Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition

Abstract

Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum nitrergic nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

“…Additionally, p38 MAPK inhibition has been shown to ameliorate ANG II-induced target organ damage (29). Also, inhibition of p38 MAPK is reported to correct nitrergic neurovascular dysfunction in corpus cavernosum of diabetic mice (28), and the arginase-induced corpus cavernosum dysfunction that we recently observed in ANG II-treated mice (40).…”

12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy

“…The important role for 12/15-lipoxygenase in increased p38 MAPK, ERK, and CREB phosphorylation, and increased activator protein-1 and CREB DNA binding and transcriptional activities, as well as fibronectin overexpression has been identified in renal mesangial cells isolated from diabetic mice [46]. We have been particularly interested in the relationship between 12/15-lipoxygenase and MAPKs, because both p38 MAPK [26-28,47-49] and, recently, ERK [50,51], have been implicated in neuropathic changes in diabetes. In particular, increased p38 MAPK phosphorylation is involved in nerve conduction deficit [27], diabetic erectile autonomic neuropathy and vasculopathy [47], mechanical hyperalgesia [28,48] and tactile allodynia [49].…”

“…We have been particularly interested in the relationship between 12/15-lipoxygenase and MAPKs, because both p38 MAPK [26-28,47-49] and, recently, ERK [50,51], have been implicated in neuropathic changes in diabetes. In particular, increased p38 MAPK phosphorylation is involved in nerve conduction deficit [27], diabetic erectile autonomic neuropathy and vasculopathy [47], mechanical hyperalgesia [28,48] and tactile allodynia [49]. Increased ERK phosphorylation contributes to tactile allodynia [50] and mechanical hyperalgesia [51].…”

Endothelial dysfunction in diabetic erectile dysfunction

“…Inhibition of p38 mitogen-activated protein kinase (MAPK) partially corrects neurostimulated and endotheliumdependent relaxation of diabetic mouse corpus cavernosal strips. 60 While the mechanism of p38 MAPK activation and its effect on endothelial dysfunction in diabetic ED is not known, the activity of p38 MAPK may be triggered by hyperglycemia and ROS, as shown in endothelial and smooth muscle cells in nonpenile vascular beds. 61 Endothelial and smooth muscle cells of the rat penis contain an extracellular isoform of superoxide dismutase (SOD), which converts superoxide radicals into hydrogen peroxide.…”