Cumulative Dose-response Research Articles

Sulodexide Inhibits Arterial Contraction via the Endothelium-Dependent Nitric Oxide Pathway.

Background/Objectives: Sulodexide (SDX) is a drug known for restoring the glycocalyx, thereby offering endothelial protection and regulating permeability. Additionally, it has antithrombotic and anti-inflammatory properties and has shown arterial vasodilatory effects. Endothelial cells play a crucial role in maintaining homeostasis, with their dysfunction being a key contributor to loss in vasodilatory response, especially in arterial pathologies. The aim of this study was to investigate the effects of SDX on stimulated vascular tonus in human arterial samples and to assess the function of the endothelial layer as a source of nitric oxide (NO). Methods: A total of 16 internal mammary artery remnants from coronary artery bypass graft surgeries were dissected into endothelium-intact and endothelium-denuded groups (n = 8 each). The arterial rings were equilibrated under tension, with their basal tonus recorded before and after phenylephrine stimulation. SDX's impact on arterial contraction was assessed through cumulative dose-response curves. NO synthase inhibitor (Nω-nitro-L-arginine methyl ester) was used to assess SDX's vasodilatory effect over the NO pathway. Results: SDX application resulted in concentration-dependent vasorelaxation in both endothelium-intact and endothelium-denuded groups at certain doses. However, the inhibitory effect of SDX was more pronounced in endothelium-intact rings at higher doses compared to endothelium-denuded rings (p < 0.05). Similar inhibition of contraction curves was achieved for both endothelium-intact and endothelium-denuded rings after L-NAME pre-incubation, suggesting a necessity for NO-related endothelial pathways. Conclusions: SDX exerts a concentration-dependent inhibition on arterial contraction, emphasizing the critical role of an intact endothelium and NO-mediated pathways in this process. This underscores SDX's potential in treating endothelial dysfunction-related pathologies.

Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28–32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

The Bronchodilator Potential of Astragalus sarcocolla: An in vitro Experiment.

To evaluate the bronchodilatory mechanism of Astragalus sarcocolla (ASE) extract on tracheal smooth muscles of rabbits. In-vitro experimental study. Place and Duration of the Study: The animal house of CMH Lahore Medical College, Lahore, and Institute of Dentistry, NUMS, from October 2022 to May 2023. Six rabbits were randomly divided into four groups. After euthanising the rabbit, the trachea was carefully dissected out and stabilised in Kreb's Henseleit solution for 30 minutes and then, stimulated by acetylcholine (Ach) 1µm, under mimicked physiological conditions. Group I served as the control group with tracheal smooth muscles stabilised with 1g tension. In Group II (positive control), tracheal smooth muscles were stimulated by potassium chloride (KCl) (80 mM and 25 mM, respectively) to get maximum tracheal smooth muscle contractions. Later, the tissue was exposed to theophylline with three molar concentrations 0.2, 0.4, 0.6, and 0.8 mM, and cumulative dose response curves were formed. In Group III (ASE group), tracheal smooth muscles were stimulated by KCl (80 mM and 25 mM) and was exposed to increasing concentration of ASE. In group IV, tissue was stimulated by KCl (25 mM) and glibenclamide (3 µM), later exposed to increasing concentration of ASE to confirm the bronchodilatory mechanism. The change in isometric contraction of the tissue was recorded using the force displacement transducer connected to a PowerLab data acquisition system. Concentration response curves were drawn, and median effective concentrations (EC50 values) and percentage inhibition were calculated. Non-linear regression was applied for the analysis of the concentration-response curves. ASE inhibited the KCl-induced low potassium (25 mM) contractions (EC50 = 0.38 mg/ml, 95% CI: 0.04 - 0.38, n = 6). It only partially inhibited the high potassium-induced contractions in tracheal smooth muscles. Pretreatment with glibenclamide showed a rightward shift of the dose-response curve. Theophylline and ASE significantly reduced the low K+ induced smooth muscle contractions in comparison to the control group (p <0.001, each). Astragalus sarcocolla extract produced bronchodilator effects through the activation of ATP sensitive potassium channels in isolated rabbit trachea. Astragalus sarcocolla, Bronchodilators, ATP-sensitive potassium channels, Effective concentration 50, Concentration response curves.

