The aggregate index of systemic inflammation may predict mortality in COVID-19 patients with chronic renal failure.

OBJECTIVE: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first detected in December 2019 and then spread globally, resulting in a pandemic. Initially, it was unknown if chronic kidney disease (CKD) contributed to the mortality caused by COVID-19. The immunosuppression associated with this disease may minimize the COVID-19-described hyper-inflammatory state or immunological dysfunction, and a high prevalence of comorbidities may lead to a poorer clinical prognosis. Patients with COVID-19 have abnormal circulating blood cells associated with inflammation. Risk stratification, diagnosis, and prognosis primarily rely on hematological features, such as white blood cells and their subpopulations, red cell distribution width, mean platelet volume, and platelet count, in addition to their combined ratios. In non-small-cell lung cancer, the aggregate index of systemic inflammation (AISI), (neutrophils x monocytes x platelets/lymphocytes) is evaluated. In light of the relevance of inflammation in mortality, the objective of this study is to determine the impact of AISI on the hospital mortality of CKD patients. PATIENTS AND METHODS: This study is an observational retrospective study. Data and test outcomes of all CKD patients, stages 3-5, hospitalized for COVID-19 and followed between April and October 2021 were analyzed. RESULTS: Patients were divided into two groups according to death (Group 1-Alive, Group 2-Died). Neutrophil count, AISI and C-reactive protein (CRP) levels were increased in Group-2 [10.3±4.6 vs. 7.65±4.22; p=0.001, 2,084.1 (364.8-2,577.5) vs. 628.9 (53.1-2,275); p=0.00 and 141.9 (20.5-318) vs. 84.75 (0.92-195); p=0.00; respectively]. Receiver operating characteristic (ROC) analysis demonstrated 621.1 as a cut-off value for AISI to predict hospital mortality with 81% sensitivity and 69.1% specificity [area under ROC curve 0.820 (95% CI: 0.733-0.907), p<.005]. Cox regression analysis was used to analyze the effect of risk variables on survival. In survival analysis, AISI and CRP were identified as important survival predictors [hazard ratio (HR): 1.001, 95% CI: 1-1.001; p=0.00 and HR: 1.009, 95% CI: 1.004-1.013; p=0.00]. CONCLUSIONS: This study demonstrated the discriminative effectiveness of AISI in predicting disease mortality in COVID-19 patients with CKD. Quantification of AISI upon admission might assist in the early detection and treatment of individuals with a bad prognosis.

Modulation of Melatonin Receptors Regulates Reproductive Physiology: The Impact of Agomelatine on the Estrus Cycle, Gestation, Offspring, and Uterine Contractions in Rats.

Agomelatine is a pharmaceutical compound that functions as an agonist for melatonin receptors, with a particular affinity for the MT1 and MT2 receptor subtypes. Its mode of action is integral to the regulation of diverse physiological processes, encompassing the orchestration of circadian rhythms, sleep-wake cycles, and mood modulation. In the present study, we delve into the intricate interplay between agomelatine and the modulation of estrus cycles, gestation periods, offspring numbers, and uterine contractions, shedding light on their collective impact on reproductive physiology. Both in vivo and in vitro experiments were performed. Wistar Albino rats, divided into four groups: two non-pregnant groups (D1 and D2) and two pregnant groups (G1 and G2). The D1 and G1 groups served as control groups, while the D2 and G2 groups received chronic agomelatine administration (10 mg/kg). Uterine contractions were assessed in vitro using myometrial strips. Luzindole, a melatonin receptor antagonist, was employed to investigate the pathway mediating agomelatine's effects on uterine contractions. In in vivo studies, chronic agomelatine administration extended the diestrus phase (p<0.05) in non-pregnant rats, prolonged the gestational period (p<0.01), and increased the fetal count (p<0.01) in pregnant rats. Additionally, agomelatine reduced plasma oxytocin and prostoglandin-E levels (p<0.01) during pregnancy. In vitro experiments showed that agomelatine dose-dependently inhibited spontaneous and oxytocin-induced myometrial contractions. Luzindole (2 µM) reverse the agomelatine-induced inhibition of myometrial contractions. These findings suggest that agomelatine holds the potential to modulate diverse reproductive parameters during the gestational period, influencing estrus cycling, gestational progression, offspring development, and the orchestration of uterine contractions.

