Sexual dysfunction in the diabetic BB/WOR rat: a role of central neuropathy

1997 ◽  
Vol 272 (1) ◽  
pp. R259-R267 ◽  
Author(s):  
K. T. McVary ◽  
C. H. Rathnau ◽  
K. E. McKenna

The pathophysiological mechanisms of diabetic impotence remain obscure. We have presented an analysis of sexual function in a diabetic rat (BB/WOR) model characterized by diffuse neuropathic changes without a confounding vasculopathy that allows us to define the neural components of erectile failure. Copulatory behavioral testing demonstrated that diabetic males were severely impaired: the controls mounted three times more than the diabetics and had about one-half the latency to first mount. The diabetics had about one-fourth the number of intromissions and took nearly twice as long to achieve first ejaculation. The number of ejaculations was drastically reduced as well. We examined sexual reflexes in the anesthetized acutely spinalized rat. These experiments tested the integrity of spinal circuits controlling sexual function. Reflex testing demonstrated that spinal sexual reflexes were also severely impaired: the onset latency of reflexes was more than doubled, and the duration of reflexes was less than one-half. More than one-half of the diabetic rats showed no penile erections. Neural studies showed even more derangement in reflex measures in rats, without erection. Nerve conduction velocity experiments suggested a peripheral neuropathic change in hypogastric nerve and motor pudendal nerve fibers. These dysfunctional findings were seen without any androgen deficiency. These results indicate that diabetic impotence in this model reflects central and peripheral neuropathic disease processes.

1990 ◽  
Vol 68 (6) ◽  
pp. 914-921 ◽  
Author(s):  
Eduardo T. Cánepa ◽  
Elena B. C. Llambías ◽  
Moisés Grinstein

In the present work we demonstrate that insulin decreases the phenobarbital-induced activities of δ-aminolevulinic acid synthase and ferrochelatase in isolated hepatocytes from normal and experimental-diabetic rats. Insulin concentrations required to produce significant inhibition in diabetic hepatocytes were higher than in normal cells. Under similar experimental conditions, insulin decreased the basal activities of δ-aminolevulinic acid synthase and ferrochelatase in hepatocytes from normal rats; no inhibitory effect was observed on the basal activity of δ-aminolevulinic acid synthase in hepatocytes from diabetic rats. Cytochrome P-450 content of both normal and diabetic cells was not affected by insulin in absence or presence of phenobarbital. The inhibitory action of insulin was exerted even when effective concentrations of glucagon, dexamethasone, or 8-(p-chlorophenylthio)-cAMP were present.Key words: δ-aminolevulinic acid synthase, ferrochelatase, cAMP, insulin, diabetic rat hepatocytes.


2011 ◽  
Vol 300 (1) ◽  
pp. H326-H334 ◽  
Author(s):  
Parisa Rahnema ◽  
Yakhin Shimoni ◽  
Anders Nygren

Hearts from streptozotocin (STZ)-induced diabetic rats have previously been shown to have impaired intercellular electrical coupling, due to reorganization (lateralization) of connexin43 proteins. Due to the resulting reduction in conduction reserve, conduction velocity in diabetic hearts is more sensitive to conditions that reduce cellular excitability or intercellular electrical coupling. Diabetes is a known risk factor for cardiac ischemia, a condition associated with both reduced cellular excitability and reduced intercellular coupling. Activation of Ca2+-independent phospholipase A2 (iPLA2) is known to be part of the response to acute ischemia and may contribute to the intercellular uncoupling by causing increased levels of arachidonic acid and lysophosphatidyl choline. Normally perfused diabetic hearts are known to exhibit increased iPLA2 activity and may thus be particularly sensitive to further activation of these enzymes. In this study, we used voltage-sensitive dye mapping to assess changes in conduction velocity in response to acute global ischemia in Langendorff-perfused STZ-induced diabetic hearts. Conduction slowing in response to ischemia was significantly larger in STZ-induced diabetic hearts compared with healthy controls. Similarly, slowing of conduction velocity in response to acidosis was also more pronounced in STZ-induced diabetic hearts. Inhibition of iPLA2 activity using bromoenol lactone (BEL; 10 μM) had no effect on the response to ischemia in healthy control hearts. However, in STZ-induced diabetic hearts, BEL significantly reduced the amount of conduction slowing observed beginning 5 min after the onset of ischemia. BEL treatment also significantly increased the time to onset of sustained arrhythmias in STZ-induced diabetic hearts but had no effect on the time to arrhythmia in healthy control hearts. Thus, our results suggest that iPLA2 activation in response to acute ischemia in STZ-induced diabetic hearts is more pronounced than in control hearts and that this response is a significant contributor to arrhythmogenic conduction slowing.


2021 ◽  
Vol 11 ◽  
Author(s):  
Jasmin Chendi Li ◽  
Anida Velagic ◽  
Cheng Xue Qin ◽  
Mandy Li ◽  
Chen Huei Leo ◽  
...  

