Metabolic Regulation in Adipocytes by Prostanoid Receptors.

Prostanoids are a group of typical lipid mediators that are biosynthesized from arachidonic acid by the actions of cyclooxygenases and their subsequent terminal synthases. Prostanoids exert a wide variety of actions through their specific membrane receptors on target cells. In addition to their classical actions, including fever, pain, and inflammation, prostanoids have been shown to play pivotal roles in various biological processes, such as female reproduction and the maintenance of vascular and gut homeostasis. Moreover, recent research using mice deficient in each of the prostanoid receptors, or using agonists/antagonists specific for each receptor clarified novel actions of prostanoids that had long been unknown, and the mechanisms therein. In this review, we introduce recent advances in the fields of metabolic control by prostanoid receptors such as in adipocyte differentiation, lipolysis, and adipocyte browning in adipose tissues, and discuss the potential of prostanoid receptors as a treatment target for metabolic disorders.

[Prostaglandins in ophthalmology]. / Prostaglandiny v oftal'mologii.

Prostaglandins are widely used in medicine as active physiological agents that form a new class of drugs for treatment of cardiovascular diseases, some forms of bronchial asthma, as well as in gynecology and ophthalmology. Development of aseptic inflammation is an example of intracellular process, in which the produced prostaglandins are able to and do cause vasodilatation, increased vascular permeability, pain and fever. These effects of prostaglandins and leukotrienes characterize the classic picture of inflammation, including the aseptic one. The use of non-steroidal anti-inflammatory drugs (NSAIDs) can provide therapeutic effect via inhibition of prostaglandin secretion. Prostaglandins play a special role in glaucoma treatment. Prostaglandin analogues are powerful agents that decrease IOP by 20-40% with a unique mechanism of action. Prostaglandin analogues have a well-balanced safety profile, which is why they are considered as a first line of therapy. However, patients with inflammatory diseases in anamnesis, such as uveitis, herpes, keratitis, as well as patients with planned cataract extraction should be careful when using prostaglandin analogues.

Mecanismo de los AINES y antiinflamatorios derivados para el control del dolor y la inflamación. Uso de antiinflamatorios en odontología / Mechanism of NSAIDs and derived drugs for pain and inflammation control. Use of anti-inflammatories in odontology

Las urgencias odontológicas son, quizá, las razones principales de atención en el consultorio, muchas veces el significado de dolor se encuentra acompañado por inflamación; el uso de antiinflamatorios no esteroideos (AINES) es común en el ejercicio de la odontología por la excelente respuesta analgésica y antiinflamatoria que tiene, por lo que es importante conocer la fisiopatología de la inflamación y el dolor y cómo actúan los AINES, ya que algunos de estos fármacos tienen respuestas adversas y sitios de acción importantes. Los factores de riesgo por inflamación y dolor nos obligan a conocer la variedad de fármacos que no entran en la clasificación de AINES y que tenemos a disposición, hay más opciones para la elección ante la presencia de inflamación por un factor en particular, cada uno de éstos tienen indicaciones y contraindicaciones que conoceremos, lo cual nos ampliará el conocimiento para dar una prescripción ante la presencia de eventos inflamatorios. Se realizó un estudio detallado de artículos bibliográficos de cada tema, los fármacos más usados en odontología son los AINES, hay poco uso y conocimiento de antiinflamatorios que podemos usar en urgencias, el porcentaje de uso de los AINES derivados del ácido propiónico es alto por la excelente respuesta en pacientes y otras veces por el desconocimiento de más opciones (AU)

Dental emergencies are perhaps the main reasons for care in the office, many times the meaning of pain is accompanied by inflammation, the use of non-steroidal anti-inflammatory drugs is common in the practice of dentistry due to the excellent analgesic and anti-inflammatory response it has, important is knowing the pathophysiology of inflammation and pain, how NSAIDs act, some of these drugs have adverse responses and important sites of action, risk factors for inflammation and pain require us to know the variety of drugs that do not enter the classification of NSAIDs and we have at our disposal, there are more options for choosing in the presence of inflammation due to a particular factor, each of these have indications and contraindications that we will know, it expands our knowledge to give a prescription in the presence of inflammatory events. A detailed study of bibliographic articles on each topic was carried out, the drugs most used in dentistry are NSAIDs, there is little use and knowledge of anti-inflammatories that we can use in the emergency room, the percentage of use of NSAIDs derived from propionic acid is high, due to the excellent response in patients and others due to lack of knowledge of more options (AU)

Prostaglandins in biofluids in pregnancy and labour: A systematic review.

