Asymmetric dimethylarginine does not inhibit arginase activity and is pro‐proliferative in pulmonary endothelial cells

Asymmetric dimethylarginine (ADMA) is an endogenously produced nitric oxide synthase (NOS) inhibitor. l ‐Arginine can be metabolised by NOS and arginase, and arginase is the first step in polyamine production necessary for cellular proliferation. We tested the hypothesis that ADMA would inhibit NOS but not arginase activity and that this pattern of inhibition would result in greater l ‐arginine bioavailability to arginase, thereby increasing viable cell number. Bovine arginase was used in in vitro activity assays with various concentrations of substrate (l ‐arginine, ADMA, N^G‐monomethyl‐l ‐arginine (L‐NMMA) and N^G‐nitro‐l ‐arginine methyl ester (l ‐NAME)). Only l ‐arginine resulted in measurable urea production (K_m = 6.9 ± 0.8 mmol/L; V_max = 6.6 ± 0.3 μmol/mg protein per min). We then incubated bovine arginase with increasing concentrations of ADMA, l ‐NMMA and l ‐NAME in the presence of 1 mmol/L l ‐arginine and found no effect of any of the tested compounds on arginase activity. Using bovine pulmonary arterial endothelial cells (bPAEC) we determined the effects of ADMA on nitric oxide (NO) and urea production and found significantly lower NO production and greater urea production (P < 0.003) with ADMA, without changes in arginase protein levels. In addition, ADMA treatment resulted in an approximately 30% greater number of viable cells after 48 h than in control bPAEC. These results demonstrate that ADMA is neither a substrate nor an inhibitor of arginase activity and that in bPAEC ADMA inhibits NO production and enhances urea production, leading to more viable cells. These results may have pathophysiological implications in disorders associated with higher ADMA levels, such as pulmonary hypertension.     

Determination of stereochemistry stability coefficients of amino acid side‐chains in an amphipathic α‐helix

Abstract: We describe here a systematic study to determine the effect on secondary structure of d ‐amino acid substitutions in the nonpolar face of an amphipathic α‐helical peptide. The helix‐destabilizing ability of 19 d ‐amino acid residues in an amphipathic α‐helical model peptide was evaluated by reversed‐phase HPLC and CD spectroscopy. l ‐Amino acid and d ‐amino acid residues show a wide range of helix‐destabilizing effects relative to Gly, as evidenced in melting temperatures (ΔT_m) ranging from ?8.5°C to 30.5°C for the l ‐amino acids and ?9.5°C to 9.0°C for the d ‐amino acids. Helix stereochemistry stability coefficients defined as the difference in T_m values for the l ‐ and d ‐amino acid substitutions [(ΔT_m′ = T_mL and T_mD)] ranging from 1°C to 34.5°C. HPLC retention times [Δt_R(X_L?X_D)] also had values ranging from ?0.52 to 7.31 min at pH 7.0. The helix‐destabilizing ability of a specific d ‐amino acid is highly dependent on its side‐chain, with no clear relationship to the helical propensity of its corresponding l ‐enantiomers. In both CD and reversed‐phase HPLC studies, d ‐amino acids with β‐branched side‐chains destabilize α‐helical structure to the greatest extent. A series of helix stability coefficients was subsequently determined, which should prove valuable both for protein structure‐activity studies and de novo design of novel biologically active peptides.     

Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats

To assess the role of central dopamine on metabolic rate, heat balance and running performance, 2.0 µL of 5 × 10^− 3 M dopamine solution (DA) or 0.15 M NaCl (SAL) was intracerebroventricularly injected in Wistar rats 1 min before running on a motor-driven treadmill, according to a graded exercise protocol, until fatigue. Oxygen consumption (VO₂) and body temperature (T_b) were recorded at rest, during exercise, and after 30 min of recovery. DA induced a marked increase in workload (~ 45%, p < 0.05). At fatigue point, DA-injected rats attained ~29% higher maximum oxygen consumption (VO_2max) and ~0.75 °C higher T_b than SAL-injected rats. Despite the higher VO_2max and T_b attained during exercise, DA-treated rats reached VO₂ basal values within the same recovery period and dissipated heat ~33% faster than SAL-treated rats (p < 0.05). The mechanical efficiency loss rate was ~40% lower in DA than in SAL-treated rats (p < 0.05), however, the heat storage was ~35% higher in the DA group (p < 0.05). Our results demonstrate that increased DA availability in the brain has a performance-enhancing effect, which is mediated by improvements in the tolerance to heat storage and increases in the metabolic rate induced by graded exercise. These data provide further evidence that central activation of dopaminergic pathways plays an important role in exercise performance.     

Chronic mercury exposure at different concentrations produces opposed vascular responses in rat aorta

Mercury chloride exposure for 30 days decreases NO bioavailability and increases oxidative stress. However, the mechanisms underlying the effects of mercury on the cardiovascular system are not completely understood, and it is not known if they are dose‐dependent or if some concentrations have no harmful effects. Thus, we investigated the effects of chronic exposure to doses low (half) and high (2.5‐fold higher) than that needed to obtain 29 nmol/L of HgCl₂ on the vascular function. Three‐month‐old male Wistar rats received intramuscular (i.m.) HgCl₂ for 30 days and were divided in three groups: lower (Low Hg); higher (High Hg); and saline was used as the control. High Hg exposure increased the contractile response to phenylephrine (PHE) in aortic rings, but Low Hg reduced it. The hyporesponsiveness in the Low Hg rats was blunted by endothelial denudation and NOS inhibition with l ‐NAME (100 μmol/L). The phosphorylated‐eNOS/eNOS protein ratio increased in the aortas of Low Hg rats. In the High Hg group, endothelial denudation increased the PHE‐induced contractions, while l ‐NAME had no effects and indomethacin (10 μmol/L), losartan (10 μmol/L) and apocynin (30 μmol/L) reduced this response. In the High Hg group, protein levels of the NADPH oxidase subunit gp91phox and cyclooxygenase‐2 increased. Our results support previous suggestions that High Hg increases oxidative stress that might activate an inflammatory cascade and the renin‐angiotensin system. However, very low Hg concentrations below the level considered safe still reduced vascular reactivity, suggesting the need for special attention to continuous exposure as a putative cause of increased cardiovascular risk.     

The improvement of exercise performance by physical training is related to increased hypothalamic neuronal activation

The effects of physical training on hypothalamic activation after exercise and their relationship with heat dissipation were investigated. Following 8 weeks of physical training, trained (TR, n = 9) and untrained (UN, n = 8) Wistar rats were submitted to a regimen of incremental running until fatigue while body and tail temperatures were recorded. After exercise, hypothalamic c‐Fos immunohistochemistry analysis was performed. The workload, body‐heating rate, heat storage and body temperature threshold for cutaneous vasodilation were calculated. Physical training increased the number of c‐Fos immunoreactive neurons in the paraventricular, medial preoptic and median preoptic nucleus by 112%, 90% and 65% (P < 0.01) after exercise, respectively. In these hypothalamic regions, increased neuronal activation was directly associated with the increased workload performed by TR animals (P < 0.01). Moreover, a reduction of 0.6°C in the body temperature threshold for cutaneous vasodilation was shown by TR animals (P < 0.01). This reduction was possibly responsible for the lower body‐heating rate (0.019 ± 0.002°C/min, TR vs 0.030 ± 0.005°C/min, UN, P < 0.05) and the decreased ratio between heat storage and the workload performed by TR animals (18.18 ± 1.65 cal/kg, TR vs 31.38 ± 5.35 cal/kg, UN, P < 0.05). The data indicate that physical training enhances hypothalamic neuronal activation during exercise. This enhancement is the central adaptation relating to better physical performance, characterized by a lower ratio of heat stored to workload performed, due to improved heat dissipation.     