Mechanism of action of &lt;i&gt;Pterorhachis&lt;/i&gt; &lt;i&gt;zenkeri&lt;/i&gt; (Meliaceae), a sexual enhancer: effect on vas deferens contractility

Background: Pterorhachis. zenkeri commonly known as “Ayilalou” or “Démareur” is an aphrodisiac plant used by Cameroonian traditional healers to enhance libido and sperm production. This study was undertaken to investigate the aphrodisiac mechanism of P. zenkeri on the contractile activity of vas deferens with regard to its function on ejaculation. Materials and Methods: The proximal parts of rat vas deferens were mounted in a 20 mL organ bath containing Krebs solution at 37°C. Cumulative dose-response curves were recorded with KCl (35-280 mM), adrenaline (7-70 µM) and aqueous extract of P. zenkeri (3,55-21,3 mg/mL). Prazosin (type 1 alpha-adrenergic receptor antagonist, 10 µM), Nifedipine (a specific L-type calcium channel antagonist, 5 µM), 2-AminoethoxydiPhenyl Borate (2-APB, IP3 receptor antagonist, 200 μM) and calcium-free medium were further used to study the mechanism of action. Results: KCl, adrenaline and aqueous extract of P. zenkeri showed a concentration-dependent effect on vas deferens contractibility. Nifedipine and Pazosin partially inhibited the effects of P. zenkeri. In calcium-free medium containing Ethylene Glycol-bis (2-aminoethylether)-N,N,N’N’-tetraacetic acid (EGTA, 1µM), P. zenkeri triggered vas deferens contraction which was completely abolished in the presence of 2-APB. These results suggest that the aqueous extract of P. zenkeri possesses bioactive compounds capable of inducing vas deferens contractions through type 1 alpha adrenergic receptors and mobilization of extra and intracellular calcium. Conclusion: These results confirm the aphrodisiac properties of P. zenkeri through the activation of the emissive phase of ejaculation.

Isometric myography is a feasible method to identify and quantify endothelial dysfunction in dogs with myxomatous mitral valve disease.

To assess the feasibility of isometric myography in pet dogs with myxomatous mitral valve disease (MMVD) to determine its use in quantifying endothelial dysfunction. 9 dogs euthanized for medical reasons. Femoral, renal, and mesenteric arteries were collected postmortem and stored in physiological saline solution at 4 °C for myography. Mitral valves were scored for myxomatous degeneration (grades 1 to 4). Sections of arteries were mounted in wells, immersed in physiological saline solution perfused with 95% O2 and 5% CO2 at 37 °C, and stretched to an internal circumference (IC) that generated the maximal difference between active and passive wall tension (IC1). Normalization factors were calculated by dividing the IC1 by the IC at which the passive wall tension was 100 mm Hg (IC100). Vasoconstriction to phenylephrine and vasodilation to acetylcholine (endothelial dependent) and sodium nitroprusside (endothelial independent) were assessed by cumulative dose-response curves. Median MMVD grade was 3. Mean values of normalization factors were 1.00 ± 0.14 (renal, n = 15), 1.00 ± 0.10 (femoral, 8), and 1.05 ± 0.12 (mesenteric, 6). Responses to phenylephrine were similar between dogs (P = .14). Reduced responses to acetylcholine compared with sodium nitroprusside were identified in 15 arteries, suggesting endothelial dysfunction. Isometric myography of arteries from pet dogs is feasible and can identify loss of endothelial-dependent relaxation in dogs with MMVD postmortem. Its use in further research can lead to a better understanding of the pathophysiology mechanisms of this disease.

Contractile effect of trimethylamine and trimethylamine-n-oxide on isolated human umbilical arteries.

