Arginase II deletion increases corpora cavernosa relaxation in diabetic mice.
BACKGROUND
Diabetes-induced erectile dysfunction involves elevated arginase (Arg) activity and expression. Because nitric oxide (NO) synthase and Arg share and compete for their substrate L-arginine, NO production is likely linked to regulation of Arg. Arg is highly expressed and implicated in erectile dysfunction.


OBJECTIVE
It was hypothesized that Arg-II isoform deletion enhances relaxation function of corpora cavernosal (CC) smooth muscle in a streptozotocin (STZ) diabetic model.


METHODS
Eight weeks after STZ-induced diabetes, vascular functional studies, Arg activity assay, and protein expression levels of Arg and constitutive NOS (using Western blots) were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT + D), Arg-II knockout (KO), and Arg-II KO+D mice (N = 8-10 per group).


METHODS
Inhibition or lack of arginase results in facilitation of CC relaxation in diabetic CC.


RESULTS
Strips of CC from Arg-II KO mice exhibited an enhanced maximum endothelium-dependent relaxation (from 70 + 3% to 84 + 4%) and increased nitrergic relaxation (by 55%, 71%, 42%, 42%, and 24% for 1, 2, 4, 8 and 16 Hz, respectively) compared with WT mice. WT + D mice showed a significant reduction of endothelium-dependent maximum relaxation (44 + 8%), but this impairment of relaxation was significantly prevented in Arg-II KO+D mice (69 + 4%). Sympathetic-mediated and alpha-adrenergic agent-induced contractile responses also were increased in CC strips from D compared with non-D controls. Contractile responses were significantly lower in Arg-II KO control and D versus the WT groups. WT + D mice increased Arg activity (1.5-fold) and Arg-II protein expression and decreased total and phospho-eNOS at Ser-1177, and nNOS levels. These alterations were not seen in Arg-II KO mice. Additionally, the Arg inhibitor BEC (50 µM) enhanced nitrergic and endothelium-dependent relaxation in CC of WT + D mice.


CONCLUSIONS
These studies show for the first time that Arg-II deletion improves CC relaxation in type 1 diabetes.
Medical College of Georgia, Department of Pharmacology and Toxicology, Augusta, GA 30912-2300, USA. hflorestoque@mail.mcg.edu
Haroldo A
HA
Toque
Rita C
RC
Tostes
Lin
L
Yao
Zhimin
Z
Xu
R Clinton
RC
Webb
Ruth B
RB
Caldwell
R William
RW
Caldwell
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism / Q000502:physiology*; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010413:Penis / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001786:Blood Glucose; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase; D000109:Acetylcholine