Atorvastatin Ameliorates Sildenafil-Induced Penile Erections in Experimental Diabetes by Inhibiting Diabetes-Induced RhoA/Rho-Kinase Signaling Hyperactivation

Authors

  • Annamaria Morelli PhD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    2. University of Florence—Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Aravinda Krishnappa Chavalmane PhD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    2. University of Florence—Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Sandra Filippi PhD,

    1. University of Florence—Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Benedetta Fibbi MD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Enrico Silvestrini PhD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Erica Sarchielli PhD,

    1. University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
    Search for more papers by this author
  • Xin-Hua Zhang MD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Linda Vignozzi MD,

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author
  • Gabriella Barbara Vannelli MD,

    1. University of Florence—Department of Anatomy, Histology and Forensic Medicine, Florence, Italy;
    Search for more papers by this author
  • Gianni Forti MD,

    1. University of Florence—Endocrinology Units, Department of Clinical Physiopathology, Florence, Italy
    Search for more papers by this author
  • Mario Maggi MD

    1. University of Florence—Andrology Unit, Department of Clinical Physiopathology, Florence, Italy;
    Search for more papers by this author

Mario Maggi, MD, University of Florence—Department of Clinical Physiopathology, Viale Pieraccini, 6, Florence, Italy 50139. Tel: +39 0554271415; Fax: +39 0554271413; E-mail: m.maggi@dfc.unifi.it

ABSTRACT

Introduction.  One of the proposed mechanisms responsible for diabetes-related erectile dysfunction (ED) is overactivity of RhoA/ROCK signaling, as seen in experimental models of chemical diabetes.

Aim.  Because statins may interfere with RhoA/Rho-kinase (ROCK) signaling through the reduction of geranyl-geranyl pyrophosphate (GGPP), required for RhoA activation, we investigated whether atorvastatin ameliorated diabetes-related ED.

Methods.  Streptozotocin-induced (8 weeks) diabetic rats and alloxan-induced (8 weeks) diabetic rabbits received atorvastatin (5 mg/kg daily) for the last 2 weeks. In vitro contractility studies were conducted in the rabbit model. In the rat model, sildenafil effect on electrical stimulation (ES)-induced erection was investigated. Atorvastatin action was also analyzed using human fetal penile smooth muscle cells (hfPSMCs) exposed to low (5 mM), high (22 mM), and very high (40 mM) glucose.

Main Outcome Measures.  Atorvastatin effect on hyperglicemia-induced RhoA/ROCK signaling was evaluated using the ROCK inhibitor Y-27632 in both animal models and by analyzing functional effects downstream to RhoA activation in hfPSMCs.

Results.  In both diabetic models, atorvastatin did not affect glycemia, lipid plasma levels, and the hypogonadal state. In diabetic rats, atorvastatin ameliorated the erectile response to the ES of the cavernous nerve and normalized sildenafil effect on erectile function, strongly decreased by diabetes. In penile tissue from diabetic animals, atorvastatin completely restored the diabetes-induced hypersensitivity to Y-27632 and prevented RhoA membrane translocation/activation. In hfPSMCs, high glucose significantly increased not only membrane RhoA expression, but also ROCK activity (increased phosphorylation of the ROCK substrate myosin phosphatase target subunit 1) and several RhoA-dependent functions such as proliferation, migration, and smooth muscle-related gene expression. Atorvastatin restored all the high-glucose-induced effects, an action specifically reverted by GGPP.

Conclusion.  Atorvastatin improves diabetes-related ED and restores sildenafil responsiveness, most probably by inhibiting RhoA/ROCK signaling, which underlies several high-glucose-induced derangements in penile smooth muscle cell commitment. Morelli A, Chavalmane AK, Filippi S, Fibbi B, Silvestrini E, Sarchielli E, Zhang X-H, Vignozzi L, Vannelli GB, Forti G, and Maggi M. Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. J Sex Med 2009;6:91–106.

Ancillary