Prostaglandins are thought to be important mediators in the initiation of human labour, however the evidence supporting this is not entirely clear. Determining how, and which, prostaglandins change during pregnancy and labour may provide insight into mechanisms governing labour initiation and the potential to predict timing of labour onset. The current study systematically searched the existing scientific literature to determine how biofluid levels of prostaglandins change throughout pregnancy before and during labour, and whether prostaglandins and/or their metabolites may be useful for prediction of labour. The databases EMBASE and MEDLINE were searched for English-language articles on prostaglandins measured in plasma, serum, amniotic fluid, or urine during pregnancy and/or spontaneous labour. Studies were assessed for quality and risk of bias and a qualitative summary of included studies was generated. Our review identified 83 studies published between 1968-2021 that met the inclusion criteria. As measured in amniotic fluid, levels of PGE2, along with PGF2α and its metabolite 13,14-dihydro-15-keto-PGF2α were reported higher in labour compared to non-labour. In blood, only 13,14-dihydro-15-keto-PGF2α was reported higher in labour. Additionally, PGF2α, PGF1α, and PGE2 were reported to increase in amniotic fluid as pregnancy progressed, though this pattern was not consistent in plasma. Overall, the evidence supporting changes in prostaglandin levels in these biofluids remains unclear. An important limitation is the lack of data on the complexity of the prostaglandin pathway outside of the PGE and PGF families. Future studies using new methodologies capable of co-assessing multiple prostaglandins and metabolites, in large, well-defined populations, will help provide more insight as to the identification of exactly which prostaglandins and/or metabolites consistently change with labour. Revisiting and revising our understanding of the prostaglandins may provide better targets for clinical monitoring of pregnancies. This study was supported by the Canadian Institutes of Health Research.

Angioedema and Fatty Acids.

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid's function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.

Regulatory systems that mediate the effects of temperature on the lifespan of Caenorhabditis elegans.

Temperature affects animal physiology, including aging and lifespan. How temperature and biological systems interact to influence aging and lifespan has been investigated using model organisms, including the nematode Caenorhabditis elegans. In this review, we discuss mechanisms by which diverse cellular factors modulate the effects of ambient temperatures on aging and lifespan in C. elegans. C. elegans thermosensory neurons alleviate lifespan-shortening effects of high temperatures via sterol endocrine signaling and probably through systemic regulation of cytosolic proteostasis. At low temperatures, C. elegans displays a long lifespan by upregulating the cold-sensing TRPA channel, lipid homeostasis, germline-mediated prostaglandin signaling, and autophagy. In addition, co-chaperone p23 amplifies lifespan changes affected by high and low temperatures. Our review summarizes how external temperatures modulate C. elegans lifespan and provides information regarding responses of biological processes to temperature changes, which may affect health and aging at an organism level.

The enzymology of the human prostanoid pathway.

Prostanoids are short-lived autocrine and paracrine signaling molecules involved in a wide range of biological functions. They have been shown to be intimately involved in many different disease states when their regulation becomes dysfunctional. In order to fully understand the progression of any disease state or the biological functions of the well state, a complete evaluation of the genomics, proteomics, and metabolomics of the system is necessary. This review is focused on the enzymology for the enzymes involved in the synthesis of the prostanoids (prostaglandins, prostacyclins and thromboxanes). In particular, the isolation and purification of the enzymes, their enzymatic parameters and catalytic mechanisms are presented.

The five primary prostaglandins stimulate contractions and phasic activity of the urinary bladder urothelium, lamina propria and detrusor.