Effects of treadmill exercise on sexual behavior and reproductive parameters in chronically stressed-male rats.

Exposure to chronic stress stimulates the hypothalamic-pituitary-adrenal (HPA) axis and then simultaneously inhibits hypothalamic-pituitary-gonadal axis (HPG) axis activity. The inhibition formed by the HPA axis is the main mechanism of action of stress on reproductive function. HPG axis activity is known to be changed by various factors, including exercise. Exercise has been found to have a number of positive effects on sexual behavior, reproductive hormones, and sperm parameters in studies with animal models for many years. The main aim of this study is to investigate the effects of chronic treadmill exercise on chronically stressed-male rats' sexual behavior, reproductive hormones, and sperm parameters. A total of 40 sexually adult male rats were randomly and equally divided into four groups as control, stress, exercise, and stress+exercise. Animals in the exercise group were subjected to the chronic treadmill exercise (moderate intensity) for 33 days with a periodic increase in speed and duration. Animals in the stress group were exposed to restraint stress for 1 h, 2 h, and 3 h during the first, second and third 15 days respectively. Sexual behavior parameters, hormone measurements, and sperm parameters were evaluated. The main effects of chronic exercise on sexual behavior were centered on a significant increase in the ejaculation frequency (EF) in the stress+exercise group. Also, sperm concentration and motility in the stress group significantly decreased, and then sperm motility was improved by exercise in the stress+exercise group. In sum, our results show that chronic treadmill exercise may improve the adverse effects of chronic stress on sexual behavior and sperm parameters in male rats in terms of some parameters.

Investigation of enhancement effects of nicotine on cholinergic neurotransmission in isolated rabbit gastric fundus: role of antioxidants.

Nicotine, which is tobacco alkaloid, still induces interests for researchers because of smokers addiction to nicotine. Nicotine having influence on the neuronal acetylcholine receptors (nAChRs) increases release of most certain neurotransmitters from the nerve endings. Also, nicotine, affecting the mitochondrial respiratory chains, contributes to the formation of reactive oxygen species. In the present study, we investigated the effects of nicotine on smooth muscles of gastric fundus on the electrical field stimulation (EFS) that induces transition contraction via stimulation nAChRs. In addition, we aimed to investigate the interaction between release of acetylcholine, induced by nicotine, and the effects of reactive oxygen species. Therefore, the effects of allopurinol (10(-6)-10(-5) M), deferoxamine (10(-4) M) and mannitol (10(-4)-5 x 10(-3) M) were tested on the transient contraction induced by nicotine. In conclusion, mannitol (5 x 10(-3) M) significantly reduced contractile response to nicotine on EFS only in high concentration. Whereas in small concentrations mannitol (10(-4) M) statistically did not cause any results. Deferoxamine and allopurinol also did not have any significant response.

Prolonged cold storage diminishes the 5-hydroxytryptamine- and potassium chloride-mediated contractions of rat thoracic aorta.

Hypothermic preservation of the organ for transplantation causes vascular damage; therefore, the preservation of vascular function is important for the organs to function correctly after transplantation. The aim of the present study is to evaluate the influence of prolonged cold storage (72 hours) on vascular responses to 5-hydroxytryptamine (5-HT) and potassium chloride (KCl), each of which causes receptor-dependent and receptor-independent contractions, respectively. We also examined the protective roles of superoxide dismutase (SOD), L-arginine, the precursor of nitric oxide, iloprost, a synthetic analogue of prostaglandin I(2) with vasodilator functions, or endothelium removal for vascular responses. Endothelium-intact rings were prepared from the rat thoracic aorta, and stored at 4 degrees C for up to 72 hours in Krebs solution alone or Krebs solution that contains SOD, L-arginine or iloprost. The vascular responses were investigated daily. The Analysis of Variance (ANOVA) followed by Dunn test was used for statistical analysis. Being kept in cold in Krebs solution diminished the vascular responses to 5-HT and KCl. The presence of SOD in Krebs solution successfully prevented the decline in these responses, while iloprost or L-arginine partially restored them. In the endothelium-denuded rings, the 5-HT-induced contraction remained protected after 72 hours, whereas the KCl-induced contraction was partially restored. These results indicate that cold preservation declines the 5-HT and KCl-induced vascular responses, which can be partially prevented by iloprost or L-arginine, and can be restored by endothelium removal or SOD. Therefore, superoxide anion and endothelium-derived factors contribute to the decline in the contracting function of the aorta during prolonged cold storage.

