS, Leite R, Inscho EW, Webb RC. Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. J Pharmacol Exp Ther 2007;322:678-685.
40. Ayan S, Yildirim S, Ucar C, Sarioglu Y, Gultekin Y, Butuner C. Corporal reactivity to adenosine and prostaglandin E1 in alloxan-induced diabetic rabbit corpus cavernosum, and the effect of insulin therapy. BJU Int 1999;83:108-112.
41. Wen J, Jiang X, Dai Y, Zhang Y, Tang Y, Sun H, Mi T, Kellems RE, Blackburn MR, Xia Y. Adenosine deaminase enzyme therapy prevents and reverses the heightened cavernosal relaxation in priapism. J Sex Med 2010;7:3011-3022.
42. Wen J, Jiang X, Dai Y, Zhang Y, Tang Y, Sun H, Mi T, Phatarpekar PV, Kellems RE, Blackburn MR, Xia Y. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J 2010;24:740-749.
43. Anderson JL, Habashi J, Carlquist JF, Muhlestein JB, Home BD, Bair TL, Pearson RR, Hart N. A common variant of the AMPD1 gene predicts improved cardiovascular survival in patients with coronary artery disease. J Am Coll Cardiol 2000;36:1248-1252.
44. Andersson KE. Neurophysiology/pharmacology of erection. Int J Impot Res 2001;13(3 suppl):S8-17.
45. Corona G, Rastrelli G, Filippi S, Vignozzi L, Mannucci E, Maggi M. Erectile dysfunction and central obesity: An Italian perspective. Asian J Androl 2014; doi: 10.4103/1008-682X.126386.
46. Chiang PH, Wu SN, Tsai EM, Wu CC, Shen MR, Huang CH, Chiang CP. Adenosine modulation of neurotransmission in penile erection. Br J Clin Pharmacol 1994;38:357-362.
47. Saenz de Tejada I, Blanco R, Goldstein I, Azadzoi K, de las Morenas A, Krane RJ, Cohen RA. Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue. Am J Physiol 1988;254:H459-467.
48. Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 1992;147:1650-1655.
49. Hoek JB. Metformin and the fate of fat. Gastroenterology 2006;130:2234-2237.
50. Filippi S, Luconi M, Granchi S, Natali A, Tozzi P, Forti G, Ledda F, Maggi M. Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation. Int J Impot Res 2002;14:295-307.
51. Gur S, Ozturk B. Altered relaxant responses to adenosine and adenosine 5′-triphosphate in the corpus cavernosum from men and rats with diabetes. Pharmacology 2000;60:105-112.
52. Vignozzi L, Filippi S, Comeglio P, Cellai I, Sarchielli E, Morelli A, Rastrelli G, Maneschi E, Galli A, Vannelli GB, Saad F, Mannucci E, Adorini L, Maggi M. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: An experimental study in the rabbit. Mol Cell Endocrinol 2014;384:143-154.
53. Xia JF, Liang QL, Hu P, Wang YM, Li P, Luo GA. Correlations of six related purine metabolites and diabetic nephropathy in Chinese type 2 diabetic patients. Clin Biochem 2009;42:215-220.
54. Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, Forti G, Mannucci E, Maggi M. Type 2 diabetes mellitus and testosterone: A meta-analysis study. Int J Androl 2011;34:528-540.
55. Petersen JS, DiBona GF. Acute sympathoinhibitory actions of metformin in spontaneously hypertensive rats. Hypertension 1996;27:619-625.
56. Colombo GL, Rossi E, De Rosa M, Benedetto D, Gaddi AV. Antidiabetic therapy in real practice: Indicators for adherence and treatment cost. Patient Prefer Adherence 2012;6:653-661.