l‐Cysteine enhances nutrient absorption via a cystathionine‐β‐synthase‐derived H2S pathway in rodent jejunum

Hydrogen sulphide (H₂S) is generated endogenously from l ‐cysteine (l ‐Cys) by the enzymes cystathionine‐β‐synthase (CBS) and cystathionine‐γ‐lyase (CSE). In addition, l ‐Cys is commonly used as a precursor in the food and pharmaceutical industries. The aim of the present study is to determine whether l ‐Cys regulates intestinal nutrient transport. To that end, the presence of CBS and CSE in the jejunum epithelium was assessed by immunohistochemistry, Western blotting and the methylene blue assay. In addition, in vivo l ‐Cys (100 mg/kg, administered immediately after the glucose load) significantly increased blood glucose levels 30 min after the oral administration of glucose to mice. This effect of l ‐Cys was completely blocked by amino‐oxyacetic acid (AOA; 50 mg/kg; administered at the same time as l ‐Cys) an inhibitor of CBS. Measurements of the short‐circuit current (I_sc) in the rat jejunum epithelium revealed that l ‐Cys (1 mmol/L; 6 min before the administration of l ‐alanine) enhances Na⁺‐coupled l ‐alanine or glucose transport, and that this effect is inhibited by AOA (1 mmol/L;10 min before the administration of l ‐Cys), but not d ,l ‐propargylglycine (PAG;1 mmol/L; 10 min before the administration of l ‐Cys), a CSE inhibitor. Notably, l ‐Cys‐evoked enhancement of nutrient transport was alleviated by glibenclamide (Gli;0.1 mmol/L; 10 min before the administration of l ‐Cys), a K⁺ channel blocker. Together, the data indicate that l ‐Cys enhances jejunal nutrient transport, suggesting a new approach to future treatment of nutrition‐related maladies, including a range of serious health consequences linked to undernutrition.     

Serotonergic mechanisms of clonidine-induced hypothermia in rats

The effects of intraventricular administration of clonidine and serotonin on metabolic, respiratory and vasomotor activities as well as on body temperature were assessed in unanesthetized rats at ambient temperatures (T_a of 8, 22 and 30°C. Intraventricular administration of clonidine and serotonin each produced a dose-dependent hypothermia at all T_a's studied. At 8 and 22°C, the hypothermia in response to clonidine and serotonin was due to decreased metabolic heat production, increased respiratory evaporative heat loss and cutaneous vasodilatation (as estimated by an increase in cutaneous temperatures). In the heat (30°C T_a), the induced hypothermia was due to increased respiratory evaporative heat loss. The clonidine hypothermia was greatly antagonized by the pretreatment of animals with 5,7-dihydroxytryptamine (a relative depletor of central serotonin content), but not with 6-hydroxydopamine (a relative depletor of central catecholamine content). The data indicate that clonidine may decrease heat production and (or) increase heat loss to elicit hypothermia, probably via activation of central serotonergic pathways.     

Effects of sodium pentobarbital on thermoregulatory responses in the rat

The effects of intraperitoneal and intraventricular administration of sodium pentobarbital on metabolic, respiratory and vasomotor activity, as well as body temperature of rats to different ambient temperatures (T_a) of 8, 22 and 30°C, were assessed. Administration of sodium pentobarbital produced hpothermia in rats at both 8 and 22°C T_a. The hypothermia in response to sodium pentobarbital was due to both decreased metabolism and cutaneous vasodilatation (as indicated by an increase in both the tail and the foot skin temperatures). There was no changes in respiratory evaporative heat loss. However, at 30°C T_a, administration of sodium pentobarbital produced no changes in either rectal temperature or other thermoregulatory responses. Furthermore, the hypothermia induced by sodium pentobarbital or ketamine was severely antagonized by depletion of brain serotonin levels with either 5,7-dihydroxytryptamine or p-chlorophenylalanine. The data indicate that anesthetics such as sodium pentobarbital and ketamine lead to hypothermia in the rat by increasing heat loss and decreasing metabolic heat production, probably via the release of endogenous serotonin within brain.     

