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1.
J Diabetes Res ; 2017: 4729284, 2017.
Article in English | MEDLINE | ID: mdl-28293643

ABSTRACT

Spinal glial cell activation and cytokine secretion have been implicated in the etiology of neuropathic pain in a number of experimental models, including diabetic neuropathy. In this study, streptozotocin- (STZ-) induced diabetic rats were either untreated or treated with gabapentin (50 mg/kg/day by gavage for 2 weeks, from 6 weeks after STZ). At 8 weeks after STZ, hypersensitivity was confirmed in the untreated diabetic rats as a reduced response threshold to touch, whilst mechanical thresholds in gabapentin-treated diabetic rats were no different from controls. Diabetes-associated thermal hypersensitivity was also ameliorated by gabapentin. We performed a cytokine profiling array in lumbar spinal cord samples from control and diabetic rats. This revealed an increase in L-selectin, an adhesion molecule important for neutrophil transmigration, in the spinal cord of diabetic rats but not diabetic rats treated with gabapentin. Furthermore, we found an increase in the number of neutrophils present in the parenchyma of the spinal cord, which was again ameliorated in gabapentin-treated diabetic rats. Therefore, we suggest that dysregulated spinal L-selectin and neutrophil infiltration into the spinal cord could contribute to the pathogenesis of painful diabetic neuropathy.


Subject(s)
Diabetes Mellitus, Experimental/pathology , Diabetic Neuropathies/pathology , Neuralgia/pathology , Neutrophil Infiltration/physiology , Spinal Cord/pathology , Amines/pharmacology , Amines/therapeutic use , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Cyclohexanecarboxylic Acids/pharmacology , Cyclohexanecarboxylic Acids/therapeutic use , Diabetes Mellitus, Experimental/immunology , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/immunology , Gabapentin , Male , Neuralgia/drug therapy , Neuralgia/immunology , Neutrophil Infiltration/drug effects , Pain Threshold/drug effects , Rats , Rats, Sprague-Dawley , Spinal Cord/immunology , gamma-Aminobutyric Acid/pharmacology , gamma-Aminobutyric Acid/therapeutic use
2.
Nat Rev Urol ; 11(4): 231-41, 2014 04.
Article in English | MEDLINE | ID: mdl-24619381

ABSTRACT

Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS.


Subject(s)
Erectile Dysfunction/drug therapy , Lower Urinary Tract Symptoms/drug therapy , Phosphodiesterase 5 Inhibitors/therapeutic use , Prostatic Hyperplasia/drug therapy , Vascular Diseases/complications , Erectile Dysfunction/etiology , Humans , Lower Urinary Tract Symptoms/etiology , Male , Microvessels , Prostatic Hyperplasia/complications
3.
J Sex Med ; 10(12): 2967-74, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24034566

ABSTRACT

INTRODUCTION: The vasa nervorum comprises a network of small diameter blood vessels that provide blood supply to nerves and ganglia. The cell bodies of autonomic nerves innervating the urogenital organs are housed in the major pelvic ganglia (MPG) in rats. The vasa nervorum of rat MPG have not been characterized previously, and it is not known whether these blood vessels are innervated by neuronal nitric oxide synthase (nNOS) containing nitrergic nerves. AIM: To characterize the blood vessels in and around the rat MPG and to assess their nitrergic innervation. MAIN OUTCOME MEASURES: Characterization of small blood vessels in and around the rat MPG and expression of nNOS in nerve fibers around those blood vessels. METHODS: MPG were obtained from healthy Sprague Dawley rats, fixed in paraformaldehyde, frozen and sectioned using a cryostat. The blood vessels and their nitrergic innervation were assessed with immunohistochemistry using antibodies against alpha-smooth muscle actin (smooth muscle marker), CD31 (endothelial marker), collagen IV (basal membrane marker) and nNOS. The immunofluorescence was imaged using a laser scanning confocal microscope. RESULTS: The neuronal cell bodies were contained within a capsule in the MPG. Blood vessels were observed within the capsule of the MPG as well as outside the capsule. The blood vessels inside the capsule were CD31-positive capillaries with no smooth muscle staining. Outside the capsule capillaries, arterioles and venules were observed. The extra-capsular arterioles and venules, but not the capillaries were innervated by nNOS-positive nerve fibers. CONCLUSIONS: This study, to our knowledge, is the first to demonstrate the blood vessel distribution pattern and their nitrergic innervation in the rat MPG. While similar studies in human pelvic plexus are warranted, these results suggest that the blood flow in the MPG may be regulated by nitrergic nerve fibers and reveal a reciprocal relationship between nerves and blood vessels.


Subject(s)
Ganglia, Sensory/blood supply , Hypogastric Plexus/blood supply , Nerve Fibers/physiology , Nitrergic Neurons/physiology , Vasa Nervorum/innervation , Actins/metabolism , Animals , Humans , Immunohistochemistry , Male , Muscle, Smooth/metabolism , Rats , Rats, Sprague-Dawley
4.
Eur J Pharmacol ; 719(1-3): 180-186, 2013 Nov 05.
Article in English | MEDLINE | ID: mdl-23872412

ABSTRACT

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.


Subject(s)
Blood Vessels/physiopathology , Diabetic Neuropathies/etiology , Diabetic Neuropathies/physiopathology , Animals , Humans , Ischemia/complications , Peripheral Nerves/blood supply , Vasa Nervorum/physiopathology
5.
Angiology ; 61(7): 651-68, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20547541

ABSTRACT

In diabetes mellitus (DM) reduced motor and sensory properties of peripheral nerves are linked with the dysfunction of neural vasculature. We investigated C-fibers and microvessels of sciatic nerve of normal, DM, and DM + epoetin delta-treated rats. C-fibers immunoreactive for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), epoetin receptor (EpoR), and common beta receptor subunit of the interleukin 3 receptor (IL-3Rbeta) were present in all rats, whereas in DM and epoetin-treated rats C-fibers also showed neuronal (nNOS) and inducible (iNOS) nitric oxide synthases. The cross-sectional area of CGRP-positive C-fibers was decreased in DM, but it recovered after epoetin treatment. In all conditions, vascular endothelium showed scarce immunolabeling for endothelial nitric oxide synthase (eNOS); the profound immunoreactivity for eNOS, EpoR, and IL-3Rbeta was in pericytes. Some perivascular autonomic nerves were damaged and IL-3Rbeta positive. Findings are discussed in terms of declined sensory conduction velocity in DM, its improvement after epoetin treatment, and the possible vascular contribution to these phenomena.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Diabetic Neuropathies/physiopathology , Erythropoietin/pharmacology , Microvessels/pathology , Nerve Fibers, Unmyelinated/drug effects , Pericytes/pathology , Sciatic Nerve/drug effects , Sciatic Nerve/pathology , Animals , Calcitonin Gene-Related Peptide/metabolism , Cytokine Receptor Common beta Subunit/metabolism , Erythropoietin/therapeutic use , Immunohistochemistry , Male , Microvessels/drug effects , Nerve Fibers, Unmyelinated/pathology , Nerve Fibers, Unmyelinated/ultrastructure , Neural Conduction/drug effects , Neural Conduction/physiology , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type II/metabolism , Pericytes/drug effects , Pericytes/physiology , Rats , Rats, Sprague-Dawley , Recombinant Proteins , Regional Blood Flow/drug effects , Sciatic Nerve/cytology
6.
J Sex Med ; 7(10): 3396-403, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20456626

ABSTRACT

INTRODUCTION: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated. AIM: To assess whether treatment with a novel PARP-1 inhibitor, GPI 15427, could improve neurovascular dysfunction in corpus cavernosum (CC) from diabetic mice. METHODS: Diabetes was induced by streptozotocin in male MF1 mice; duration was 6 weeks. Intervention GPI 15427 treatment (20mg/kg/day intraperitoneal [i.p.]) was given for 2 weeks following 4 weeks of untreated diabetes. CC strips were mounted in aerated organ baths for measurement of pharmacological or electrical stimulation-evoked changes in smooth muscle tension. MAIN OUTCOME MEASURES: Contractile responses to noradrenergic stimulation and to pharmacological agents stimulating endothelium-dependent and -independent relaxation, and nerve-mediated relaxations against a background precontraction. RESULTS: Contractions in response to phenylephrine or activation of noradrenergic nerves were not significantly altered by diabetes. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted CC was approximately 28% reduced by diabetes: GPI 15427 treatment completely corrected this diabetic deficit. Similarly, maximal nitric oxide (NO)-mediated endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, against phenylephrine precontraction, were attenuated approximately 37% and 23% by diabetes, respectively. These deficits were completely reversed by PARP-1 inhibition. Furthermore, GPI 15427 corrected a modest diabetic deficit in sensitivity to nitroprusside (EC(50) reduced by 0.14 log units); a similar trend was observed for acetylcholine-induced relaxation. CONCLUSIONS: GPI 15427 treatment provides marked benefits for NO-dependent neurovascular function in diabetic mouse CC. Therefore, PARP-1 inhibition may be worthy of further investigation for diabetes-associated ED.


Subject(s)
Diabetes Mellitus, Experimental/complications , Impotence, Vasculogenic/drug therapy , Organic Chemicals/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors , Acetylcholine/pharmacology , Animals , Blood Glucose/analysis , Dose-Response Relationship, Drug , Impotence, Vasculogenic/etiology , Male , Mice , Nitroprusside/pharmacology , Organic Chemicals/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Penile Erection/drug effects , Penile Erection/physiology , Penis/drug effects , Penis/physiopathology , Phenylephrine/pharmacology , Poly(ADP-ribose) Polymerases/physiology
7.
Angiology ; 61(4): 405-14, 2010 May.
Article in English | MEDLINE | ID: mdl-19815604

ABSTRACT

Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with renal failure. It is now known that these agents also show a broad range of cell- and tissue-protective effects. In the current study, we explored whether an ESA, epoetin delta, affects vascular pathology linked to diabetes mellitus (DM). In a rat model of streptozotocin-induced DM, we investigated, by pre-embedding electron-immunocytochemistry, whether epoetin delta affects DM-induced structural changes in cerebrovascular endothelium of the rat basilar artery and influences the subcellular distribution of endothelial nitric oxide synthase (eNOS). Epoetin delta treatment influenced DM-induced changes to the distribution of eNOS in, and the structure of, the endothelial cell. This may indicate potential beneficial effects of epoetin delta on cerebrovascular endothelium and suggests eNOS as a possible target molecule of epoetin delta in DM.


Subject(s)
Basilar Artery/drug effects , Basilar Artery/pathology , Diabetes Mellitus, Experimental/pathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Erythropoietin/pharmacology , Animals , Basilar Artery/enzymology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/enzymology , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Endothelial Cells/pathology , Endothelium, Vascular/enzymology , Male , Nitric Oxide Synthase Type III/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Proteins , Streptozocin
8.
Curr Drug Targets ; 9(1): 60-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18220713

ABSTRACT

Neuropathy is a common complication of diabetes mellitus, which reduces the quality of life and may be life-threatening. The etiology is complex and multifactorial: hyperglycemia and dyslipidemia give rise to oxidative stress and formation of advanced glycation and lipoxidation end products. These stimulate inflammatory processes, nuclear factor kappa B (NFkappaB) activation being of central importance. Many of the drugs that have been developed for treatment of diabetic complication at least in part work through suppressing either NFkappaB activation itself, or the production of cytokines that stimulate NFkappaB, such as tumor necrosis factor (TNF) alpha. To date there have been few tests of drugs that are specific inhibitors of the NFkappaB / TNFalpha axis. However preliminary results in animal models are encouraging and go some way in establishing the NFkappaB cascade as an important therapeutic target for diabetic vascular complications in general, and neuropathy in particular.


Subject(s)
Diabetic Neuropathies/immunology , NF-kappa B/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Diabetic Neuropathies/etiology , Diabetic Neuropathies/physiopathology , Disease Models, Animal , Drug Delivery Systems , Humans , NF-kappa B/metabolism , Oxidative Stress , Tumor Necrosis Factor-alpha/metabolism
9.
Exp Neurol ; 207(1): 23-9, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17560573

ABSTRACT

Interleukin-6 (IL-6) is a member of the neuropoietic cytokine family and has a multifunctional biological role in regulating the immune response, acute phase reactions, and hematopoiesis. IL-6 is also important in neural development and has neurotrophic actions. The aim was to ascertain whether IL-6 treatment could rectify some of the adverse early changes in neurovascular function in streptozotocin-induced diabetic rats. After 4 weeks of untreated diabetes, rats were treated with IL-6 (1-10 microg/kg thrice weekly) for 4 weeks. Diabetes caused 22% and 22.5% reductions in sciatic nerve motor and saphenous nerve sensory conduction velocity, respectively, which were dose dependently corrected by treatment. Diabetic rats also showed thermal hyperalgesia and tactile allodynia, which were completely corrected by IL-6; however, IL-6 was ineffective against mechanical hyperalgesia. Sciatic nerve endoneurial perfusion was 42.2% reduced by diabetes and blood flow was returned to the nondiabetic range by 10 microg/kg IL-6 treatment. The ED(50) values for these actions ranged from 1.2 microg/kg for sensory conduction velocity to 3.2 microg/kg for sciatic nerve perfusion. Thus, IL-6 treatment improved several measures of nerve dysfunction in experimental diabetes, and these effects correlated with a recovery of nerve blood flow. The magnitude of these beneficial effects and the potential joint neurotrophic and vascular action suggests that IL-6 could be a candidate for further evaluation in clinical trials of diabetic neuropathy.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Diabetic Neuropathies/physiopathology , Interleukin-6/pharmacology , Peripheral Nerves/blood supply , Peripheral Nerves/physiopathology , Animals , Dose-Response Relationship, Drug , Femoral Nerve/physiopathology , Hyperalgesia/physiopathology , Interleukin-6/administration & dosage , Male , Neural Conduction/drug effects , Neurons, Afferent , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Sciatic Nerve/physiopathology
10.
Eur J Pharmacol ; 561(1-3): 63-71, 2007 Apr 30.
Article in English | MEDLINE | ID: mdl-17291486

ABSTRACT

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.


Subject(s)
Allopurinol/pharmacology , Diabetic Angiopathies/drug therapy , Diabetic Nephropathies/drug therapy , Enzyme Inhibitors/pharmacology , Neural Conduction/drug effects , Reactive Oxygen Species/metabolism , Xanthine Oxidase/drug effects , Acetylcholine/metabolism , Allopurinol/administration & dosage , Animals , Diabetes Mellitus, Experimental , Diabetic Angiopathies/enzymology , Diabetic Nephropathies/enzymology , Diabetic Neuropathies/drug therapy , Disease Models, Animal , Enzyme Inhibitors/administration & dosage , Ganglia, Autonomic/blood supply , Ganglia, Autonomic/drug effects , Hyperalgesia/drug therapy , Male , Mesenteric Artery, Superior/drug effects , Mesenteric Artery, Superior/pathology , Pain/drug therapy , Polarography , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Sciatic Nerve/blood supply , Sciatic Nerve/drug effects , Xanthine Oxidase/metabolism
11.
Curr Diabetes Rev ; 3(3): 149-58, 2007 Aug.
Article in English | MEDLINE | ID: mdl-18220666

ABSTRACT

Diabetes is a major risk factor for erectile dysfunction. The condition degrades both neural and vascular endothelium penile control systems. Experimental and epidemiological evidence suggest that both hyperglycemia and dyslipidemia contribute to the etiology. These are the driving forces for elevated oxidative stress and the formation of advanced glycation and lipoxygenation end products, the major target being the nitric oxide systems of nerve and endothelium. This causes reversible functional loss followed by less reversible degenerative changes. These mechanisms have direct effects, such as the nitric oxide quenching, but perhaps more importantly, indirect effects on the regulation of nitric oxide synthase expression and activity, which can involve recruitment of proinflammatory cell signaling pathways. The latter include protein kinase C, mitogen-activated kinases, and the nuclear factor kappa B cascade. Diabetes also changes the trophic influences on nerve and endothelium. Together, these form potential therapeutic targets against diabetic erectile function, and indeed vascular disease in general.