Effects of varicocele on electrical field stimulation-induced biphasic twitch responses in the ipsilateral and contralateral rat vasa deferentia.

AIM: Although little is known about the mechanisms, varicocele is considered as one of the factors leading to male infertility. Since reduced motility of the vas deferens was shown to contribute to male infertility, in this study we aimed to investigate the effect of varicocele on electrical field stimulation (EFS)-induced biphasic contractions of the vas deferens in order to evaluate the effect of varicocele on the motility of the vas deferens. MATERIAL AND METHODS: A total of 26 Sprague-Dawley rats (200-250 g) were assigned randomly into two groups: sham (n = 10) and varicocele (n = 16). Varicocele was produced by partial obstruction of the left renal vein. Four weeks after the surgical procedure, vasa deferentia were harvested and EFS-induced responses were recorded from the strips prepared from ipsilateral and contralateral sides via Grass isometric force displacement transducers. Exogenous alpha-beta methyl ATP was applied at the concentration of 10(-5)M to the vasa deferentia strips, and exogenous noradrenalin was applied cumulatively at the concentrations between 10(-7) and 10(-4)M. At the end of each experiment, 80 mM KCl was applied to induce contractions. All contractions were expressed as the percentage of the 80 mM KCl-induced contractions. RESULTS: Varicocele significantly inhibited both phases of EFS-induced biphasic contractions in the ipsilateral side, whereas in the contralateral site it did not produce any change. However, there was no change in exogenously applied alpha-beta methyl ATP, noradrenalin and KCl-evoked contractions of the vasa deferentia obtained from both sides. CONCLUSIONS: These results suggest that varicocele affects the ipsilateral vas deferens motility by reducing neurotransmitter release.

The effect of tryptophan administration on ileum contractility and oxidant status in mice.

L-tryptophan (TRP) is the precursor amino acid for the synthesis of serotonin (5-HT). 5-HT is effective both on the food intake and gastrointestinal system contractility. The aim of this study was to search the effects of systemic TRP treatment on 5-HT levels of ileum and searching the effect of ileal contractility and oxidant status. Swiss-albino mice were divided into two groups: 1. Control, 2. TRP-treated (100 mg/kg/24 h, i.p., for 7 days). Body weights were recorded at the beginning and at the end of experiments. Acetylcholine-induced contractile responses in the isolated ileum were recorded on polygraph. Ileal tissue malondialdehyde and glutathione levels determined by spectrophotometric and ileal tissue 5-HT levels were measured by immunohistochemical methods. TRP treatment decreased body weight and increased ileal contractile response. In the TRP-treated group, ileum malondialdehyde levels increased and glutathione levels decreased. Immunohistochemical detection showed that ileal 5-HT levels were increased by TRP treatment. There is a relationship between increased oxidative stress and increased contractility in the ileal tissue of the TRP-treated animals. These effects may be related to increased ileal 5-HT synthesis.

Examination of the rescue effects of folic acid on derangement of the tubo-ovarian ultrastructural architecture caused by methotrexate.