A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder

Rationale Nitrous oxide (N₂O) can initially lower core temperature (T _core), but hypothermic tolerance develops with chronic administration. Therefore, one or both of T _core’s controlling determinants, heat production (HP) and heat loss (HL), must adapt across repeated N₂O administrations. Simultaneous measurements of HP, HL, and T _core during chronic N₂O administrations will elucidate this adaptive process and constitute a rigorous model for studying the systems-level dynamics of tolerance in both mature and young animals. This approach is justified by the need to better understand the increased vulnerability to addiction associated with adolescent drug use. Objectives The objective of the study was to measure HL and HP across repeated steady-state administrations of 60% N₂O in young and mature rats. Materials and methods Synchronous measurements of HP (indirect calorimetry), HL (direct calorimetry), and T _core (telemetry) were obtained during 60% N₂O administrations in adolescent (28–45 days, n = 11) and mature rats (>90 days, n = 8). Rats received five 90-min drug exposures (every other day). Results Compared to mature rats, adolescents initially exhibited greater hypothermia, but acquired tolerance more rapidly and actually developed hyperthermia during the fifth administration. In both groups, N₂O consistently increased HL, but progressive increases of intrasessional HP over repeated administrations prevented hypothermia and subsequently promoted hyperthermia in adolescent rats. Conclusions Adolescent rats hyper-adapt to N₂O hypothermia. Increases of intrasessional HP across N₂O administrations explained both tolerance to N₂O hypothermia and the unexpected hyperthermia observed in adolescents. These findings raise the possibility that the increased vulnerability to addiction associated with adolescent drug use involves a hyper-adaptive tolerance mechanism.     

Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Rationale Some argue that pharmacological effects trigger corrective regulatory responses of varying strength. If so, some commonly used in vivo measures of initial drug sensitivity are difficult to interpret because the measured effects represent a combination of underlying pharmacological effects and regulatory counter-responses with the relative contribution of each influenced by individual and dose-related factors. Objectives The objective of this study was determine if core temperature (T _core), a common measure in drug research, can mask the variability both in underlying pharmacological effects and physiological counter-responses during an initial administration of the hypothermia-promoting drug, nitrous oxide (N₂O). Methods T _core was measured synchronously with its determinants, heat production (HP) and heat loss (HL) during steady-state N₂O administration. Drug-naive rats received a 90-min exposure to 0, 15, 30, 50, 60, or 75% N₂O plus a paired control gas exposure (n ≥ 8 per group). HP was measured via indirect calorimetry, HL via direct calorimetry, and T _core via telemetry. Results T _core was unaltered by concentrations ≤50% N₂O, but at 30 and 50% N₂O, this stability masked significant increases of HL that were offset by increases of HP. On average, hypothermia accompanied 60 and 75% N₂O inhalation owing to uncompensated increases of HL. However, some rats administered with these doses also exhibited T _core stability via significant opposing changes of HL and HP. Conclusions A common in vivo measure of initial drug sensitivity can fail to disclose underlying pharmacological sensitivity owing to regulatory counter-responses. This concept has implications for understanding relationships between phenotypic variation in initial drug sensitivity and subsequent drug-taking phenotypes.     