The aim of this study is to investigate the effect of trimethylamine (TMA) and trimethylamine-n-oxide (TMAO) on the contractility of human umbilical artery and the possible mechanisms involved. Vasoactive responses to TMA and TMAO on human umbilical artery rings were measured in isolated organ baths. Cumulative dose-response curves for TMA and TMAO were obtained before and after incubation with atropine, yohimbine, prazosin, indomethacin, verapamil, and Ca+2 -free Krebs-Henselite solution. Administration of cumulative TMA and TMAO resulted in dose-dependent contraction at concentrations ranging from 10 to 100 mM on human umbilical artery rings. TMA-induced contractions were more potent than TMAO-induced contractions (TMA: -logEC50 = 1.00 ± 0.02, TMAO: -logEC50 = 0.57 ± 0.02). Contraction responses to TMA were significantly lower in the presence of verapamil and in the absence of external Ca+2 (p < 0.001, p < 0.05, respectively). Our results showed that TMA and TMAO caused vasoconstriction in isolated human umbilical artery rings. Our findings also indicated that TMA but not TMAO-induced vasoconstriction was partially dependent on extracellular Ca2+ and calcium influx through L-type Ca2+ channels. Our results suggest that TMA and TMAO may have the potential to contribute to cardiovascular diseases through their direct effect on vascular contractility in human arteries.

Combined uterorelaxant effect of magnesium sulfate and terbutaline: Studies on late pregnant rat uteri in vitro and in vivo.

Preterm delivery and its complications are among the biggest challenges and health risks in obstetrical practice. Several tocolytic agents are used in clinical practice, although the efficacy and side effect profiles of these drugs are not satisfying. The aim of this study was to investigate the uterus relaxant effect of the coadministration of β2 -mimetic terbutaline and magnesium sulfate (MgSO4 ) in an isolated organ bath and to perform in vivo smooth muscle electromyographic (SMEMG) studies in pregnant rats. In addition, we also investigated whether the tachycardia-inducing effect of terbutaline can be reduced by the presence of magnesium, due to the opposite heart rate modifying effects of the two agents. In the isolated organ bath studies, rhythmic contractions of 22-day- pregnant Sprague-Dawley rats were stimulated with KCl, and cumulative dose-response curves were constructed in the presence of MgSO4 or terbutaline. The uterus-relaxing effects of terbutaline were also investigated in the presence of MgSO4 in both normal buffer and Ca2+ -poor buffer. The in vivo SMEMG studies were carried out under anesthesia with the subcutaneous implantation of an electrode pair. The animals were treated with MgSO4 or terbutaline alone or in combination in a cumulative bolus injection. The implanted electrode pair also detected the heart rate. Both MgSO4 and terbutaline reduced uterine contractions in vitro and in vivo, furthermore, the administration of a small dose of MgSO4 significantly enhanced the relaxant effect of terbutaline, especially in the lower range. However, in Ca2+ -poor environment, MgSO4 was not able to increase the effect of terbutaline, indicating the role of MgSO4 as a Ca2+ channel blocker. In the cardiovascular studies, MgSO4 significantly decreased the tachycardia-inducing effect of terbutaline in late pregnant rats. The combined application of MgSO4 and terbutaline may have clinical significance in tocolysis, which must be confirmed in clinical trials. Furthermore, MgSO4 could substantially reduce the tachycardia-inducing side effect of terbutaline.

Non-genomic uterorelaxant actions of corticosteroid hormones in rats: An in vitro and in vivo study

AimsWe aimed to identify the short-term effects of a glucocorticoid (GC) and a mineralocorticoid (MC) on non-pregnant and late pregnant rat uterine contractions to estimate their tocolytic potential. MethodsThe in vitro contractility studies were performed with uterine tissues from non-pregnant and 22-day pregnant SPRD rats. The cumulative dose-response of fludrocortisone (FLU) and dexamethasone (DEX) was measured alone or in the presence of steroid receptor antagonist mifepristone (MIF) or spironolactone (SPR). [35S]GTPγS and cAMP immunoassays were carried out to detect the activated G-proteins and cAMP, respectively. The in vivo uterine action of single doses of FLU and DEX was measured by smooth muscle electromyography. The results were statistically analyzed with an unpaired t-test. ResultsFLU and DEX relaxed both pregnant (33 and 34%) and non-pregnant (37 and 34%) uteri in vitro. MIF inhibited the relaxing effect of DEX, especially in the pregnant uterus, but reduced the effect of FLD only in non-pregnant tissues. GTPγS studies showed a MIF-sensitive elevation in activated G-proteins both in pregnant and non-pregnant uteri by DEX, whereas FLU induced activation only in non-pregnant samples. DEX relaxed pregnant and non-pregnant uteri in vivo in a MIF-sensitive way. SignificanceDEX can inhibit contractions in the late pregnant uterus in a non-genomic manner, while FLU seems to be ineffective. Its action is mediated by a G-protein-coupled receptor that can be blocked by mifepristone. Further investigations are necessary to determine the required dose and duration of GCs in the therapy of premature birth.