The purpose of this examination was to observe the effects of folic acid (FA) on methotrexate (MTX)-induced derangements in the fallopian tubes. Investigators in this study sought to explore whether MTX-induced dysfunction in the fallopian tubes would be lessened by the addition of FA to MTX treatment. For this study, 18 albino Wistar rats were randomly divided into 6 groups, each of which comprised 3 rats; 0.1 mg/kg FA, 1 mg/kg MTX + 0.1 mg/kg FA, 5 mg/kg MTX + 0.1 mg/kg FA, 1 mg/kg MTX, and 5 mg/kg MTX were given to groups 2, 3, 4, 5,and 6, respectively; group 1 was the control group. After MTX injection, fallop-ian tube samples from all groups were prepared for examination under electron microscopy. The findings observed in groups 1 and 2 were similar. The level of cellular destruction was greater with the higher doses of MTX without FA; in particular, loss of cilia in the epithelium was prominent in groups 5 and 6. However, there was less cellular destruction observed in groups 3 and 4 than in groups 5 and 6. As a result, the addition of FA should not be overlooked, even when a single-dose MTX regimen is chosen for the treatment of patients with unruptured ectopic pregnancy.

The effect of systemic leptin administration on aorta smooth muscle responses in diabetic rats.

Leptin produces effects in central nervous system and peripheral tissues via its specific receptors. Leptin also stimulates nitric oxide release in a concentration-dependent manner. In this study, our aim was to test the hypothesis that whether leptin has a modulatory role on endothelium or smooth muscle function in streptozotocin (STZ)-induced diabetic rats. Wistar-Albino rats were divided into four groups: 1 -- Control, 2 -- Diabetic, 3 -- Control + leptin and 4 -- Diabetic + leptin. Experimental diabetes was produced by intraperitoneal injection of a single dose of STZ (55 mg/kg). Diabetes was determined by increased fasting blood glucose level on the 7th day of the experiment. Leptin (0.1 mg/kg/day) was administered intraperitoneally for 5 days. At the end of the 5th day, thoracic aortas were isolated and phenylephrine (Phe)-induced contractions and acetylcholine (ACh)-induced relaxations of each group were estimated. In diabetic rats, Phe-induced contractility was increased (p < 0.05). Leptin pre-treatment increased the Phe-induced contractility significantly in aortic rings obtained from diabetic rats (p < 0.05). In normal rats, leptin administration produced only a slight and non-significant increase in Phe-induced contractions. Although the relaxant responses were decreased in diabetic rats, leptin administration enhanced the ACh-induced relaxation in both normal and diabetic animals significantly. As a conclusion; chronic leptin pre-treatment caused a significant increase both in Phe-induced contractions and ACh-induced Endothelial-Derived Relaxing Factor (EDRF)/Nitric oxide-mediated relaxations in the aortic rings isolated from streptozotocin-induced diabetic rats. This peptide hormone caused a significant increase in the relaxations obtained by ACh while not inducing a significant alteration in the contractile effect of Phe in control rats.

Effects of dexfenfluramine on serotonin levels of mice ileum, contractility, glutathione and malondialdehyde level.

UNLABELLED: Dexfenfluramine is one of the anorectic drugs that suppresses food intake which acts via inhibition of reuptake of serotonin into brain terminal. Gastrointestinal tract is the main source of peripheral serotonin which is involved in the regulation of gastrointestinal motility. During the use of anorectic drugs, the antioxidant defence is affected especially by reactive oxygen species. The purpose of this study to search: The effect of dexfenfluramine on serotonin levels of ileum and the effect of dexfenfluramine on ileal contractility and oxidative stress. MATERIALS AND METHODS: Twenty-two adult male Swiss-albino mice were divided two groups (1) Control, (2) Dexfenfluramine treated (i.p. twice a day 0.2 mg kg(-1) in 0.2 ml saline solution for 7 days). Animal body weights were recorded at the beginning and at the end of the experimental period. Ileum tissues contractile responses to different concentrations of KCl and acethycholine were recorded on polygraph. In the meantime ileal tissue malondialdehyde, a product of lipid peroxidation, and glutathione, endogenous antioxidant levels were assessed by spectrophotometric methods. Ileal tissue serotonin level determined by immunohistochemical method. Body weights decrease and ileal contractile response of acethycholine increased significantly by dexfenfluramine treatment. Meanwhile, ileum glutathione levels decreased and malondialdehyde levels increased in dexfenfluramine treated group. Immunohistochemical detection showed that ileal serotonin levels increased by dexfenfluramine treatments. As a conclusion, there is a relationship between increased ileal contractility and oxidant status in dexfenfluramine treated animals. These effects can be related by increased serotonin levels which is induced by dexfenfluramine in ileum.

