Efectos del tungstato de sodio y sulfato de vanadilo sobre la liberación de prostanoides del lecho vascular mesentérico de ratas diabéticas / Effects of sodium tungstate and vanadyl sulphate on the liberation of prostanoids of the mesenteric vascular bed in diabetic rats

La pérdida del rol modulador del endotelio podría estar implicada en la patogénesis de las complicaciones vasculares diabéticas. Los compuestos de metales de transición tales como wolframio y vanadio se han propuesto como posibles agentes en el tratamiento de la diabetes al simular los efectos de la insulina. El lecho vascular mesentérico interviene en la resistencia vascular y constituye una fuente de compuestos vasoactivos como los prostanoides. El objetivo de este trabajo fue estudiar los efectos de los tratamientos con tungstato de sodio y sulfato de vanadilo sobre los parámetros metabólicos y la liberación de prostanoides del lecho vascular mesentérico en un modelo experimental de diabetes inducida por estreptozotocina. En ratas diabéticas se observó un aumento significativo de los niveles plasmáticos de glucosa, triglicéridos y colesterol total. Por su parte, se observó una reducción significativa en la liberación de los prostanoides vasodilatadores como la prostaciclina y la prostaglandina E2 y del vasoconstrictor tromboxano A2 por el lecho vascular mesentérico. Tanto el tungstato de sodio como el sulfato de vanadilo normalizaron la glucemia, la trigliceridemia y la colesterolemia en las ratas diabéticas. Por otra parte, solo el tratamiento con tungstato de sodio revirtió la reducción en la liberación de prostanoides vasodilatadores, mejorando en los animales diabéticos la relación prostaciclina/tromboxano, un indicador de disfunción vascular. En conclusión, a diferencia del sulfato de vanadilo, el tungstato de sodio demuestra ser más eficaz para controlar las alteraciones metabólicas y de la producción de prostanoides vasodilatadores observadas en la diabetes experimental inducida por estreptozotocina

The loss of the modulator role of the endothelium could be involved in the pathogenesis of diabetic vascular complications. Transition metal compounds, such as tungsten and vanadium, have been proposed as possible agents in the treatment of diabetes by simulating the effects of insulin. The mesenteric vascular bed intervenes in vascular resistance and is a source of vasoactive compounds, such as prostanoids. The aim of this work was to study the effects of sodium tungstate and vanadyl sulphate treatments on the metabolic parameters and the release of prostanoids of the mesenteric vascular bed in an experimental model of Streptozotocin-induced diabetes. In diabetic rats, a significant increase was observed in plasma levels of glucose, triglycerides and total cholesterol. On the other hand, there was a significant reduction in the release of vasodilator prostanoids, such as prostacyclin and prostaglandin E2 and vasoconstrictor thromboxane A2 through the mesenteric vascular bed. Both sodium tungstate and vanadyl sulphate normalised glycaemia, triglyceridaemia and cholesterolaemia in rats diabetics. On the other hand, only treatment with sodium tungstate reversed the reduction in the release of vasodilator prostanoids, improving in diabetic animals the prostacyclin/thromboxane ratio, an indicator of vascular dysfunction. In conclusion, unlike vanadyl sulphate, sodium tungstate is shown to be more effective in controlling metabolic changes and the production of vasodilator prostanoids observed in experimental diabetes induced by streptozotocin

Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta.

Effects of endothelial removal and hypoxia on responses to adenosine, 5'-(N-ethylcarboxamido)-adenosine (NECA), 2-chloroadenosine, N6-cyclohexyladenosine (CHA), sodium nitroprusside, and acetylcholine were examined in guinea pig aortic rings. Rings contracted with 2 microM prostaglandin F2 alpha (PGF2 alpha) relaxed in a dose-dependent manner in response to all drugs. The order of potency of adenosine compounds was NECA greater than 2-chloroadenosine greater than adenosine greater than CHA. Endothelial rubbing potentiated the PGF2 alpha response by 11 +/- 3%, eliminated the acetylcholine (ACh) response, but had no effect on nitroprusside and CHA responses. Responses to adenosine, NECA, and 2-chloroadenosine were significantly depressed by rubbing (P less than 0.05). Oxyhemoglobin (5 microM) and metyrapone (0.1 mM) reduced ACh responses in intact rings but had no effect on the adenosine and nitroprusside responses. Indomethacin treatment (10 microM) did not alter ACh, nitroprusside, or adenosine responses in intact rings. Hypoxia (10% O2) potentiated maximal responses to adenosine (+26 +/- 3%) and nitroprusside (+28 +/- 4%) in intact and rubbed rings and reduced the maximal response to ACh in intact rings (-28 +/- 3%). It is concluded that 1) adenosine mediates relaxation in guinea pig aorta by endothelial-dependent and -independent mechanisms, 2) receptors involved in both endothelial-dependent and -independent relaxations are characteristic of the A2 adenosine subtype, 3) the endothelial response appears unrelated to EDRF or prostanoid release, and 4) the adenosine response is significantly potentiated by hypoxia.