Preliminary Mechanistic Study on the Trachea Smooth Muscle Relaxant Activity of Aqueous Leaf Extract of Tridax Procumbens in Male Wistar Rats.

ObjectivesAqueous leaf extract of Tridax procumbens (ALETP) has potent relaxant activity. However, this relaxant activity in respiratory smooth muscle remains uninvestigated. This study investigates the effect of ALETP on the contractile activity of tracheal smooth muscle (TSM) in adult male Wistar rats.MethodsTwelve male Wistar rats divided into 2 groups and were treated with either 100 mg/kg of ALETP (ALETP treatment group) or vehicle (distilled water; control group) through oral gavage for 4 weeks. Dose responses of TSM from the 2 groups to acetylcholine (10–9 to 10–5 M), phenylephrine (10–9 to 10–5 M), and potassium chloride (KCl; 10–9 to 10–4 M) were determined cumulatively. Furthermore, cumulative dose responses to acetylcholine (10–9 to 10–5 M) after pre-incubation of TSM with atropine (10–5 M), L-NAME (10–4 M), indomethacin (10–4 M), and nifedipine (10–4 M), were determined.ResultsTreatment with ALETP substantially inhibited TSM contraction stimulated by cumulative doses of acetylcholine, phenylephrine, and KCl. Furthermore, preincubation of TSM from the 2 groups in atropine significantly inhibited contractility in TSM. Incubation in L-NAME and indomethacin also significantly inhibited contractility in TSM of ALETP-treated rats compared to that of controls. Contractile activity of the TSM was also inhibited significantly with incubation in nifedipine in ALETP-treated rats.ConclusionALETP enhanced relaxant activity in rat TSM primarily by blocking the L-type calcium channel and promoting endothelial nitric oxide release. ALETP contains agents that may be useful in disorders of the respiratory tract.

This Month in Adult Urology

This Month in Adult Urology

Dementia Associated with Anticholinergic Drugs Used for Overactive Bladder: A Nested Case-Control Study Using the French National Medical-Administrative Database.

We analyzed the relationship between use of anticholinergic drugs to treat overactive bladder (OAB) and risk of incident dementia in older patients, overall and for each drug separately. We conducted a nested case-control study using the French National Medical-Administrative Database. We identified incident dementia cases and controls from January 1, 2013 to December 31, 2018 in individuals aged ≥60 years. Controls were matched 5:1 to cases by date of case diagnosis (index date), age, sex, and income. We set a 5-year exposure period ending 2 years before the index date (lag-time period to avoid protopathic bias). We quantified cumulative exposure to flavoxate, oxybutynin, solifenacin, trospium, and fesoterodine using defined daily doses (DDDs). We performed conditional logistic regression analyses adjusted for factors known to be associated with OAB and/or dementia including obesity, diabetes, stroke, coronary heart disease, and psychotic disorders. We analyzed 4,810 cases and 24,050 matched controls with a median age of 82 years. OAB anticholinergic use was associated with an increased risk of dementia (adjusted OR [aOR]=1.23, 95% CI 1.10-1.37) with a cumulative dose-response: aOR=1.07 (95% CI 0.91-1.25) for 1-90 DDDs, aOR=1.29 (1.05-1.58) for 91-365 DDDs and aOR=1.48 (1.22-1.80) for >365 DDDs. Considering each OAB anticholinergic separately showed a particularly marked increased risk of dementia for oxybutynin and solifenacin, but no increased risk for trospium. When treating OAB in older patients, OAB anticholinergics should be used with caution, taking into account the patient's cognitive status, the anticholinergic load, and the different therapeutic options.

