Corpus cavernosal smooth muscle relaxation effect of a novel AMPK activator, beta-lapachone

Jae Hyun Bae, Jin Wook Kim, Gi Ryang Kweon, Myoung Gyu Park, Kyeong Hoon Jeong, Je Jong Kim, Du Geon Moon

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4 Citations (Scopus)

Abstract

Introduction. Adenosine monophosphate-activated protein kinase (AMPK) activation is suggested to relax smooth muscle by endothelial nitric oxide synthase (eNOS) phosphorylation. Aim. To assess the mechanism and effect of a novel AMPK activator, beta-lapachone, upon cavernosal smooth muscle relaxation and the therapeutic potential for erectile dysfunction. Methods. Human umbilical vein endothelial cells (HUVECs) were treated with beta-lapachone. The lysates were blotted with specific antibodies for phosphorylated AMPK (p-AMPK) or phosphorylated eNOS (p-eNOS). The membranes were re-blotted for total AMP total eNOS, or beta-actin. The eNOS activity was measured by the conversion of L-14C-arginine to L-14C-citrulline in HUVECs lysates. In a separated experiment, cavernosal strips from New Zealand white rabbits were harvested for organ bath study and the relaxation effect of beta-lapachone on phenylephrine-induced contracted strips was evaluated and compared with sodium nitroprusside, zaprinast, metformin, and aminoimidazole carboxamide ribonucleotide (AICAR). Methylene blue and L-NAME were used to assess the inhibition of cyclic guanosine monophosphate/nitric oxide pathway. Zinc-protoporphyrin-IX (ZnPP) was also used to investigate the contribution of mevalonate pathway. Main Outcome Measures. The expression of p-AMPK, p-eNOS, AMPK and eNOS induced by beta-lapachone in HUVECs study and the percent relaxation of cavernosal tissue in organ bath study. Results. Beta-lapachone clearly induced AMPK phosphorylation and, as a consequence, eNOS phosphorylation in HUVECs. Beta-lapachone-induced upregulation of eNOS activity was also observed in HUVECs and steadily increased up to 1 hour. In organ bath study, beta-lapachone significantly relaxed the phenylephrine pretreated strips in a dose-dependent manner. This relaxation effect was not totally blocked by methylene blue or L-NAME. After removing endothelium, the relaxation was totally blocked by ZnPP. Conclusions. A novel AMPK activator, beta-lapachone has a strong relaxation effect on precontracted cavernosal smooth muscle strips in the rabbit. And phosphorylation of AMPK and eNOS strongly related to the action of beta-lapachone. Mevalonate pathway also might be considered as a suggestive mechanism.

Original languageEnglish
Pages (from-to)2205-2214
Number of pages10
JournalJournal of Sexual Medicine
Volume8
Issue number8
DOIs
Publication statusPublished - 2011 Aug

Keywords

  • AMPK Activator
  • Beta-Lapachone
  • Corpus Cavernosum
  • ENOS
  • Penile Erection
  • Smooth Muscle Relaxation

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynaecology
  • Urology

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    Bae, J. H., Kim, J. W., Kweon, G. R., Park, M. G., Jeong, K. H., Kim, J. J., & Moon, D. G. (2011). Corpus cavernosal smooth muscle relaxation effect of a novel AMPK activator, beta-lapachone. Journal of Sexual Medicine, 8(8), 2205-2214. https://doi.org/10.1111/j.1743-6109.2010.01809.x