Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db-/- Type II Diabetic and Obese Mice

J Pharmacol Exp Ther. 2015 May;353(2):330-9. doi: 10.1124/jpet.114.220970. Epub 2015 Mar 4.

Abstract

Type 2 diabetes mellitus (DM2) and obesity are major risk factors for erectile dysfunction (ED). In diabetes, increased oxidative stress leads to decreased nitric oxide (NO) bioavailability, and diabetic patients appear to be less responsive to conventional therapy with phosphodiesterase type 5 inhibitors. We investigated whether the soluble guanylyl cyclase stimulator BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4ylamine) is effective in improving impaired corpus cavernosum (CC) relaxation in obese DM2 mice by reducing oxidative stress. Adult db/db(-/-) mice or their lean db(/+) littermates were used to assess vascular function, cGMP levels, antioxidant status, NADPH oxidase expression, and superoxide formation in the absence or presence of BAY 41-2272. Results showed that BAY 41-2272 (10(-8) to 10(-5) M) potently relaxed CC from db(/+) or db/db(-/-) mice in a similar manner. BAY 41-2272 significantly enhanced both endothelium-dependent and nitrergic relaxation induced by electrical field stimulation (EFS), and improved the impaired relaxation to acetylcholine and EFS in the diabetic animals in a concentration-dependent manner (10(-8) to 10(-7) M). BAY 41-2272 increased cGMP levels and potentiated relaxation responses to exogenous NO in CC. Total antioxidant status was reduced in plasma and urine whereas expression of vascular NADPH oxidase subunits (gp91phox, p22phox, and p47phox) was increased in the CC of db/db(-/-) mice, suggesting a state of oxidative stress. These effects were prevented by BAY 41-2272 in a concentration-dependent manner. These results suggest that BAY 41-2272 improves CC relaxation in db/db(-/-) mice by increasing cGMP and augmenting antioxidant status, making this drug is a potential novel candidate to treat ED.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cyclic GMP / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Drug Interactions
  • Epithelium / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Guanylate Cyclase / metabolism*
  • Lipids / blood
  • Male
  • Mice
  • Mice, Obese
  • Muscle Relaxation / drug effects
  • NADPH Oxidases / metabolism
  • Nitroprusside / pharmacology
  • Obesity / physiopathology*
  • Oxidative Stress / drug effects
  • Penile Erection / drug effects
  • Penile Erection / genetics*
  • Penis / drug effects
  • Penis / metabolism
  • Penis / pathology
  • Penis / physiopathology
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Soluble Guanylyl Cyclase
  • Vasodilation / drug effects

Substances

  • 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
  • Blood Glucose
  • Lipids
  • Pyrazoles
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Nitroprusside
  • NADPH Oxidases
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP