Effects of eugenol on nerve and vascular dysfunction in streptozotocin-diabetic rats.

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.

Effects of poly(ADP-ribose) polymerase inhibition on dysfunction of non-adrenergic non-cholinergic neurotransmission in gastric fundus in diabetic rats.

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.

Aviation medicine in the United Kingdom: cold war and peace dividend, 1946-2000.

This is the third of three brief papers that summarize the history of aviation medicine in the Royal Air Force. Unusually, at the end of the Second World War, British aviation medicine research did not enter a period of decline. The needs of the Royal Air Force during the Cold War ensured the continuing development of the RAF Institute of Aviation Medicine. However, reduction of the threat with the end of the Cold War led to the requirement for a peace dividend. British aviation medicine research has now entered a commercial era, competing for funding from industry as well as from the Royal Air Force.

Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes.

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.

Aviation medicine in the United Kingdom: from the end of World War I to the end of World War II, 1919-1945.

This is the second of three brief papers that summarize the history of Aviation Medicine in the Royal Air Force. British aviation medicine research was rescued from the doldrums of retrenchment after the end of the First World War by the need to support attempts on world records for height and speed. Despite this, the outbreak of the Second World War still found the British inadequately prepared. This part of the account of British aviation medicine research charts its transition from an organization with three full-time workers into a thriving research institute.

Aviation medicine in the United Kingdom: early years, 1911-1918.

This is the first of three brief papers that summarize the history of aviation medicine in the Royal Air Force. Just as the generals and politicians were slow to appreciate the potential of the airplane, so the medical establishment was slow in understanding that the flight environment involved medical and physiological challenges. This note outlines the development of research to support British military aviators up to the formation of the Royal Air Force in 1918.

Effects of alpha-lipoic acid on impaired gastric fundus innervation in diabetic rats.

Diabetes mellitus is a major cause of neuropathy, leading to adverse effects including autonomic gastrointestinal dysfunction. Oxidative stress contributes to the etiology of diabetic neuropathy. The aim was to examine whether treatment with the antioxidant, alpha-lipoic acid (LA), could prevent or correct diabetic functional defects in the gastric fundus non-adrenergic, non-cholinergic (NANC) nerves, which use nitric oxide as their major neurotransmitter. LA (100 mg/kg/d) was given in a prevention study for 8 weeks following streptozotocin-diabetes induction, and in an intervention study for 4 weeks after 4 weeks of untreated diabetes. Fundus strips were studied in vitro after precontraction with 5-hydroxytryptamine in the presence of guanethidine and atropine to isolate NANC relaxation to electrical field stimulation. After 4 and 8 weeks of diabetes, there were 26% and 48% deficits in maximum relaxation, respectively. Prevention LA treatment gave 83% protection; intervention LA prevented the deterioration between 4 and 8 weeks of diabetes and corrected the initial 4 week deficit by 56%. Diabetes also resulted in a failure to maintain relaxation for prolonged stimulation, which was prevented by LA. Thus, LA prevented and reversed the development of impaired gastric fundus NANC responses in diabetic rats, which has potential therapeutic implications for gastrointestinal autonomic neuropathy.