Subject(s)
Diabetes Complications/pathology , Diabetes Mellitus, Experimental/complications , Erectile Dysfunction/etiology , Animals , Cholesterol/biosynthesis , Glycation End Products, Advanced/metabolism , Glycation End Products, Advanced/physiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/etiology , Male , Models, Biological , Nitric Oxide/physiology , Nitric Oxide Synthase/metabolism , Oxidative Stress/physiology , Penile Erection/drug effects , Penile Erection/physiology , Reactive Oxygen Species/pharmacology , Signal Transduction/physiology , rho-Associated Kinases/physiology , rhoA GTP-Binding Protein/physiology
12.
Urology ; 68(1): 214-8, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16806421

ABSTRACT

OBJECTIVES: Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-kappaB, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-kappaB deactivation against direct antioxidant effects has been difficult. NF-kappaB is negatively regulated by the inhibitor of kappaB (IkappaB) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the IkappaB kinase 2 inhibitor, AS602868, on corpus cavernosum function in diabetic mice. METHODS: Diabetes was induced by streptozotocin; the duration was 6 weeks. Intervention AS602868 treatment (100 mg/kg/day) was given for 2 weeks after 4 weeks of untreated diabetes. Corpora cavernosum were isolated in organ baths for measurement of agonist-evoked or electrical stimulation-evoked smooth muscle tensions. RESULTS: The maximal nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was reduced approximately 30% by diabetes (P <0.001). AS602868 treatment completely reversed the deficit (P <0.001). Maximal nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 32% by diabetes (P <0.05). This was completely restored by IkappaB kinase 2 inhibition (P <0.01). Furthermore, AS602868 treatment also completely corrected (P <0.01) an approximate 20% diabetic deficit (P <0.001) in maximal endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside. CONCLUSIONS: Inhibition of IkappaB kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-kappaB activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , I-kappa B Kinase/antagonists & inhibitors , NF-kappa B/physiology , Penile Erection/physiology , Animals , Atropine/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , Guanethidine/pharmacology , In Vitro Techniques , Male , Mice , Mice, Mutant Strains , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Nitric Oxide Donors/pharmacology , Nitroprusside/pharmacology , Penis/blood supply , Penis/physiology , Phenylephrine/pharmacology , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology
13.
Planta Med ; 72(6): 494-500, 2006 May.
Article in English | MEDLINE | ID: mdl-16773532

ABSTRACT

Hyperglycaemia in diabetes mellitus results in oxidative stress and pro-inflammatory changes which contribute to vascular complications including endothelial dysfunction and peripheral neuropathy. The aim of this study was to examine whether treatment with the dominant ingredient of clove oil, eugenol, which has antioxidant and anti-inflammatory properties, could improve diabetic vascular and nerve function in streptozotocin-induced diabetic rats. Intervention treatment was given for 2 weeks following 6 weeks of untreated diabetes. Dose-ranging studies on diabetic deficits in sciatic nerve motor and saphenous nerve sensory nerve conduction velocities gave ED50 values of 28 mg/kg and 9 mg/kg, respectively, conduction velocity being within the non-diabetic range at a dose of 200 mg/kg. Sciatic nerve endoneurial blood flow was 49% reduced by diabetes and this was completely corrected by 200 mg/kg eugenol treatment. Gastric fundus maximum nitrergic nerve-mediated relaxation was 44% reduced by diabetes; eugenol corrected this deficit by 69%. For renal artery rings, maximum endothelium-dependent relaxation to acetylcholine was 51% reduced by diabetes; eugenol corrected this deficit by 60%, with improvements in both nitric oxide and endothelium-derived hyperpolarising factor (EDHF)-mediated vasorelaxation components. Diabetes increased renal artery sensitivity to phenylephrine-mediated contraction, however, this was unaffected by eugenol treatment. Thus, aspects of both vascular and neural complications in experimental diabetes are improved by eugenol, which could have potential therapeutic implications for diabetic neuropathy and vasculopathy.