Statins stimulate voltage‐gated Ca2+ channels in arterial smooth muscle cells to induce rapid vasoconstriction in resistance‐size cerebral arteries

Statins are cholesterol‐lowering drugs with a range of beneficial vascular effects. Vascular effects are believed to result from long‐term statin therapy and reduction of cholesterol and mevalonate biosynthesis, and the inhibition of mevalonate‐dependent Rho/ROCK signaling. However, no studies have investigated the direct effects of acute statin application on fresh isolated resistance cerebral arteries using therapeutic concentrations of statins. Here, we examined acute vascular effects of rosuvastatin and simvastatin on Sprague Dawley rat cerebral arteries and underlying molecular mechanisms. We used pressurized arterial myography, simultaneous measurement of vessel Ca2+ fluorescence and diameter, pharmacological modulation, RNAi, Western blotting and biotinylation. Intravascular pressure in the mounted cerebral artery segments was gradually increased to 60 mmHg to stimulate the development of myogenic tone. At 60 mmHg, cerebral arteries developed ~36% myogenic tone, after which a cumulative dose response (0.01‐1000 nM) to rosuvastatin was performed and diameter changes recorded. Our data shows that, at 0.1, 1 and 10 nM concentrations, rosuvastatin induced a potent vasoconstriction – an observation never reported previously with any statin. Intriguingly, rosuvastatin, at 100 nM and 1000 nM concentrations (supratherapeutic), abolished myogenic tone and caused robust vasodilation. Rosuvastatin‐induced vasoconstriction reached a plateau at 1 nM concentration, which was used as reference for mechanistic studies. Within 2‐3 minutes of application, rosuvastatin and simvastatin constricted cerebral arteries by ~26 μm and ~24 μm, respectively. Endothelium denudation (intact ~23 μm vs denuded ~25 μm), or mevalonate supplementation did not alter statin‐induced vasoconstriction (control ~28 μm vs mevalonate ~29 μm), suggesting endothelium‐ and HMG‐CoA reductase‐independent mechanism. In contrast, removal of extracellular Ca2+with EGTA (~6 μm) or the application of nimodipine (~5 μm), a selective blocker of smooth muscle cell voltage‐gated Ca2+ channel, CaV1.2, or siRNA knockdown of CaV1.2 each abolished cerebral artery vasoconstriction and reduced [Ca2+]i, indicating that the Ca2+ entry through CaV1.2 plays a critical role here. Application of thapsigargin, a blocker of SR/ER membrane Ca2+‐ATPase pump, SERCA, but not ryanodine, a blocker of ryanodine receptor‐mediated Ca2+ release, fully reversed statin‐induced cerebral artery constriction and reduced [Ca2+]i. Arterial biotinylation data showed that short‐term statin exposure did not alter the surface expression, distribution and function of CaV1.2 channels.Altogether, our data demonstrate that statins at therapeutic concentrations directly stimulate smooth muscle cell CaV1.2 and Ca2+ influx to induce rapid vasoconstriction in resistance cerebral arteries.