Introduction:Endothelial dysfunction is a major risk factor for several of the vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but the role of HNO in diabetes mellitus associated endothelial dysfunction in the carotid artery remains unknown.Aim: To assess how diabetes affects the role of endogenous NO• and HNO in endothelium-dependent relaxation in rat isolated carotid arteries.Methods: Male Sprague Dawley rats were fed a high-fat-diet (HFD) for 2 weeks prior to administration of low dose streptozotocin (STZ; 35 mg/kg i. p./day) for 2 days. The HFD was continued for a further 12 weeks. Sham rats were fed standard chow and administered with citrate vehicle. After 14 weeks total, rats were anesthetized and carotid arteries collected to assess responses to the endothelium-dependent vasodilator, acetylcholine (ACh) by myography. The combination of calcium-activated potassium channel blockers, TRAM-34 (1 μmol/L) and apamin (1 μmol/L) was used to assess the contribution of endothelium-dependent hyperpolarization to relaxation. The corresponding contribution of NOS-derived nitrogen oxide species to relaxation was assessed using the combination of the NO• synthase inhibitor, L-NAME (200 μmol/L) and the soluble guanylate cyclase inhibitor ODQ (10 μmol/L). Lastly, L-cysteine (3 mmol/L), a selective HNO scavenger, and hydroxocobalamin (HXC; 100 μmol/L), a NO• scavenger, were used to distinguish between NO• and HNO-mediated relaxation.Results: At study end, diabetic rats exhibited significantly retarded body weight gain and elevated blood glucose levels compared to sham rats. The sensitivity and the maximal relaxation response to ACh was significantly impaired in carotid arteries from diabetic rats, indicating endothelial dysfunction. The vasorelaxation evoked by ACh was abolished by L-NAME plus ODQ, but not affected by the apamin plus TRAM-34 combination, indicating that NOS-derived nitrogen oxide species are the predominant endothelium-derived vasodilators in sham and diabetic rat carotid arteries. The maximum relaxation to ACh was significantly decreased by L-cysteine in both sham and diabetic rats, whereas HXC attenuated ACh-induced relaxation only in sham rats, suggesting that diabetes impaired the contribution of NO•, whereas HNO-mediated vasorelaxation remained intact.Conclusion: Both NO• and HNO contribute to endothelium-dependent relaxation in carotid arteries. In diabetes, NO•-mediated relaxation is impaired, whereas HNO-mediated relaxation was preserved. The potential for preserved HNO activity under pathological conditions that are associated with oxidative stress indicates that HNO donors may represent a viable therapeutic approach to the treatment of vascular dysfunction.


1998 ◽  
Vol 274 (6) ◽  
pp. E984-E991 ◽  
Author(s):  
Firas Saker ◽  
Juan Ybarra ◽  
Patrick Leahy ◽  
Richard W. Hanson ◽  
Satish C. Kalhan ◽  
...  

Results of previous studies indicated that treatment of diabetic rats (induced by streptozotocin) with cobalt chloride (CoCl2) resulted in a significant decrement in serum glucose concentration. The present study was designed to determine the potential role of enhanced glucose uptake vs. decreased glucose production in the above response. The rate of systemic appearance of glucose, measured under fasting conditions using [3-3H]glucose tracer, was reduced from 35.5 ± 2.5 to 17.5 ± 1.8 μmol ⋅ kg−1 ⋅ min−1in diabetic rats treated with 2 mM CoCl2 added to the drinking water for 10–14 days ( P < 0.01). Tissue accumulation of intravenously administered 2-deoxy-[14C]glucose was significantly reduced in kidney and eye of diabetic rats treated with CoCl2, whereas the uptake remained unchanged in several other tissues including cerebrum, red and white skeletal muscle, heart, and liver. The relative content of phospho enolpyruvate carboxykinase (PEPCK) mRNA was increased 3.1-fold in livers of diabetic compared with normal rats ( P < 0.001), and treatment of diabetic rats with CoCl2 decreased hepatic PEPCK mRNA levels to normal. The content of PEPCK mRNA in the liver was decreased by 33% in CoCl2-treated normal rats ( P < 0.05). Treatment with CoCl2 resulted in no change in cAMP levels in the livers of either diabetic or normal rats. These results suggest that the glycemia-lowering effect of CoCl2 is mediated by reductions in the rate of systemic appearance of glucose and hepatic gluconeogenesis.


2003 ◽  
Vol 284 (2) ◽  
pp. F282-F292 ◽  
Author(s):  
Eric Cellier ◽  
Marilyne Mage ◽  
Johan Duchêne ◽  
Christiane Pécher ◽  
Réjean Couture ◽  
...  

Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B2 kinin receptor (B2R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B2R activation. These observations are consistent with a potential therapeutic role of BK and B2R during glomerulosclerosis.