Subject(s)
Antioxidants/pharmacology , Clove Oil/pharmacology , Diabetic Angiopathies/drug therapy , Diabetic Neuropathies/drug therapy , Eugenol , Phytotherapy , Animals , Antioxidants/administration & dosage , Antioxidants/therapeutic use , Clove Oil/administration & dosage , Clove Oil/therapeutic use , Diabetes Mellitus, Experimental , Diabetic Angiopathies/chemically induced , Diabetic Neuropathies/chemically induced , Dose-Response Relationship, Drug , Male , Neural Conduction/drug effects , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Renal Artery/physiology , Sciatic Nerve/blood supply , Sciatic Nerve/physiology , Sciatic Neuropathy/chemically induced , Sciatic Neuropathy/drug therapy , Splanchnic Circulation/drug effects , Streptozocin , Vasodilation/drug effects
14.
Eur J Pharmacol ; 538(1-3): 148-53, 2006 May 24.
Article in English | MEDLINE | ID: mdl-16650403

ABSTRACT

Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.


Subject(s)
Benzamides/pharmacology , Calpain/antagonists & inhibitors , Diabetes Mellitus, Experimental/physiopathology , Nitrergic Neurons/drug effects , Penis/drug effects , Acetylcholine/pharmacology , Animals , Blood Glucose/metabolism , Body Weight , Diabetes Mellitus, Experimental/blood , Dose-Response Relationship, Drug , Electric Stimulation , Male , Mice , Muscle Relaxation/drug effects , Muscle, Smooth, Vascular/drug effects , Nitrergic Neurons/physiology , Nitroprusside/pharmacology , Organ Size , Penis/innervation , Penis/physiopathology , Phenylephrine/pharmacology , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology
15.
Nitric Oxide ; 15(4): 344-50, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16644248

ABSTRACT

Diabetes mellitus compromises nitric oxide (NO)-mediated endothelium-dependent relaxation of blood vessels, which has been linked to the excessive generation of reactive oxygen species. There are also deleterious effect on nitrergic innervation, contributing to autonomic neuropathy symptoms such as impotence and gastroporesis. Poly(ADP-ribose) polymerase (PARP) is a nuclear protein stimulated by DNA damage, caused, for example, by oxidative stress. Activation has been linked to impaired endothelial nitric oxide synthase (eNOS)-mediated vasodilation in experimental diabetes. There is no information on the potential role of PARP in nitrergic nerve dysfunction, therefore, the aim was to examine the effects of PARP inhibition, using 3-aminobenzamide (3-AB) on neurally mediated gastric fundus relaxation in streptozotocin-induced diabetic rats. Eight weeks of diabetes caused a 42.5% deficit in maximum relaxation of in vitro gastric fundus strips to electrical stimulation of the non-adrenergic non-cholinergic innervation. This was largely prevented or corrected (4 weeks of treatment following 4 weeks of untreated diabetes) by 3-AB. Diabetes also markedly attenuated the maintenance of relaxation responses to prolonged stimulation, and this was partially corrected by 3-AB treatment. Experiments in the presence of the NOS inhibitor, N(G)-nitro-L-arginine, and/or blockade of the co-transmitter, vasoactive intestinal polypeptide, by alpha-chymotrypsin, showed that the beneficial effects of 3-AB were primarily due to improved nitrergic neurotransmission. Thus, PARP plays an important role in defective nitrergic neurotransmission in experimental diabetes, which may have therapeutic implications for treatment of aspects of diabetic autonomic neuropathy.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Gastric Fundus/innervation , Poly(ADP-ribose) Polymerase Inhibitors , Synaptic Transmission , Animals , Diabetes Mellitus, Experimental/enzymology , Male , Rats , Rats, Sprague-Dawley
16.
Vet J ; 172(3): 455-9, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16249104