BACKGROUND: Inflammation is often associated with several bladder dysfunctions, including overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/PBS). As such, inflammation of the bladder and the actions of inflammatory mediators may contribute to the development of urinary symptoms. This study assessed the actions of PGE2, PGF2, PGD2, TXA2, and PGI2 on urinary bladder urothelium with lamina propria (U&LP), and detrusor smooth muscle. METHODS: Studies were carried out using isolated tissue baths, where strips of porcine bladder U&LP or detrusor were exposed to varying concentrations of prostaglandin agonists (1 µM and 10 µM). RESULTS: All assessed prostaglandin agonists contracted both the U&LP and detrusor smooth muscle, with the rank order of contractile response effectiveness as: PGE2 > PGF2α > TXA2 > PGD2 > PGI2. In U&LP, treatment with PGE2 (10 µM) increased tonic contractions by 1.36 ± 0.09 g (n = 42, p < 0.001) and phasic contractions by 40.4 ± 9.6% (n = 42, p < 0.001). In response to PGF2α (10 µM), U&LP tonic contractions increased by 0.79 ± 0.06 g (n = 14, p < 0.001) and phasic activity by 13.3% ± 5.3% (n = 15, p < 0.05). In detrusor preparations, PGE2 (10 µM) increased tonic contractions by 1.32 ± 0.13 g (n = 38, p < 0.001) and PGF2α (10 µM) by 0.97 ± 0.14 g (n = 12, p < 0.001). Only 34% (n = 48) of all detrusor preparations exhibited spontaneous activity prior to the addition of any agonist at a frequency of 2.03 ± 0.12 cpm. In preparations that did not exhibit initial phasic activity, all of the prostaglandin agonists were capable of commencing phasic activity. CONCLUSIONS: The urinary bladder U&LP and detrusor respond to a variety of prostaglandin agonists, with their activation resulting in direct contractions, as well as increases to spontaneous contractile activity. This study presents the prostaglandin receptor system as a potential therapeutic target for lower urinary tract dysfunction.

Cardiovascular Biology of Prostanoids and Drug Discovery.

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.

[Vascular Remodeling Induced by Biological Stresses].

The thymus is a vital organ for functional immune systems, and is the site of T cell development, which plays a central role in cellular immune defenses. Unlike other major organs, the thymus is highly dynamic in size and structure. It shrinks immediately upon bacterial infection, aging, pregnancy, mental stress, nutritional deficiency, and more. The reduction in size and function of the thymus during such biological events is called thymic involution or thymic atrophy; thymic involution is a particularly important issue because dysfunctional T cell immunity increases the risks of tumorigenesis and infectious diseases. However, the molecular mechanisms underlying thymic involution remain obscure. Our recent study indicated that blood vessels are remodeled during thymic involution that occurs upon aging, estradiol-treatment, or nutritional deficiency. We also found that prostanoid synthesis is induced during thymic involution. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), aspirin or etodolac, at least partially inhibited thymic involution-induced remodeling of the blood vessels, suggesting that prostanoids are involved in blood vessel remodeling. Our results revealed the potential role of blood vessel remodeling during thymic involution, which can lead to biological stress-induced immunosenescence.

The oxytocin-prostaglandins pathways in the horse (Equus caballus) placenta during pregnancy, physiological parturition, and parturition with fetal membrane retention.

Despite their importance in mammalian reproduction, substances in the oxytocin-prostaglandins pathways have not been investigated in the horse placenta during most of pregnancy and parturition. Therefore, we quantified placental content of oxytocin (OXT), oxytocin receptor (OXTR), and prostaglandin E2 and F2 alpha during days 90-240 of pregnancy (PREG), physiological parturition (PHYS), and parturition with fetal membrane retention (FMR) in heavy draft horses (PREG = 13, PHYS = 11, FMR = 10). We also quantified OXTR and prostaglandin endoperoxide synthase-2 (PTGS2) mRNA expression and determined the immunolocalization of OXT, OXTR, and PTGS2. For relative quantification of OXT and OXTR, we used western blotting with densitometry. To quantify the prostaglandins, we used enzyme immunoassays. For relative quantification of OXTR and PTGS2, we used RT-qPCR. For immunolocalization of OXT, OXTR, and PTGS2, we used immunohistochemistry. We found that OXT was present in cells of the allantochorion and endometrium in all groups. PTGS2 expression in the allantochorion was 14.7-fold lower in FMR than in PHYS (p = 0.007). These results suggest that OXT is synthesized in the horse placenta. As PTGS2 synthesis is induced by inflammation, they also suggest that FMR in heavy draft horses may be associated with dysregulation of inflammatory processes.