Light and electron microscope examination of the effects of methotrexate on the endosalpinx.

OBJECTIVE: To examine the effects of increasing doses of methotrexate (Mtx) on the fallopian tubes. STUDY DESIGN: The study was carried out on 24 female rats (Albino Wistar type, 250-300 g). The rats were randomly divided into four groups of six. Different doses of Mtx were given to the rats by i.p. injection: 1mg/kg to those in group 1, 5mg/kg in group 2 and 10 mg/kg in group 3. Rats in group 4 received injections of physiological serum only and were treated as the control group. Ten days after the injection, the fallopian tubes of the rats were removed for examination separately by light and electron microscopy (EM) for comparison. RESULTS: Light microscopy showed that in group 1 the surface epithelial cells were normal and the lamina propria was infiltrated by numerous inflammatory cells with a prevalence of polymorphonuclear leucocytes. Findings in groups 2 and 3 were similar: the lamina propria was infiltrated with granulocytes in one specimen from each of the two groups, and granulocytes were also observed among epithelial cells. In the control group all surface structures were found to be in a normal condition. Electron microscopy showed cilial loss in the epithelial cells and central crystolysis in mitochondria in all group 1 specimens. Findings in groups 2 and 3 were similar. The cytoplasm of the epithelial cells seemed to be dense, there was prominent crystolysis (crystalloid formation) in the mitochondria, and vacuolisation (vacuole formation) in the cytoplasm seemed to be augmented. Cilial loss was prominent, and the basal membrane was irregular. Epithelial cell nuclei were in disorder. Lipid granules were observed extensively in epithelial cells. Eosinophils seemed to be dominant in connective tissues below the epithelium. In all control group specimens the epithelium seemed to be normal with all organelles in place; the condition of intercellular junctions, ciliated epithelium and all mitochondria also seemed to be normal, and the basal membrane was observed to be in order. CONCLUSION: In view of these findings, we conclude that the ultrastructural derangements resulting from administration of Mtx in doses in excess of 1mg/kg can cause a reduction in the surface epithelium's ability to make rhythmic lashing movements and can impair the patency of the fallopian tubes. All these disturbances could be involved to some degree in the causation of infertility and recurrent ectopic pregnancy. Therefore, the dosage of Mtx should be limited to use of the lowest effective dose to avoid these adverse effects.

Tryptophan administration increase contractility and change the ultrastructure of mice duodenum.

Serotonin (5-HT) is a metabolite of tryptophan (TRP). 5-HT has been shown to induce contractions in rat duodenum and ileum. We planned to investigate the in vivo effects of TRP administration on duodenal contractility and ultrastructure together. Two equal groups of adult male Swiss-albino mice were used in the experiments. Controls (CONT) and TRP treated (100 mg/kg/24 hr in 0.2 ml. saline solution ip, 7 days). Body weights were recorded at the beginning and at the end of experiments. Duodenum tissues contractility responses to different concentration of KCl and acethycholine (ACh) were recorded on polygraph. The ultrastructural changes in duodenum observed by transmission electron microscopic (TEM) method and 5-HT levels determined by immunohistochemical method. Body weights decreased and duodenal contractile response of ACh increased significantly by TRP treatment. The duodenal ultrastructural changes in TRP group illustrated partially loss of apical surface and fusion in microvilli. Immunohistochemical detection showed that 5-HT increased by TRP treatment. There is a relation between duodenal contractility increased by TRP treatment and changes in the duodenal tissue 5-HT level and ultrastructure.