ABSTRACT

Kilham's rat virus (KRV) is a parvovirus commonly known to affect laboratory rats. Qualitative immunohistochemical analysis revealed that aorta isolated from KRV-infected streptozotocin (STZ)-induced diabetic adult rats expressed markedly greater levels of inducible nitric oxide synthase (iNOS) than aorta from KRV-infected controls. In contrast with the prevailing literature, nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was not blunted by STZ-diabetes, but was comparable to relaxations of aorta from controls. However, with increasing ex vivo duration, a decreased response to acetylcholine was observed in the STZ-diabetic aorta. In addition, whereas contraction responses to phenylephrine were not significantly altered over time in control tissue, aorta from STZ-diabetic rats developed increased tensions. The data suggest that increased iNOS-derived nitric oxide masks expected acetylcholine-mediated relaxation deficits as a result of KRV-infection, and that the deficit is unmasked by iNOS turnover ex vivo.


Subject(s)
Aorta, Thoracic/physiopathology , Diabetes Mellitus, Experimental/physiopathology , Nitric Oxide Synthase Type II/physiology , Parvoviridae Infections/physiopathology , Parvovirus/physiology , Animals , Aorta, Thoracic/enzymology , Aorta, Thoracic/immunology , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/virology , Endothelium, Vascular/enzymology , Endothelium, Vascular/immunology , Endothelium, Vascular/physiology , In Vitro Techniques , Male , Muscle Relaxation/physiology , Parvoviridae Infections/enzymology , Parvoviridae Infections/immunology , Rats , Rats, Sprague-Dawley
17.
Ann N Y Acad Sci ; 1043: 784-92, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16037306

ABSTRACT

Advanced glycation and lipoxidation end products (AGEs/ALEs) have been implicated in the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy, and retinopathy. This article reviews the evidence regarding the peripheral nerve and its vascular supply. Most investigations done to assess the role of AGEs/ALEs in animal models of diabetic neuropathy have used aminoguanidine as a prototypic inhibitor. Preventive or intervention experiments have shown treatment benefits for motor and sensory nerve conduction velocity, autonomic nitrergic neurotransmission, nerve morphometry, and nerve blood flow. The latter depends on improvements in nitric oxide-mediated endothelium-dependent vasodilation and is responsible for conduction velocity improvements. A mechanistic interpretation of aminoguanidine's action in terms of AGE/ALE inhibition is made problematic by the relative lack of specificity. However, other unrelated compounds, such as pyridoxamine and pyridoxamine analogues, have recently been shown to have beneficial effects similar to aminoguanidine, as well as to improve pain-related measures of thermal hyperalgesia and tactile allodynia. These data also stress the importance of redox metal ion-catalyzed AGE/ALE formation. A further approach is to decrease substrate availability by reducing the elevated levels of hexose and triose phosphates found in diabetes. Benfotiamine is a transketolase activator that directs these substrates to the pentose phosphate pathway, thus reducing tissue AGEs. A similar spectrum of improvements in nerve and vascular function were noted when using benfotiamine in diabetic rats. Taken together, the data provide strong support for an important role for AGEs/ALEs in the etiology of diabetic neuropathy.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Diabetic Angiopathies/prevention & control , Diabetic Neuropathies/prevention & control , Glycation End Products, Advanced/antagonists & inhibitors , Guanidines/therapeutic use , Lipid Peroxidation/physiology , Animals , Lipid Peroxidation/drug effects , Pyridoxamine/therapeutic use
18.
Eur J Pharmacol ; 502(1-2): 143-8, 2004 Oct 11.
Article in English | MEDLINE | ID: mdl-15464100