Role of Prostaglandins in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer's diseases, amyotrophic lateral sclerosis and Parkinson's disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.

Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery.

Upon stimulation, endothelial cells release various factors to regulate the vascular tone. In particular, vasorelaxing factors, called endothelium-derived relaxing factors (EDRFs), are altered in the production and/or release, as well as their signaling every vessel and under pathophysiological states, including cardiovascular, kidney, and metabolic diseases. Although indoxyl sulfate is known as a protein-bound uremic toxin and circulating levels are elevated in the impaired kidney functions, direct impact on the vascular function, especially EDRF's signaling, remains unclear. In this study, we hypothesize that acute exposure to indoxyl sulfate could alter vascular relaxation in the rat superior mesenteric artery. Accordingly, we measured acetylcholine (ACh)-induced endothelium-dependent relaxation in the absence and presence of several inhibitors to divide into each EDRF, including nitric oxide (NO), vasodilator prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF). Indoxyl sulfate reduced the sensitivity to ACh but not sodium nitroprusside. Under cyclooxygenase (COX) inhibition or inhibitions of COX plus source of EDHF, such as small (SKCa)- and intermediate (IKCa)-conductance calcium-activated K+ channels, the decreased sensitivity to ACh in indoxyl sulfate exposed vessel was still preserved. However, under inhibition of NO synthase (NOS) or inhibitions of NOS and COX, the difference of sensitivity to ACh between vehicle and indoxyl sulfate was eliminated. These findings indicated that acute exposure of indoxyl sulfate in the rat superior mesenteric artery specifically explicitly impaired NO signaling but not EDHF or vasodilator PGs.

Mechanisms of Nephrogenesis Revealed by Zebrafish Chemical Screen: Prostaglandin Signaling Modulates Nephron Progenitor Fate.

Nephron development involves the creation of discrete segment populations that are specialized to fulfill unique physiological roles. As such, renal function is reliant on the proper execution of segment patterning programs. Despite the central importance of nephron segmentation, the genetic mechanisms that regulate this process are far from understood, in large part due to the experimental complexities and cost of interrogating these events in the mammalian metanephros. For this reason, forward genetics utilizing phenotypic screening in the zebrafish pronephros provides an avenue to gain novel insights about the mechanisms of nephron segmentation in the vertebrate kidney. Discoveries from zebrafish can highlight possible conserved pathways and provide a useful starting point for reverse genetic analyses with other animal models or in vitro approaches. In this review, we discuss the results of a novel chemical screen using the zebrafish to identify segmentation regulators. Through this screen, we identified for the first time that prostaglandin signaling can modulate nephron segmentation, and that it is normally requisite during development to mitigate segment fate choice in the embryonic kidney. We briefly discuss how these discoveries relate to current knowledge about nephron segmentation. Finally, we explore the possible implications of these findings for understanding renal ontogeny and disease, and how this knowledge may be useful for ongoing research initiatives that are aimed at deciphering how to build or rebuild the human kidney.

Endothelium-dependent relaxation mechanisms involve nitric oxide and prostanoids in the isolated bovine digital vein.