Effect of glycerol on endothelium-derived factors in the vasculature of the rabbit kidney.

1. In the present study, endothelium-derived relaxing factor (EDRF/nitric oxide (NO)), conversion of big endothelin (ET)-1 to endothelin-1 (ET-1) and the role of reactive oxygen species were investigated in kidneys isolated from glycerol (GLY)-pretreated rabbits. 2. Acetylcholine (ACh)-induced vasodilation that is due to the release of EDRF/NO is significantly decreased, whereas big ET-1-induced vasoconstriction was increased in kidneys isolated from GLY-pretreated rabbits. 3. Pretreatment of rabbits with the xanthine oxidase inhibitor allopurinol and the NO precursor L-arginine reversed the inhibition of ACh-induced vasodilation due to GLY and protects the kidney vasculature. 4. Big ET-1, but not ET-1, responses were found to be significantly increased in kidneys isolated from GLY-pretreated rabbits. This increase is attributed to the higher conversion rate of big ET-1 to ET-1 because the ET-converting enzyme (ECE) inhibitor phosphoramidon, at a concentration of 10(-6) mol/L, causes an inhibition in the response to big ET-1 by 52.6% in normal kidneys, whereas this inhibition with the same concentration of phosphoramidon was found to be significantly decreased in kidneys isolated from GLY-pretreated rabbits. 5. The non-selective NO synthase inhibitor N(G)-nitro-L- arginine methyl ester (L-NAME) caused a significant potentiation in the vasoconstrictor response to ET-1 in normal isolated perfused rabbit kidneys. However, L-NAME did not alter the responses to ET-1 in GLY-pretreated kidneys. 6. These results indicate that accumulation of reactive oxygen species causes an inhibition in NO bioavailability. Increased conversion of big ET-1 to ET-1 may also contribute to the mechanism of vascular damage due to GLY.

Nitric oxide and prostanoid-dependent relaxation induced by angiotensin II in the isolated precontracted mouse tracheal muscle and the role of potassium channels.

In this study we examined the mechanism of the concentration-dependent relaxant effect of angiotensin II (A II) on mouse isolated tracheal rings precontracted by carbachol. The contractile effect of carbachol is increased while the relaxant effect of A II decreased by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME). This finding suggests that the L-arginine nitric oxide (NO) pathway is activated by the peptide. The relaxing effect of A II was also mediated through the release of cyclo-oxygenase products of arachidonic acid, as evidenced by the inhibition of the response by lysine acetylsalicylic acid (ASA) pretreatment. A II also caused a relaxation in the isolated tracheal rings precontracted by K(+)(>60 m m). K(+)-channel blockers partially inhibited the relaxant effect of A II in carbachol-precontracted mouse tracheal rings. A non-selective blocker of K(+)channels, tetraethylammonium, completely abolished the relaxation induced by A II. Among the other channel blockers, the inhibitory effect of apamine and glibenclamide was higher than that of iberiotoxin, indicating the involvement of K(ATP)and small conductance K(Ca)channels in the relaxing response to the octapeptide. These results suggest that the mechanisms, involved in the relaxation induced by A II in the isolated mouse tracheal rings precontracted by carbachol, were firstly l -arginine NO and cyclo-oxygenase products of arachidonic acid, secondly K(+)channels.

The contribution of nitric oxide and endothelins to angiotensin: II. Evoked responses in the rat isolated uterus smooth muscle.