2013 ◽  
Vol 304 (7) ◽  
pp. H935-H945 ◽  
Author(s):  
Natalia I. Gokina ◽  
Adrian D. Bonev ◽  
Alexander P. Gokin ◽  
Gabriela Goloman

Diabetes mellitus in pregnancy is associated with impaired endothelium-mediated dilatation of maternal arteries, although the underlying cellular mechanisms remain unknown. In this study, we hypothesized that diabetes during rat gestation attenuates agonist-induced uterine vasodilation through reduced endothelial cell (EC) Ca2+ elevations and impaired smooth muscle cell (SMC) hyperpolarization and SMC intracellular Ca2+ concentration ([Ca2+]i) responses. Diabetes was induced by an injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with a citrate buffer. Fura-2-based measurements of SMC [Ca2+]i or microelectrode recordings of SMC membrane potential were performed concurrently with dilator responses to ACh in uteroplacental arteries from control and diabetic pregnant rats. Basal levels of EC [Ca2+]i and ACh-induced EC [Ca2+]i elevations in pressurized vessels and small EC sheets were studied as well. Diabetes reduced ACh-induced vasodilation due to a markedly impaired EDHF-mediated response. Diminished vasodilation to ACh was associated with attenuated SMC hyperpolarization and [Ca2+]i responses. Basal levels of EC [Ca2+]i and ACh-induced EC [Ca2+]i elevations were significantly reduced by diabetes. In conclusion, these data demonstrate that reduced endothelium-mediated hyperpolarization contributes to attenuated uteroplacental vasodilation and SMC [Ca2+]i responses to ACh in diabetic pregnancy. Impaired endothelial Ca2+ signaling is in part responsible for endothelial dysfunction in the uterine resistance vasculature of diabetic rats. Pharmacological improvement of EC Ca2+ handling may provide an important strategy for the restoration of endothelial function and enhancement of maternal blood flow in human pregnancies complicated by diabetes.


2005 ◽  
Vol 288 (6) ◽  
pp. F1183-F1190 ◽  
Author(s):  
Rekha Singh ◽  
Ashok K. Singh ◽  
David J. Leehey

Recent evidence suggests that the intrarenal renin-angiotensin system (RAS) may play an important role in the development of glomerular changes associated with diabetic nephropathy. In this study, the glomerular RAS was examined in male Sprague-Dawley rats made diabetic with streptozotocin (STZ), and the findings compared with those obtained in control nondiabetic rats. In diabetic rat glomerular extracts, angiotensinogen and angiotensin II (ANG II) levels were increased significantly by 2.2- and 1.9-fold, respectively, compared with nondiabetic controls. No significant differences in ANG I and angiotensin-converting enzyme (ACE) levels were observed between these groups. The HPLC analysis of the glomerular extracts demonstrated that exogenous ANG I was converted into various ANG peptides including ANG II, ANG(1–9), and ANG(1–7). A significant increase in formation of ANG II from exogenous ANG I was observed in STZ rats compared with control rats. Preincubation of glomerular extracts with captopril resulted in a 20–30% decrease in ANG II conversion from exogenous ANG I in diabetic and control rats. The possible role of ANG(1–9) in formation of ANG II was examined by HPLC. Exogenous ANG(1–9) in glomerular extracts was converted into ANG II, this conversion being significantly higher in STZ rats than in control rats. These findings provide new information that ANG(1–9) is produced in rat glomerular extracts, can be converted to ANG II, and that this conversion is also stimulated in diabetic rat glomeruli. Thus this study demonstrates that in diabetic rats, glomerular ANG II levels are increased due to an increase in angiotensinogen and an increase in the formation of ANG II.


2007 ◽  
Vol 292 (2) ◽  
pp. H912-H920 ◽  
Author(s):  
Nazmi Yaras ◽  
Ayca Bilginoglu ◽  
Guy Vassort ◽  
Belma Turan

Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT1) and enhancement in PKC activity in the heart point out the role of AT1 blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT1 blocker, candesartan, on abnormal Ca2+ release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6–8 h at 37°C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca2+ transients, as well as depressed Ca2+ loading of sarcoplasmic reticulum, basal Ca2+ level, and spatiotemporal properties of the Ca2+ sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT1 receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca2+ release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.


2009 ◽  
Vol 87 (9) ◽  
pp. 711-719 ◽  
Author(s):  
Rui Zhao ◽  
Qing-wang Li ◽  
Jian Li ◽  
Tao Zhang

Lycium barbarum polysaccharide (LBP) has been shown to have hypoglycemic and antioxidative properties, although its mode of action is yet unknown. Because oxidative stress is implicated in the pathogenesis of diabetic nephropathy, we evaluated the protective effect of LBP-4, the major active component of Lycium barbarum, on the defensive antioxidative mechanism in kidneys in a streptozotocin-induced diabetic rat model. Moreover, we investigated the effects of LBP-4 on the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in isolated mesangial cells. The role of protein kinase C (PKC)-dependent and -independent pathways in LBP-4-reduced ERK1/2 was studied by bisindolylmaleimide (BIM) IV, an inhibitor of PKC. Diabetic rats treated with LBP-4 (10 mg/kg) for 8 weeks showed increased activity of antioxidant enzymes and increased scavenging of oxygen radicals, while the activity of PKC in the renal cortex was maintained at a physiological level. The decreased activation of ERK1/2 in mesangial cells, through the involvement of PKC, could explain the protective mechanism in kidneys of diabetic rats treated with LBP-4.


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