Endothelial dysfunction contributes to the development of ungulate's laminitis. Although extensively studied in equines, the endothelial function is not fully examined in bovine digital veins (BDVs). BDVs were studied under isometric conditions to describe the acetylcholine (ACh) endothelium-dependent relaxation. Concentration-response curves were constructed to phenylephrine, ACh, and sodium nitroprusside (SNP). Relaxation responses were evaluated using either phenylephrine or depolarizing high-potassium Krebs solution (DKS) as precontraction agents. Endothelium denudation and incubation with L-NAME (300 µM), indomethacin (10 µM) or both were used to explore endothelial-mediated mechanisms. Endothelium denudation did not modify phenylephrine and SNP responses, however, significantly (p < 0.05) converted a relaxation (63.2 ± 5%) response to ACh into a contraction (30.3±9%). The ACh-evoked relaxation was significantly (p < 0.05) reduced in the presence of indomethacin (37.5 ± 6%) and L-NAME (6.40 ± 2%). The presence of both inhibitors abolished the ACh-evoked relaxation. Although DKS caused a higher precontraction than phenylephrine, ACh-evoked relaxation (22.4 ± 3.4%) was still observed and was reduced by the combination of inhibitors (7.0 ± 1.0%). The ACh endothelium-dependent relaxation in BDVs is essentially mediated by nitric oxide and endothelium-derived prostanoids. The BDV endothelium function is a dynamic component in the control of the bovine digital blood flow, particularly under endothelial dysfunction conditions when venoconstriction might lead to postcapillary resistance increase.

Association between use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs and erectile dysfunction: A systematic review.

OBJECTIVE: There are various etiologies of erectile dysfunction (ED), including endothelial dysfunction, atherosclerosis, and chronic inflammation. Aspirin has a protective role against endothelial dysfunction and atherosclerosis, whease all non-steroidal anti-inflammatory drugs (NSAIDs) are known for their anti-inflammatory properties. However, association between the use of aspirin or non-aspirin NSAIDs and ED is controversial. Therefore, we reviewed this relationship. METHODS: We systematically reviewed the pathophysiology of ED, physiological effect of prostaglandins, pharmacological action of NSAIDs, and clinical and basic research studies that evaluated the effect of aspirin or non-aspirin NSAIDs on ED. RESULTS: The research studies that assessed association between aspirin or non-aspirin NSAIDs are limited, and only 12 articles have been published. One clinical and three basic studies have claimed that aspirin or non-aspirin NSAIDs are beneficial for ED by preserving nitric oxide synthase impairment or penile blood hypercoagulability. One basic and two clinical studies considered them as risk factors because they interfered with prostaglandin production. By contrast, four clinical studies showed irrelevant results after controlling various medical indications. In addition, the mechanical effect of aspirin or non-aspirin NSAIDs on the nitric oxide pathway is still controversial. CONCLUSIONS: The available research studies revealed that association between aspirin or non-aspirin NSAIDs and ED is controversial. Considering the high frequency of drug use, further clinical and basic investigations should be conducted to clarify their exact relationship.