Role of prostanoids in cerebrovascular responses during seizures in piglets.

We examined the role of prostanoids to bicuculline-induced seizures in newborn pigs. Using the closed cranial window method and radioimmunoassay for prostanoids, we found that pial arterioles dilated during seizures; this dilation was associated with increased cortical periarachnoid cerebrospinal fluid (CSF) levels of prostaglandin E2, 6-ketoprostaglandin F1 alpha, prostaglandin F2 alpha, and thromboxane B2. Using radioactive microspheres, we found cerebral blood flow (CBF) increased dramatically during seizures in piglets. To examine the effects of pharmacological blockade of cyclooxygenase, we determined CBF in piglets pretreated with indomethacin (5 mg/kg) and in a corresponding group of piglets made hypothermic to be sure preseizure CBF values were similar. In the hypothermic group, CBF increased during seizure, but the increase in CBF during seizure in the indomethacin group was reduced dramatically in all brain areas. We conclude that 1) bicuculline-induced seizures result in pial arteriolar dilation and increased CBF; 2) CSF levels of prostanoids increase during seizures; and 3) pretreatment with indomethacin severely blunts increases in CBF during seizures.

Role of glomerular prostanoid in control of glomerular filtration rate in rats.

It is generally accepted that the main action of glomerular prostanoids (GPs) on glomerular filtration rate (GFR) is to modulate the activity of different vasoconstrictors, specially in states of renal hypoperfusion. However it was also suggested that GPs may directly affect GFR. The present study was focused on this last hypothesis, in different experimental models, in rats. In adriamycin induced acute renal failure, the transient decrease of GFR is associated with higher levels of thromboxane B2. Later on, when GFR returns to normal, vasodilator prostaglandins synthesis was also increased. In captopril induced renal failure in Na depleted rats (where GPs synthesis remained normal), stimulation of PGE2 and PGI2 production by K and NaCl was associated with a significant improvement of GFR. Furthermore, the increase in GFR induced by NaCl was prevented by inhibition of prostaglandin synthesis. Infusion of atrial natriuretic peptide in euvolemic rats induce a marked elevation both of GFR and PGE2 synthesis. It was abolished by previous administration of prostaglandin synthesis inhibitor. In conclusion, glomerular prostanoids may influence GFR, either directly, or as mediator or modulator of other vasoactive hormones.

The multimolecular cascade of spinal cord injury. Studies on prostanoids, calcium, and proteinases.

Experimental spinal cord injury in animals induced by weight drop produces neurological deficit and paralysis. Correlation of the progressive morphological changes in the lesion by both light and electron microscopy with the biochemical alterations revealed ischemia, edema, hemorrhage, tissue necrosis, granular changes in axons, vesicular degeneration of myelin and axonal calcification. The biochemical pathology was that of degradation of axonal (neurofilaments) and myelin proteins (MBP and PLP) with increased activities of proteolytic enzymes and particularly the neutral proteinase. The level of total calcium increased progressively in the lesion to a peak at 8 hrs. and subsequently remained constant thereafter. The capacity of calcium for activating proteinases and lipases and fostering the degradation of axon and myelin proteins as well as the liberation of arachidonic acid required for the synthesis of prostanoids must be relevant. An increased production of prostanoids is indicated by elevation of thromboxane (TxB2), a stable metabolite of TXA2 at 1 hour after injury. The 6-keto-PG1(1)a was also increased but to a lesser extent. We suspect that the activation of arachidonic acid metabolism contributes to post-traumatic vascular injury and the progressive ischemia. These putative roles for calcium in proteolysis and lipolysis, inducing degradation of macromolecules and production of prostanoids which initiate edema, lysolecithin a myelinolytic factor and mitochondrial dysfunction in spinal cord injury are discussed.

[The significance of eicosanoids in glomerular diseases]. / Die Bedeutung von Eicosanoiden bei glomerulären Erkrankungen.