The present study was designed to determine the role of endogenous endothelin peptides and nitric oxide on angiotensin II (All) responses in the isolated nonpregnant rat uterine smooth muscle. AII (10, 20, or 50 ng/ml) increases rhythmic oscillations dose dependently (32.7 +/- 8.9, 55.96 +/- 10.3, and 62.78 +/- 17.7% increase, respectively). L-arginine methyl ester (L-NAME; 10(-5) M) did not affect the increase in rhythmic oscillations induced by All (10, 20, or 50 ng/ml) (17.5 +/- 12.1, 31.5 +/- 18.3, and 52.5 +/-11.8% increase, respectively, n = 6, p > 0.05). It reduced the contractile responses to AII (10 ng/ml: from 4.63 +/- 0.6 to 1.8 +/-0.7 cm2, p < 0.05: and 20 ng/ml: from 5.59 +/- 0.8 to 2.11 +/- 0.4 cm2, p < 0.05, n = 6). L-arginine (10 mM) decreased the contractile response obtained by AII (10 or 20 ng/ml) (1.93 +/- 1.05, p < 0.05 and 2.14 +/- 0.7 cm2, p < 0.05, respectively, n = 6). BQ 485 (50 ng/ml) decreased both the number of rhythmic oscillations and the contractility increased by AII. Bosentan (10(-5) M) induced an increase in the number of rhythmic oscillations but decreased the contractile responses to the higher concentrations of All. These data show that endogenous NO and endothelin peptides contribute to the motility changes induced by AII and may play an important role in the pathophysiological events of the uterine function.

Does thromboxane A2 synthase inhibitor UK-38485 prevent the vasoconstrictor effects of endothelin-1 on rabbit basilar artery?

Prevention of the production of thromboxane A2--a potent vasoconstrictor and aggregating metabolite of arachidonic acid--or infusion of the stable analogues of prostacyclin--which is another cyclo-oxygenase metabolite of arachidonic acid--has been shown to be beneficial in cerebral vasoconstriction. Endothelin-1, a peptide derived from endothelial cells, has been shown to induce a long-lasting cerebral vasoconstriction both in vivo and in vitro. The purpose of this study was to investigate the role of a novel thromboxane A2-synthase inhibitor UK 38485 on the acute vascular and morphological effects of Endothelin-1 applied intra-arterially on rabbit basilar arteries. The inguinal region of twenty four anaesthetized albino rabbits of both sexes were dissected and a catheter was inserted into the aorta via the femoral artery, for control angiography of the basilar artery and intra-arterial injection of ET-1 (0.25 ng total dose) and UK 38485 at a dose of 0.05 microgram kg-1 min-1 for 20 min or saline. Angiographic vasoconstriction quantification and morphological investigations of both vessels and brain stem either by light microscopy or transmission electron microscopy were the techniques applied for the study. We found out that, although the systemic administration of UK 38485 resulted in a potent antagonism of the acute vasoconstriction as visualized in angiographic studies, it did not affect the morphological changes induced by Endothelin-1 on the vessel wall. The results indicated that there might have been an interaction between Endothelin-1 and the prostaglandin synthesis mechanism in acute cerebral vasoconstriction.

Nitric oxide-mediated relaxation induced by bradykinin in the isolated mouse trachea.

We examined the nature of the relaxant effect of bradykinin on mouse isolated tracheal rings. Bradykinin produced a concentration-dependent relaxation in mouse tracheal rings contracted by carbachol. Potentiation of the contractile effect of carbachol and inhibition of the relaxant effect of bradykinin by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), L-glutamine (L-Gln) and methylene blue (MeB) suggested that the peptide activated the L-arginine nitric oxide (NO) pathway. Part of the relaxant effect of bradykinin was also mediated through the release of cyclooxygenase metabolites of arachidonic acid, as evidenced by the inhibition of this response by lysine acetylsalicylic acid (ASA) pretreatment. Bradykinin also caused a relaxant response in precontracted tracheal rings in the presence of lower but not higher concentrations of K+ (> 60 mM). NG-nitro-L-arginine methyl ester and L-Gln did not alter the contractile effect of K+. K+ channel blockers partially inhibited the relaxant effect of bradykinin in carbachol-induced precontracted tracheal rings. Tetraethylammonium, a non-selective blocker of K+ channels, completely abolished the relaxant response to the peptide. Among the other channel blockers, the inhibitory effect of glibenclamide was slightly greater than that of apamine and iberiotoxin, indicating the involvement of K(ATP) channels in the relaxant response to the peptide. These results suggest that the mechanisms of the relaxation induced by bradykinin in carbachol-induced precontracted mouse tracheal muscle primarily involve activation of L-arginine NO and arachidonic acid cyclooxygenase pathways and secondly K+ channels.