Biomonitoring the cardiorenal effects of Luehea divaricata Mart.: An ethnoguided approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Luehea divaricata Mart. (Malvaceae) is an important medicinal species that is widely used as a diuretic in the Brazilian Pantanal region. An ethanolic supernatant that was obtained from an infusion of leaves of this species (ESLD) was recently shown to exert hypotensive and diuretic activity. Nevertheless, the secondary metabolites that are responsible for this activity and the molecular mechanisms of pharmacological action remain unknown. AIM: We performed a detailed study to identify possible active metabolites that are present in different ESLD fractions and investigated their effects on renal and peripheral arteriolar tone. We further evaluated their interrelations with sustained diuretic and hypotensive actions. MATERIALS AND METHODS: The ESLD was first obtained from L. divaricata leaves, and liquid-liquid fractionation was performed. The fractions were analyzed by liquid chromatography-mass spectrometry. An ethyl acetate fraction (AceFr), n-butanolic fraction (ButFr), and aqueous fraction (AqueFr) were then orally administered in male Wistar rats in a single dose or daily for 7 days. The doses were previously defined based on the yield that was obtained from each fraction. Hydrochlorothiazide was used as a positive control. Blood pressure, heart rate, urinary volume, pH, density, and urinary sodium, potassium, chloride, and calcium levels were measured. Serum levels of nitrite, thiobarbituric acid reactive species, nitrotyrosine, aldosterone, vasopressin, and plasma angiotensin converting enzyme activity were also measured. Finally, the direct effects of the ButFr on renal and mesenteric arteriolar tone and the role of nitric oxide and prostaglandins in the renal and hemodynamic effects were investigated. RESULTS: Of the fractions that were tested, only the ButFr exerted significant diuretic and saluretic effects. The AceFr and ButFr also had acute hypotensive effects, but only the ButFr maintained its response after 7 days of treatment. Prolonged treatment with the ButFr increased serum nitrite levels and significantly reduced oxidative and nitrosative markers of stress. Additionally, the ButFr caused a vasodilatory response in the renal and mesenteric arteriolar beds through the release of nitric oxide and prostaglandins. Finally, the diuretic and hypotensive effects of the ButFr were completely blocked by pretreatment with Nω-nitro-L-arginine methyl ester and indomethacin, thus demonstrating the direct involvement of nitric oxide and prostaglandins in these effects. CONCLUSION: The ButFr that was obtained from Luehea divaricata exerted sustained diuretic and hypotensive effects. These effects were apparently attributable to the release of nitric oxide and prostaglandins, which reduce renal and peripheral arteriolar tone and lead to an increase in the glomerular filtration rate and a reduction of global peripheral resistance. These findings suggest that the ButFr may be a potential complementary therapy for several conditions in which diuretic and hypotensive effects are required.

Gallic acid, a phenolic compound isolated from Mimosa bimucronata (DC.) Kuntze leaves, induces diuresis and saluresis in rats.

Although present in the leaves of Mimosa bimucronata (DC.) and many other medicinal plants commonly used to augment urinary volume excretion, the effects of gallic acid as a diuretic agent remain to be studied. Wistar rats were orally treated with vehicle, hydrochlorothiazide, or gallic acid. The effects of gallic acid in the presence of hydrochlorothiazide, furosemide, amiloride, L-NAME, atropine, and indomethacin were also investigated. Diuretic index, pH, conductivity, and electrolyte excretion were evaluated at the end of the experiment (after 8 or 24 h). Gallic acid induced diuretic and saluretic (Na+ and Cl-) effects, without interfering with K+ excretion, when orally given to female and male rats at a dose of 3 mg/kg. These effects were associated with increased creatinine and conductivity values while pH was unaffected by any of the treatments. Plasma Na+, K+, and Cl- levels were not affected by any of the acute treatments. The combination with hydrochlorothiazide or furosemide was unable to intensify the effects of gallic acid when compared with the response obtained with each drug alone. On the other hand, the treatment with amiloride plus gallic acid amplified both diuresis and saluresis, besides to a marked potassium-sparing effect. Its diuretic action was significantly prevented in the presence of indomethacin, a cyclooxygenase inhibitor, but not with the pretreatments with L-NAME or atropine. Although several biological activities have already been described for gallic acid, this is the first study demonstrating its potential as a diuretic agent.

Diabetes modifies the role of prostanoids and potassium channels which regulate the hypereactivity of the rabbit renal artery to BNP.

Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP. Arterial relaxations to BNP were enhanced in diabetic rabbits. Indomethacin enhanced BNP-induced relaxation in control rabbits but showed no effect in diabetic rabbits. BNP-induced release of thromboxane A2 or prostacyclin was not different in both groups of animals. Iberiotoxin had no effect on relaxations to BNP in both groups of animals. Charybdotoxin displaced to the right the concentration-response curve to BNP in both group of animals, and inhibited BNP-induced relaxation only in diabetic rabbits. Glibenclamide did not modify the BNP-induced relaxations in control rabbits, but inhibited it in diabetic rabbits. These results suggest that diabetes induces hypereactivity of the rabbit renal artery to BNP by mechanisms that at least include (1) a reduced vasoconstrictor influence of arachidonic acid metabolites via cyclooxygenase 2, which is not related with changes in thromboxane A2 and prostacyclin release from the arterial wall and (2) a selectively increased modulatory activity of KATP and endothelial IKCa channels.