Effects of Rosuvastatin on Nitric Oxide–Dependent Function in Aorta and Corpus Cavernosum of Diabetic Mice

Abstract

Elevated plasma lipids contribute to neurovascular dysfunction in diabetes. Statins have lipid-lowering properties and can modulate endothelial nitric oxide (NO) bioavailability. The aim was to assess the impact of these factors on autonomic nitrergic nerve and endothelial function. Thus, the effects of diabetes and treatment with the HMG-CoA reductase inhibitor rosuvastatin (RSV) were examined on corpus cavernosum and aorta from streptozotocin-induced diabetic mice in a 4-week prevention study and a 2-week intervention study, following 4 weeks of untreated diabetes. Cotreatment with mevalonate was used to assess the dependence of RSV's effects on HMG-CoA reductase blockade. Diabetes caused a 25% reduction in NO-mediated endotheliumdependent relaxation to acetylcholine for aorta and cavernosum. Relaxations of cavernosum were in the nondiabetic range following prevention or reversal treatment. The aortic deficit was completely prevented and 60% reversed by RSV. Maximum NO-dependent nonadrenergic, noncholinergic nerve-mediated relaxations of cavernosum were reduced 25-33% by diabetes. RSV treatment prevented 75% and reversed 71% of this diabetic deficit. Cotreatment with mevalonate inhibited the beneficial actions of RSV on aorta and cavernosum. Total plasma cholesterol was unaltered by diabetes or treatment. Thus, RSV corrected defective NO-mediated nerve and vascular function in diabetic mice independent of cholesterol lowering but via effects dependent on cholesterol biosynthesis pathway inhibition.

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

“…6,7 This is the first study to demonstrate that chronic p38 MAPK inhibition can reverse these deficits, despite only partial recovery of reduced smooth muscle responsiveness to nitric oxide.…”

“…Relaxation to nitroprusside was unaltered in diabetic C57 mouse cavernosum; however, reduced responsiveness was previously reported for the MF1 model. 6,7,19 Cultured vascular smooth muscle cells develop increased levels of phosphorylated p38 MAPK in response to high glucose, as do aortas from diabetic rats. 22 Thus, activation of p38 MAPK may play a role in situations where smooth muscle responsiveness to nitric oxide is reduced as its inhibition partially reversed the deficit in the present study.…”

“…For example, responsiveness of penile tissue to the nitric oxide donor, sodium nitroprusside, is often unaffected by diabetes; however, decreased relaxation has also been observed. 7,[18][19][20] One group found that the defect was normalized in diabetic rats when the tension readings were expressed relative to tissue weight, to take account of differing tissue weights. 21 However, in that study diabetes was induced in immature animals and the metabolic changes could have altered the normal growth and maturation of corpus cavernosum.…”

“…Nitric oxide-dependent deficits in cavernosum smooth muscle relaxation are evident in diabetic animals and man. [5][6][7][8] Inhibition of p38 MAPK prevents somatic neuropathy in experimental diabetes including nerve conduction velocity deficits, tactile allodynia and inflammatory pain. 9,10 Nonetheless, a potential role for p38 MAPK in autonomic nitrergic nerve dysfunction has not been studied.…”

Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome

“…27,28 Recently the hydroxymethylglutaryl (HMG) coenzyme A reductase inhibitor rosuvastatin has been shown to exert beneficial effects on erectile function in diabetic mice. 29 Moreover, in patients with ED who received sildenafil, atorvastatin tended to improve erectile function. 30 Thus, impairment of erectile function by treatment with statins is unlikely.…”