Effects of Simulated Long Duration Spaceflight on Erectile Function

The goal of NASA along with other space agencies in the world is to send manned missions to the moon in the coming years, and eventually to Mars. The long‐term health risks of spaceflight have been attributed primarily to cosmic radiation and microgravity and the adverse effects as seen in the astronauts and model animals include DNA damage, mitochondrial dysregulation, oxidative damage, epigenetic changes, telomere length changes and microbiome shifts all of which affect the cardiovascular system. However, little is known about the effect of spaceflight on erectile function which is an important quality of life aspect for men. The aim of our study was to investigate the effect of simulated long duration space flight on erectile function. We hypothesized that both hindlimb unloading (HLU) and radiation will adversely affect erectile function. 86 adult male Sprague‐Dawley rats were used for these studies. Half the animals underwent 4 weeks of HLU, and all animals were divided into 3 groups: those that received sham radiation, 0.75 Gy, and 1.5 Gy galactic cosmic radiation, respectively at the Ground‐based GCR simulator at the NASA Space Radiation laboratory. The animals were then monitored for 6‐9 months before they were sacrificed, following which Corpus cavernosum (CC) and the distal internal pudendal arteries (dIPA) were harvested and used for ex vivo functional assessment. Tissue and wire myography studies were performed to assess adrenergic and endothelium‐dependent vasoconstrictions using phenylephrine (PE), norepinephrine, and endothelin. This was done by measuring the cumulative dose‐responses to the agonists in both the CC and dIPA. Endothelium‐dependent and ‐independent relaxations were also assessed using acetylcholine and diethylamine nononate. Non‐adrenergic non‐cholinergic (NANC) transmission was assessed using electrical stimulation (Estim); 30V electric pulses were delivered to the tissues with frequency ranging from 1‐32Hz following the administration of atropine and guanethidine and pre‐constriction with PE. Finally, Estim was done without atropine and guanethidine to assess the parasympathetic mediated relaxation in the tissues. The effects of HLU and radiation on the contractile and relaxation responses were assessed by two‐way repeated measures ANOVA. HLU and radiation significantly reduced both endothelium‐dependent and ‐independent vasodilatation in the dIPA and CC. Also, HLU and radiation significantly reduced the adrenergic constriction of CC in response to PE and norepinephrine. However, neither HLU nor radiation influenced the endothelium‐dependent vasoconstriction in the dIPA. Finally, radiation reduced the relaxation in both CC and dIPA while HLU increased the dIPA relaxation following Estim for both the parasympathetic mediated and NANC mediated responses. These results therefore showed the effects of HLU and radiation on erectile function, with exposure to cosmic radiation being primarily responsible for the detrimental effects. Further research needs to be done on this subject to show more mechanistically how spaceflight can affect erectile function and ways to combat the problem to ensure that astronauts can return to their normal sexual lives after long trips to space.

Effects of prenatal opioid exposure and early life adversity on opioid‐induced antinociception

Diagnoses of maternal opioid use disorder (MOUD) at delivery increased more than 500% between 1999 and 2017 in the United States. Today, cases of in utero opioid exposure due to MOUD exceed cases of the most common birth defects, including cleft lip, cleft palate, clubfoot, and Down syndrome, combined. Children exposed to opioids in utero are at increased risk of adverse childhood experiences (ACEs) due to parental care being compromised by SUDs. These ACEs include abuse, neglect, loss of a parent from death or incarceration, parental divorce, and household domestic violence. Altered sensitivity to opioid analgesia later in life is one potential outcome shared by in utero opioid exposure and ACEs that may contribute to poorly controlled pain and increased risk of opioid addiction. Studies using rat models of prenatal opioid exposure (POE) or early life adversity (ELA) have shown that each decreases opioid‐induced antinociception long after exposure has ceased. However, the contributions of POE and ELA, alone and in combination, to opioid analgesic response in humans remains unknown. In this study, we used a rodent model of combined POE and ELA to disambiguate their long‐term effects more quickly and with greater experimental control than human studies. We hypothesized that combined POE and ELA will decrease morphine‐induced antinociception in adolescence relative to POE or ELA alone. We used a two‐by‐two between‐subjects factorial design in which timed‐pregnant Long‐Evans rats were exposed to morphine (15 mg/kg/day; “POE” group) or saline (“vehicle” group) via subcutaneous osmotic minipump from gestation day 9 until delivery. Litters were fostered to untreated dams then randomly assigned to normal housing or ELA conditions using a limited bedding and nesting procedure from postnatal days 3‐11. Morphine‐induced antinociception was measured between postnatal days 30 and 54 using a warm‐water tail withdrawal (WWTW) assay. Cumulative dose‐response of morphine‐induced antinociception was determined on test day 0 (1.0‐30 mg/kg morphine, s.c.) and test day 13 (3.0‐100 mg/kg, s.c.). On test days 1‐12, rats were dosed with 18 mg/kg, s.c., every 12 hours, and WWTW was conducted on odd test days. Interesting, preliminary results of this ongoing study indicate that morphine‐induced antinociception was enhanced on test day 0 in POE + normal‐housed males (n = 2). These rats exhibited 100% maximum possible effect (MPE) and significantly higher potency (mean ED50=5.96 mg/kg; 95% CI = ‐12.12, 24.05), while mean MPE for the other groups (n=2‐3) was less than 70% and mean ED50&gt;17 mg/kg. Males exhibited partial tolerance throughout the 12‐day chronic morphine treatment period. In the POE + normal‐housed males, MPE decreased from 100% on test day 1 to 58% on test day 11. For the remaining groups, MPE decreased from 44‐57% on test day 1 to 12‐23% on test day 11. Morphine was more potent in the POE + normal‐housed males on test day 13 (mean ED50=66.21 mg/kg; 95% CI = ‐281.6, 414) than in other males (mean ED50&gt;104.4 mg/kg). No clear group effect was observed in females. These unexpected results suggest a complex sex‐dependent interaction between POE and ELA on opioid antinociception.

