Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats

Abstract

Males with diabetes mellitus have an increased prevalence of erectile dysfunction. Some of the organic causes have been studied in corpus cavernosum strips isolated from men undergoing penile prosthesis implantation. Defects in endothelium-dependent and nerve-mediated vascular smooth muscle relaxation have been found [1]. Similar deficits were noted for alloxan-diabetic rabbits [2] and recently diminished neurogenic erections were reported in streptozotocin-diabetic rats [3]. The nitric oxide (NO) systems of corpus cavernosum endothelium and nerve supply are crucial for smooth muscle relaxation and erectile Diabetologia (1999) Summary Diabetes mellitus is associated with impotence in animal models and patients. Raised reactive oxygen species contribute to diabetic neurovascular deficits, which are amenable to antioxidant treatment. Our aim was to examine the effects of streptozotocin-induced diabetes in rats and long-term treatment with the antioxidant, a-lipoic acid, on responses of an in vitro corpus cavernosum preparation. Diabetes duration was 8 weeks and preventive and reversal (4 weeks untreated diabetes, 4 weeks of treatment) studies were done. Four and 8 weeks of diabetes caused an about 41 % reduction in endothelium-dependent nitric oxide mediated relaxation to acetylcholine in phenylephrine-precontracted cavernosum. This deficit was prevented (93.9 ± 7.1 %) by treatment with a-lipoic acid; reversal studies showed 64.9 ± 19.5 % correction. Neither diabetes nor treatment with a-lipoic acid altered endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside. Stimulation of corpus cavernosum autonomic innervation caused noradrenergic-mediated contractions that were unaffected by diabetes or a-lipoic acid. Non-adrenergic, non-cholinergic nerve responses, largely dependent on nitric oxide, were seen after phenylephrine precontraction in the presence of atropine and guanethidine. Non-adrenergic, non-cholinergic stimulation caused frequency dependent relaxation to a maximum of about 40 %. Diabetes reduced this to about 25 %, however with preventive a-lipoic acid treatment, non-adrenergic, noncholinergic relaxation was in the nondiabetic range. In the reversal a-lipoic acid treated diabetic group, its deficit was corrected by 52.1 ± 14.6 %. Thus, diabetes reduces endothelium and non-adrenergic, noncholinergic nerve nitric oxide-mediated relaxation of corpus cavernosum smooth muscle, which is likely to be the organic base for impotence. Prevention and partial correction by a-lipoic acid emphasises the importance of reactive oxygen species and suggests a potential therapeutic approach. [Diabetologia (1999) 42: 343±350]

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

“…In contrast, when diabetes was induced in mature rats, there is no reduction in cavernosum weight and diabetic defects in endothelium-dependent but not endothelium-independent relaxation were observed. 18 In the present study, using mature mice, there was a modest body weight loss with diabetes, but no effect on cavernosum weight so the argument does not apply.…”

“…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.…”

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

“…It appears that the autonomic nervous system may be affected early in the progress of diabetic neuropathy, 8 but some studies on the noradrenergic innervation of the penis have reported little or no change in the contractile responses to noradrenergic nerve stimulation in the CC of rats that have been diabetic for up to 8 weeks. 9 The vasoconstrictor neurotransmitter NA is also known to increase in concentration in a variety of tissues including the rat heart, tail artery and whole penis, [10][11][12] and the time course of these changes often involves a peak in concentration that can occur after several, or many months of hyperglycaemia. However, while some authors have found a reduction in the noradrenergic [13][14][15] and nitrergic 16,17 innervation in diabetic erectile tissue, the results on the noradrenergic nerves are not confirmed in a recent publication 12 and in the present work.…”

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

“…In addition, both endothelial and nonadrenergic and noncholinergic (NANC) nerve-derived NO-mediated smooth muscle relaxation is diminished by diabetes in corpus cavernosum of animal models and humans (13)(14)(15)(16)(17)(18). Normal erectile function involves nerve-mediated increases in arterial inflow to corpus cavernosum, relaxation of smooth muscle, and restriction of venous outflow.…”