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]

We examined the effect in rats of 2 months of streptozotocin-induced diabetes mellitus on relaxation and contraction of aortas in vitro. A further diabetic group was treated from time of diabetes induction with a 1% dietary supplement of vitamin E. Diabetes caused a 26.5% deficit (p < 0.001) in maximum endothelium-dependent relaxation to acetylcholine in phenylephrine-precontracted aortas. This was 64.3% attenuated (p < 0.01) by vitamin E treatment; maximum relaxation was not significantly altered compared to non-diabetic rats. Vitamin E treatment of non-diabetic rats did not significantly affect acetylcholine-induced relaxation. Diabetes or treatment did not significantly alter acetylcholine sensitivity. Endothelium-independent relaxation response to glyceryl trinitrate was not affected by diabetes or vitamin E treatment, indicating that vascular smooth muscle responses to nitric oxide remained unaltered. There was a 35.4% reduction in the maximum contractile response to phenylephrine with diabetes (p < 0.05) which was unaffected by vitamin E treatment. The data suggest that the chronic deficit in nitric oxide-mediated endothelium-dependent relaxation in diabetes depends largely upon excess activity of reactive oxygen species. Treatment with vitamin E to increase free radical scavenging specifically protected vascular endothelium although it had no effect on deficits in vascular smooth muscle contractile responses.

5-Hydroxytryptamine (5-HT)(1B) receptors mediate contraction in human pulmonary arteries, and 5-HT(1B) receptor-mediated contraction is enhanced in pulmonary arteries from hypoxic rats. Here we further examine the role of this receptor in the development of pulmonary hypertension (PHT) by examining (1) the effects of a 5-HT(1B/1D)-receptor antagonist (GR127935) on hypoxia-induced PHT (CHPHT) in rats and (2) CHPHT in 5-HT(1B)-receptor knockout mice. In rats, hypoxia increased right ventricular pressure and right ventricular hypertrophy and induced pulmonary vascular remodeling associated with an increase in pulmonary arterial wall thickness. GR127935 (3 mg. kg(-1). d(-1)) reduced all of these indices. 5-HT(1)-mediated contraction was enhanced in pulmonary arteries of the CHPHT rats. The effects of GR127935 on PHT indices were associated with an attenuation of the enhanced contractile responses to 5-HT and the 5-HT(1)-receptor agonist, 5-carboxamidotryptamine (5-CT), in isolated pulmonary arteries. In wild-type mice, hypoxia increased right ventricular hypertrophy, which was absent in 5-HT(1B)-receptor knockout mice. Hypoxia increased pulmonary vascular remodeling in wild-type mice, and this was reduced in the 5-HT(1B)-receptor knockout mice. Hypoxia increased 5-HT(1)-mediated contraction in pulmonary arteries from the wild-type mice and this was attenuated in the 5-HT(1B)-receptor knockout mice. In conclusion, the 5-HT(1B) receptor plays a role in the development of CHPHT. One possible mechanism may be via enhanced 5-HT(1) receptor-mediated contraction of the pulmonary arterial circulation.

We examined whether chronic treatment with the free radical scavengers butylated hydroxytoluene (1 g kg-1 day-1) and N-acetyl-L-cysteine (250 mg kg-1 day-1), or the inhibitor of advanced glycosylation reactions, aminoguanidine (1 g kg-1 day-1), could prevent the development of relaxation and contraction abnormalities in aorta from 2 month streptozotocin-diabetic rats. Diabetes caused a 24% deficit in maximal endothelium-dependent relaxation to acetylcholine for phenylephrine precontracted aortas (P < 0.01). This was unaffected by tissue-bath glucose concentration (5.5 or 40 mM), or by addition of 1 mM L-arginine. Butylated hydroxytoluene, N-acetyl-L-cysteine and aminoguanidine treatments gave substantial protection, maximum relaxation remaining in the non-diabetic range. Neither diabetes nor treatment affected endothelium-independent relaxation to glyceryl trinitrate. To test the suggestion that aminoguanidine could act as an inhibitor of constitutive nitric oxide synthase, acute aminoguanidine effects on endothelium-dependent relaxation to acetylcholine were also examined. No inhibition was noted. A modest increase in phenylephrine sensitivity with diabetes (P < 0.05) was unaffected by butylated hydroxytoluene or N-acetyl-L-cysteine, but partially prevented by aminoguanidine (P < 0.05). The data, therefore, provide evidence for the involvement of reactive oxygen species and the advanced glycosylation process particularly for impaired endothelium-dependent relaxation in experimental diabetes.

We examined the effects of 2 months of streptozotocin-induced diabetes mellitus in rats on relaxation and contraction of corpus cavernosum and the mesenteric vascular bed in vitro. A further diabetic group was treated from diabetes induction with 10 mg/kg/day of the aldose reductase inhibitor, WAY121509. For corpus cavernosum, maximal acetylcholine-induced relaxation was 35.5% reduced (p < 0.001) by diabetes, and this deficit was completely prevented by WAY121509 treatment. Neither diabetes nor treatment affected contractile responses to field stimulation of noradrenergic nerves; however, nonadrenergic noncholinergic nerve relaxation responses were 32.9% decreased by diabetes and WAY 121509 attenuated this by 84% (p < 0.001). For the mesenteric vascular bed, diabetes depressed maximal endothelium-dependent vasodilation to acetylcholine by 25.2% (p < 0.001), and this was partially (50.6%; p < 0.01) prevented by WAY121509. Nitric oxide synthase blockade revealed endothelium-derived hyperpolarising factor-mediated vasodilation to acetylcholine that was 73.5% (p < 0.001) depressed by diabetes; WAY121509 provided partial (43.4%; p < 0.001) protection. Neither diabetes nor treatment affected endothelium-independent vasorelaxation to the nitric oxide donor, sodium nitroprusside, in corpus cavernosum or mesenteric vessels. Thus the data show protective effects of WAY121509 on nitric oxide-mediated cavernosal vasorelaxation responses and on mesenteric endothelium-derived hyperpolarising factor responses. Together these findings could account for the beneficial effects of aldose reductase inhibition on diabetic complications in experimental models.