Possible mechanisms in Ficus exasperata ethanol root fraction amelioration of lead-induced corpus cavernosal contractile impairments in male Wistar rats.

Background:Lead exposure is reported to cause impaired male reproductive tract functions often due to elevated oxidative species. F. exasperata leaf extract contains potent phyto-antioxidants with beneficial endothelial functions. Objectives: This study investigates the effect of ethanolic extract of F. exasperata (EEFE) treatment on the corpus cavernosal contractile activity in lead-exposed adult male Wistar rats. Materials &amp; Methods: Corpus cavernosum strips (CS) were excised from control, EEFE only treated (400 mg/kg), lead + EEFE treated and lead only treated (100 mg/kg) male Wistar rats. Cumulative contractile responses of CS to acetylcholine, potassium chloride, and calcium influx were determined. Furthermore, cumulative dose responses to acetylcholine after incubation in LNAME, indomethacin, nifedipine, and acetovanillone were also determined by measuring isometric contractions using Ugo Basile data capsule acquisition system. Results: Relaxation(%) response to cumulative doses of acetylcholine (10-9–10-5 M) was enhanced in EEFE only treated (59%) compared to lead only (45%). Contractile response to KCl (10-60 M) was restrained in control and EEFE cotreated when compared to lead only treated. Preincubation of the CS with nifedipine (10-4 M) suppressed the relaxation(%) in the lead + EEFE co-treated. Preincubation of the CS in indomethacin improved the relaxant response(%) of the CS in EEFE only and lead + EEFE co-treated (53.53% ±2.80 &amp; 54.65%± 2.95 respectively) compared with the lead only treated (45.40%±1.79). Preincubation with L-NAME significantly reduced relaxation response(%) in EEFE only treated group. Relaxation response(%) of the CS was enhanced in the lead + EEFE group after preincubation with acetovanillone. Conclusion: The study suggests that L-type and voltage-gated calcium channels, NO, and potent antioxidant activity, are important in EEFE amelioration of lead-induced contractile impairments.

Carotid smooth muscle contractility changes after severe burn

Severe burns result in cardiovascular dysfunction, but responses in the peripheral vasculature are unclear. We hypothesize that severe burns disturb arterial contractility through acute changes in adrenergic and cholinergic receptor function. To address this, we investigated the changes in carotid artery contractility and relaxation following a severe burn. Thirty-four adult Sprague–Dawley male rats received a 40% total body surface area (TBSA) scald burn and fluid resuscitation using the Parkland formula. Control animals received sham burn procedure. Animals were serially euthanized between 6 h and 14 days after burn and endothelium-intact common carotid arteries were used for ex vivo force/relaxation measurements. At 6 h after burn, carotid arteries from burned animals demonstrated a > 50% decrease in cumulative dose-responses to norepinephrine (p < 0.05) and to 10−7 M angiotensin II (p < 0.05). Notably, pre-constricted carotid arteries also demonstrated reduced relaxation responses to acetylcholine (p < 0.05) 6 h after burn, but not to sodium nitroprusside. Histologic examination of cross-sectional planes revealed significant increases in carotid artery wall thickness in burned rats at 6 h versus 3 days, with increased collagen expression in tunica media at 3 days (p < 0.05). Carotid artery dysfunction occurs within 6 h after severe burn, demonstrating decreased sensitivity to adrenergic- and angiotensin II-induced vasoconstriction and acetylcholine-induced relaxation.