In vitro susceptibility rhythms. II. Biological-time-dependent differences in effect of beta 1- and beta 2-adrenergic agonists of rat aorta and influence of endothelium.

Time-dependent variations in the vasodilator effects of beta-adrenergic agonists terbutaline (Ter) and dobutamine (Dob) were studied in isolated rings of rat thoracic aorta in both endothelium-intact and endothelium-denuded preparations. Rats were housed in light from 08:00 to 20:00 and in darkness from 20:00 to 08:00 and sacrificed at six different times of the day. In endothelium-intact and endothelium-denuded aortic rings precontracted submaximally with phenylephrine (Phe), addition of Ter and Dob produced concentration-dependent relaxations. Removal of endothelium reduced the relaxant responses and area under curve (AUC) values and augmented the EC50 values to Ter and Dob at most, but not all, time points. Two-way analysis of variance (ANOVA) revealed that AUCs, maximum responses, and EC50 values significantly depended on both treatment (endothelium intact/endothelium denuded) and time of sacrifice. Results of the present study clearly show that in vitro sensitivity of rat thoracic aorta to beta-adrenergic agonists displays temporal variations depending on the time of animal sacrifice, and the presence of endothelium modifies the rhythmicity in beta-adrenergic activity. These variations may be due to the circadian rhythmicity in the adenylyl cyclase-cAMP-phosphodiesterase system that mediates the responses to beta-adrenergic agonists.

The effects of captopril and naloxone on restraint-cold-stress- and ethanol-induced gastric lesions in rats.

1. This study was undertaken to investigate the effect of captopril (1 microgram/kg or 1 mg/kg, i.p.) on the actions of naloxone (5 mg/kg, i.p. in gastric ulceration induced by ethanol and restraint-cold-stress. 2. Neither naloxone (5 mg/kg, i.p.) nor captopril (1 mg/kg, i.p.) alone induced any change in the indices of the ulcer in either group. 3. Captopril at a lower dose (1 microgram/kg, i.p.), when combined with naloxone (5 mg/kg, i.p.), significantly reduced cumulative ulcer length only in the ethanol-treated group (from 54.9 +/- 7.2 mm to 22.5 +/- 6.2 mm). 4. However, a high dose of captopril (1 mg/kg) plus naloxone pretreatment caused a significant reduction in both ethanol (from 54.9 +/- 7.2 mm to 24.9 +/- 6.5 mm) and restraint-cold-stress (from 19.0 +/- 3.0 mm to 5.3 +/- 1.0 mm)-induced ulcer formation. 5. Acetylsalycilic acid, when used together with captopril, increased the ulcer formation induced by stress. 6. Naloxone, by increasing the release of prostaglandins, has been shown to prevent ulcer formation induced by several noxious stimuli. 7. Therefore, the effect of the combination might be due to the synergistic interaction of both drugs on prostaglandin synthesis.

In vitro evidence of tissue susceptibility rhythms. I. Temporal variation in effect of potassium chloride and phenylephrine on rat aorta.

In this study, time-dependent variations in the in vitro sensitivity of rat thoracic aorta rings to potassium chloride (KCl) and phenylephrine (Phe) were investigated. Animals were synchronized with a 12h light and 12h darkness (lights on 08:00-20:00) schedule, and thoracic aortas were obtained at six different times of the day (1, 5, 9, 13, 17, and 21 hours after lights on). In order to avoid endothelial influence, all experiments were performed in endothelium-denuded preparations. Responses to KCI showed time-dependent variations in all the concentrations used. Phe-induced contractions also exhibited time-dependent differences. The rhythmic pattern of Phe responses did not change with the presence of the alpha1-adrenergic antagonist prazosin. In addition, both the EC50 values of KCl and Phe, and also the K(B) values of prazosin, displayed rhythmicity. In conclusion, time of obtaining tissues is an important factor for experimental standardization in, at least, vascular smooth muscle preparations.