Extracellular signal-regulated kinase (ERK) inhibition decreases arginase activity and improves corpora cavernosal relaxation in streptozotocin (STZ)-induced diabetic mice.

Abstract

INTRODUCTION:

Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known.

AIM:

We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice.

METHODS:

The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10(-5) M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10(-4) M]).

MAIN OUTCOME MEASURES:

Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0 ± 5% vs. 82.5 ± 7%) and nitrergic stimulation (27 ± 2% vs. 76 ± 6%) by electrical field stimulation (EFS, 1-32 Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27 ± 2% vs. 60 ± 4%) and endothelium-dependent relaxation responses (38.0 ± 5% vs. 67.5 ± 6%). Acute treatment with the arginase inhibitor BEC (10(-4) M) also improves EFS-induced relaxation in diabetic mice (31 ± 3% vs. 49 ± 2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice.

CONCLUSION:

These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.

• Authors: Kenia P Nunes, Haroldo A Toque, Ruth B Caldwell, R William Caldwell, R Clinton Webb
• Journal: The journal of sexual medicine (J Sex Med) Vol. 8 Issue 12 Pg. 3335-44 (Dec 2011) ISSN: 1743-6109 [Electronic] Netherlands
• PMID: 21995824 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 International Society for Sexual Medicine.

Chemical References

• Flavonoids
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• Extracellular Signal-Regulated MAP Kinases
• Arginase
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Analysis of Variance
• Animals
• Arginase (biosynthesis, drug effects, metabolism)
• Diabetes Mellitus, Experimental
• Disease Models, Animal
• Endothelium, Vascular (drug effects)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, drug effects)
• Flavonoids (therapeutic use)
• Impotence, Vasculogenic (drug therapy)
• Male
• Mice
• Nitric Oxide Synthase Type III (metabolism)
• Penile Erection (drug effects)
• Penis (blood supply, drug effects)
• Signal Transduction (drug effects)
• Vasodilation (drug effects)