Vasorelaxation induced by methyl cinnamate,the major constituent of the essential oil of Ocimum micranthum,in rat isolated aorta

The aim of the present study was to investigate the vascular effects of the E‐isomer of methyl cinnamate (E‐MC) in rat isolated aortic rings and the putative mechanisms underlying these effects. At 1–3000 μmol/L, E‐MC concentration‐dependently relaxed endothelium‐intact aortic preparations that had been precontracted with phenylephrine (PHE; 1 μmol/L), with an IC₅₀ value (geometric mean) of 877.6 μmol/L (95% confidence interval (CI) 784.1–982.2 μmol/L). These vasorelaxant effects of E‐MC remained unchanged after removal of the vascular endothelium (IC₅₀ 725.5 μmol/L; 95% CI 546.4–963.6 μmol/L) and pretreatment with 100 μmol/L N^G‐nitro‐l ‐arginine methyl ester (IC₅₀ 749.0 μmol/L; 95% CI 557.8–1005.7 μmol/L) or 10 μmol/L 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (IC₅₀ 837.2 μmol/L; 95% CI 511.4–1370.5 μmol/L). Over the concentration range 1–3000 μmol/L, E‐MC relaxed K⁺‐induced contractions in mesenteric artery preparations (IC₅₀ 314.5 μmol/L; 95% CI 141.9–697.0 μmol/L) with greater potency than in aortic preparations (IC₅₀ 1144.7 μmol/L; 95% CI 823.2–1591.9 μmol/L). In the presence of a saturating contractile concentration of K⁺ (150 mmol/L) in Ca²⁺‐containing medium combined with 3 μmol/L PHE, 1000 μmol/L E‐MC only partially reversed the contractile response. In contrast, under similar conditions, E‐MC nearly fully relaxed PHE‐induced contractions in aortic rings in a Ba²⁺‐containing medium. In preparations that were maintained under Ca²⁺‐free conditions, 600 and 1000 μmol/L E‐MC significantly reduced the contractions induced by exogenous Ca²⁺ or Ba²⁺ in KCl‐precontracted preparations, but not in PHE‐precontracted preparations (in the presence of 1 μmol/L verapamil). In addition, E‐MC (1–3000 μmol/L) concentration‐dependently relaxed the contractions induced by 2 mmol/L sodium orthovanadate. Based on these observations, E‐MC‐induced endothelium‐independent vasorelaxant effects appear to be preferentially mediated by inhibition of plasmalemmal Ca²⁺ influx through voltage‐dependent Ca²⁺ channels. However, the involvement of a myogenic mechanism in the effects of E‐MC is also possible.     

Characterization of relaxant mechanism of H2S in mouse corpus cavernosum

The aim of this study was to investigate the mechanism of H₂S‐induced relaxation in mouse corpus cavernosal tissue. l ‐cysteine (10^?6 × 10^?3 mol/L) and exogenous H₂S (NaHS; 10^?6 to 10^?3 mol/L) induced concentration‐dependent relaxation. l ‐cysteine‐induced relaxations was reduced by d,l ‐propargylglycine, a cystathionine gamma lyase (CSE) inhibitor but not influenced by aminooxyacetic acid, a cystathionine beta synthase (CBS) inhibitor. l ‐cysteine induced relaxations, but not of those of H₂S diminished in endothelium‐denuded tissues. N^ω‐nitro‐l ‐arginine (l ‐NA; 10^?4 mol/L), a nitric oxide synthase inhibitor, and ODQ (10^?4 mol/L), a guanylyl cyclase inhibitor, increased the H₂S‐induced relaxation. Zaprinast (5 × 10^?6 mol/L) and sildenafil (10^?6 mol/L), phosphodiesterase inhibitors, inhibited H₂S‐induced relaxation. Adenylyl cyclase inhibitors N‐ethylmaleimide (2.5 × 10^?5 mol/L) and SQ22536 (10^?4 mol/L) reduced relaxation to H₂S. Also, H₂S‐induced relaxation was reduced by KCl (50 mmol/L), 4‐aminopyridine (10^?3 mol/L), a K_v inhibitor, glibenclamide (10^?5 mol/L), a K_ATP inhibitor or barium chloride (10^?5 mol/L), a K_IR inhibitor. However, H₂S‐induced relaxation was not influenced by apamin (10^?6 mol/L), a SK_Ca²⁺ inhibitor, charybdotoxin (10^?7 mol/L), an IK_Ca²⁺ and BK_Ca²⁺ inhibitor or combination of apamin and charybdotoxin. Nifedipine (10^?6 mol/L), an L‐type calcium channel blocker and atropine (10^?6 mol/L), a muscarinic receptor blocker, inhibited H₂S‐induced relaxation. However, H₂S‐induced relaxation was not influenced by ouabain (10^?4 mol/L), a Na⁺/K⁺‐ATPase inhibitor. This study suggests that H₂S endogenously synthesizes from l ‐cysteine by CSE endothelium‐dependent in mouse corpus cavernosum tissue, and exogenous H₂S may cause endothelium‐independent relaxations via activation of K channels (K_ATP channel, K_V channels, K_IR channels), L‐type voltage‐gated Ca²⁺ channels, adenylyl cyclase/cAMP pathway and muscarinic receptor, and there is the interaction between H₂S and NO/cGMP.     

