p38 Mitogen-activated protein kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice.
BACKGROUND
Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.


OBJECTIVE
We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.


METHODS
Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 µg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 µg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.


METHODS
Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.


RESULTS
AngII increased SBP (22%) and increased CC arginase activity and expression (∼twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.


CONCLUSIONS
p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
Toque
Haroldo A
HA
Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. hflorestoque@mail.mcg.edu
Romero
Maritza J
MJ
Tostes
Rita C
RC
Shatanawi
Alia
A
Chandra
Surabhi
S
Carneiro
Zidonia N
ZN
Inscho
Edward W
EW
Webb
Robert Clinton
RC
Caldwell
Ruth B
RB
Caldwell
Robert William
RW
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010413:Penis / Q000378:metabolism* / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases; D001119:Arginase; C093642:SB 203580
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