Trimetazidine Use and the Risk of Parkinsonism: A Nationwide Population-Based Study.

An association between trimetazidine (TMZ), an anti-anginal drug, and parkinsonism has been reported in a number of studies. However, evidence from studies with long-term follow-up and better validity is lacking. We investigated the risk of TMZ-associated parkinsonism, specifically the incidence rate, cumulative dose–response relationship, and combined effects with other parkinsonism-inducing medications. This propensity score-matched retrospective cohort study was conducted using 14-year health insurance claims data in South Korea. The risk of parkinsonism was evaluated using multivariate Cox proportional hazard regression analysis, adjusted for comorbidities and concurrent medications. A total of 9712 TMZ users and 29,116 matched non-TMZ users were included. TMZ users had a significantly higher incidence rate of parkinsonism than non-TMZ users (9.34 vs. 6.71 per 1000 person-years; p < 0.0001). TMZ use significantly increased the risk of parkinsonism (adjusted hazard ratio = 1.38; 95% confidence interval = 1.26–1.51). Increased risks were observed with accumulated doses of TMZ, as well as concurrent use of other parkinsonism-inducing medications. The findings indicate that TMZ use significantly increases the risk of parkinsonism in the South Korean population. Closer monitoring should be considered for TMZ users, especially for those who are older, using TMZ at high cumulative doses and other parkinsonism-inducing medications.

Occupational radiation and haematopoietic malignancy mortality in the retrospective cohort study of US radiologic technologists, 1983–2012

ObjectivesTo evaluate cumulative occupational radiation dose response and haematopoietic malignancy mortality risks in the US radiologic technologist cohort.MethodsAmong 110 297 radiologic technologists (83 655 women, 26 642 men) who completed...

Differential temporal response patterns in rat cocaine self-administration studies: The cumulative record dose-response function

Differential temporal response patterns in rat cocaine self-administration studies: The cumulative record dose-response function

Contribution of Splenic Resistance Arteries to Splanchnic Blood Overflow in Cirrhosis.

In liver cirrhosis, a marked splanchnic vasodilation causes an increase in portal blood flow, contributing to the development of portal hypertension. To evaluate if, in experimental cirrhosis, a different vascular reactivity exists between splenic and mesenteric components of the splanchnic circulation. Liver cirrhosis was induced in Sprague Dawley rats by common bile duct ligation. In sections of splenic and superior mesenteric arteries, cumulative dose-response curves were obtained. mRNA expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and prostaglandin I2 synthase (PTGIS) was evaluated. In cirrhotic rats, mesenteric but not splenic arteries showed a significant increase in endothelium-dependent relaxation to acetylcholine. In control and cirrhotic rats, COX inhibition alone did not significantly change the response of mesenteric arteries to acetylcholine; after inhibiting also NOS, the relaxation was completely abolished in control but only partially decreased in cirrhotic rats. After the inhibition of COX and NOS, the relaxation to acetylcholine was similarly decreased in splenic arteries from control and cirrhotic animals. The contraction induced by phenylephrine of both mesenteric and splenic arteries was decreased in cirrhotic rats. PTGIS mRNA expression did not differ in splenic and mesenteric arteries from control and cirrhotic rats; in cirrhotic rats, eNOS and iNOS mRNA expression was increased in mesenteric but not in splenic vascular bed. In cirrhotic rats, a decreased splenic arterial response to vasoconstrictors, rather than an increased response to vasodilators, contributes to splanchnic vasodilation, while in mesenteric arteries also an increased response to vasodilators secondary to, but not only, eNOS and iNOS overexpression, plays a role.