Prostanoids are local cyclooxygenase products, synthesized by mesangial and epithelial cells of the glomerulus as well as by a variety of inflammatory cells and platelets. Prostaglandins and thromboxane have direct vasodilatory and vasoconstrictory effects and can modulate glomerular function. Arachidonic acid, the main substrate for cyclooxygenase, can also be metabolized by the lipoxygenase pathway to leukotrienes, substances which are primarily synthesized in inflammatory cells. In several models induction of immunologic glomerular injury is associated with an increased glomerular formation of cyclooxygenase and lipoxygenase products. The changes in cyclooxygenase products have been shown to account for some hemodynamic changes found in some of these models. Increased renal prostanoid formation is also present in patients with glomerular disease. There is some evidence that increased renal PG-formation in patients with moderate glomerular disease regulates GFR and mediates proteinurie in some of these patients. Leukotrienes are chemotactive substances which modulate the function of inflammatory cells, stimulate the growth of mesangial cells, and constrict mesangial cells in culture. Thus, these compounds might be mediators in the induction of immune mediated glomerular disease.

Prostanoid modulation (mediation?) of certain behavioral effects of ethanol.

Prostaglandin E1 (PGE1) and prostanoid precursor fatty acids enhance the acute sedative effects of ethanol in mice, and reduce the intensity of withdrawal after chronic exposure to ethanol. Aspirin, and other inhibitors of prostanoid synthesis, attenuate ethanol's sedative effects, and interfere with the beneficial effects of prostanoid precursors (but not of PGE1 itself) in withdrawal. Neither aspirin nor indomethacin administered alone affect withdrawal behavior. In contrast, ethanol impairment of rotorod behavior is not affected by prostanoid precursors nor by aspirin. These findings support a role for prostanoids as modulators (? mediators) of certain direct effects of ethanol and a role for prostanoid deficiency in the pathogenesis of withdrawal behavior.

The biology, pathophysiology and control of eicosanoids in inflammation.

The involvement in inflammatory conditions of those cyclo-oxygenase and lipoxygenase derivatives of arachidonic acid (5,8,11,14-eicosatetraenoic acid), which are known as the eicosanoids, is reviewed in the light of recent studies. Although it is now generally recognized that cyclo-oxygenase products are fundamental to the inflammatory process as chemical mediators, and that inhibition of the cyclo-oxygenase enzyme pathway explains the mode of action of most non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed in veterinary practice, evidence for the involvement of lipoxygenase products of arachidonate metabolism in inflammation is increasing. The leukotrienes (LTs) are 5-lipoxygenase-derived eicosanoids which have been shown to be leucotactic and involved in anaphylactic and hypersensitivity reactions. Leucocytes, drawn to sites of injury by chemotaxis, themselves liberate pro-inflammatory eicosanoids which perpetuate the response and may aggravate the clinical condition. At therapeutic dose rates, most NSAIDs have no effect on the biosynthesis of LTs, whereas corticosteroids, by inhibiting the release of arachidonic acid, may prevent the formation of both cyclo-oxygenase and lipoxygenase products. However, because of the undesirable side-effects of steroids, the clinical use of these agents in treating inflammatory conditions is sometimes limited. Novel non-steroid inhibitors of cyclo-oxygenase and lipoxygenase enzyme pathways could offer more effective and safer control of inflammation in animals.

Eicosanoids in health and in disease: an appraisal.

Oxygenation of the 20-carbon polyunsaturated fatty acid, arachidonic acid, which is found in most body cells of all domestic animals, leads to the formation of a group of compounds possessing biological activity. These compounds, collectively known was eicosanoids, currently receive considerable attention owing to their involvement in a wide variety of physiological and pathophysiological processes. Particular interest has been focussed in recent years on the role and control of prostanoids and leukotrienes in inflammatory and allergic conditions in animals and man. Arachidonic acid metabolites are also recognised to be intimately involved in reproductive and perinatal processes; with platelet aggregation and vascular homeostasis; kidney function; fever; certain tumours and many other normal and disease conditions. Eicosanoid research in veterinary medicine is still at a relatively early stage in many respects and in this review an attempt is given to highlight some of the functions of this important series of compounds both in health and in disease. As more evidence comes to light, it is possible that veterinary surgeons may have to consider revising their clinical approach to the treatment of certain disease states where eicosanoids are implicated or where chemotherapy may interfere with their normal physiological activities.