ABSTRACT

Peroxynitrite, the reaction product of nitric oxide and superoxide, may contribute to vascular tissue oxidant stress in diabetes mellitus. The aim was to establish whether the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) could improve nitric oxide-dependent autonomic nerve and microvascular penile function in the diabetic mouse. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention FeTMPyP treatment (25 mg kg(-1) day(-1)) was given for 2 weeks following 4 weeks untreated diabetes. Corpus cavernosum were isolated in organ baths for measurement of agonist or electrical stimulation-evoked nerve-mediated tension responses. Maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 35% reduced by diabetes; FeTMPyP treatment reversed this deficit by 45%. The concentration response-curve for nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated by diabetes; FeTMPyP restored the deficit to the nondiabetic range. Sensitivity (EC50) to the nitric oxide donor, sodium nitroprusside, was reduced by approximately 0.56 log10 M units in diabetes; however, FeTMPyP treatment failed to significantly reverse this deficit. Therefore, the peroxynitrite mechanism contributes to nitric oxide-dependent diabetic autonomic neuropathy and vasculopathy and may be a potential target for clinical trials using peroxynitrite decomposition catalysts.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Metalloporphyrins/therapeutic use , Penis/drug effects , Penis/physiology , Peroxynitrous Acid/metabolism , Animals , Diabetes Mellitus, Experimental/metabolism , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Metalloporphyrins/pharmacology , Mice , Vasodilation/drug effects , Vasodilation/physiology
19.
Eur J Pharmacol ; 475(1-3): 99-106, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12954365

ABSTRACT

Increased activity of the beta-isoform of protein kinase C (PKC) has been linked to the vascular and neural complications of diabetes mellitus. Treatment with the PKCbeta inhibitor, (s)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, (LY333531), improves somatic nerve function and blood flow in diabetic rats. The aim was to assess whether LY333531 treatment could prevent nitric oxide-dependent autonomic nerve and vascular dysfunction in a diabetic mouse model. Diabetes was induced by streptozotocin; duration was 4 weeks. Aorta and corpus cavernosum were isolated and mounted in organ baths and agonist or electrical stimulation-evoked nerve-mediated tension responses were examined. Maximum nitric oxide-mediated endothelium-dependent relaxation of phenylephrine-precontracted aorta and cavernosum to acetylcholine were more than 30% reduced by diabetes. LY333531 treatment (10 mg kg(-1) day(-1)) completely prevented the diabetic deficit in cavernosum, and 75% prevented the deficit in aorta. Maximum nitric oxide-dependent non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 43% reduced by diabetes; LY333531 attenuated the deficit by 44%. For diabetic aorta, but not cavernosum, sensitivity (EC50) to phenylephrine-mediated contraction was increased by approximately 0.85 log10 M units; LY333531 treatment completely prevented this effect. Thus, PKCbeta activation contributes to nitric oxide-dependent vascular and autonomic nerve dysfunction in diabetic mice and could prove suitable for further study in clinical trials of diabetic autonomic neuropathy and vasculopathy.


Subject(s)
Aorta, Thoracic/enzymology , Diabetes Mellitus, Experimental/enzymology , Penis/enzymology , Protein Kinase C/antagonists & inhibitors , Animals , Aorta, Thoracic/drug effects , Diabetes Mellitus, Experimental/physiopathology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , In Vitro Techniques , Indoles/pharmacology , Male , Maleimides/pharmacology , Mice , Mice, Inbred C57BL , Muscle Relaxation/drug effects , Muscle Relaxation/physiology , Penis/drug effects , Protein Kinase C/physiology , Protein Kinase C beta
20.
Diabetes ; 52(9): 2396-402, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12941781

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 endothelium-dependent 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.


Subject(s)
Aorta/physiology , Diabetes Mellitus, Experimental/drug therapy , Fluorobenzenes/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Penis/physiology , Pyrimidines , Sulfonamides , Acetylcholine/pharmacology , Animals , Aorta/drug effects , Cholesterol/biosynthesis , Diabetes Mellitus, Experimental/metabolism , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/metabolism , Electric Stimulation , Erectile Dysfunction/drug therapy , Erectile Dysfunction/metabolism , Male , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Penis/drug effects , Rosuvastatin Calcium , Vasodilation/drug effects , Vasodilator Agents/pharmacology
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