Potential excitatory role of nitric oxide on 2‐deoxy‐d‐glucose‐induced gastric motility in rats

Previous studies have shown that 2‐deoxy‐d ‐glucose (2‐DG) increases gastric motility via the vagus nerve, but the underlying mechanism remains elusive. Since nitric oxide (NO) is involved in gastric motility, a possible interplay between 2‐DG and NO can be suggested. In the present study, Wistar rats (250‐350 g) of both sexes were intravenously injected with 2‐DG (200 mg/kg), and the effects of the intravenous injection of the nitric oxide synthase (NOS) inhibitors; nitro‐l ‐arginine methyl ester (l ‐NAME, 10 mg/kg) and N^ω‐nitro‐l ‐arginine (l ‐NNA, 10 mg/kg) were investigated. Animals were anaesthetized and cannulated for intravenous drug injections while the left vagal nerve was electrically stimulated (0.1‐10 Hz, 0.5 ms duration, 12 V, for 60 seconds), and intragastric pressure and gastric motility changes were monitored using a latex gastric balloon. 2‐DG increased the mean intragastric pressure (baseline, 5.0±0.4 cmH₂O; after 2‐DG, 14.4±1.5 cmH₂O; P=.0156) and significantly increased the gastric motility index, while NOS inhibitors significantly attenuated both parameters. However, pretreatment with NOS inhibitors significantly augmented the gastric responses to peripheral electrical vagal stimulation. These results suggest that NO plays an excitatory role in gastric responsiveness to 2‐DG and that this function may be effected in the central nervous system.     

Endothelial and neuronal nitric oxide synthases variably modulate the oestrogen‐mediated control of blood pressure and cardiovascular autonomic control

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Nitric oxide signalling is involved in diarylheptanoid‐induced increases in femoral arterial blood flow in ovariectomized rats

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DIRECT EFFECT OF DEXMEDETOMIDINE ON RAT ISOLATED AORTA INVOLVES ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND ACTIVATION OF THE LIPOXYGENASE PATHWAY

• 1 The aims of the present in vitro study were to examine the roles of pathways associated with arachidonic acid metabolism in dexmedetomidine‐induced contraction and to determine which endothelium‐derived vasodilators are involved in the endothelium‐dependent attenuation of vasoconstriction elicited by dexmedetomidine.
• 2 Dexmedetomidine (10^?9–10^?6 mol/L) concentration–response curves were constructed in: (i) aortic rings with no drug pretreatment; (ii) endothelium‐denuded aortic rings pretreated with either 2 × 10^?5 mol/L quinacrine dihydrochloride, 10^?5 mol/L nordihydroguaiaretic acid (NDGA), 3 × 10^?5 mol/L indomethacin or 10^?5 mol/L fluconazole; and (iii) endothelium‐intact aortic rings pretreated with either 5 × 10^?5 mol/L N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME), 10^?5 mol/L fluconazole, 10^?5 mol/L indomethacin, 10^?5 mol/L glibenclamide, 5 × 10^?3 mol/L tetraethylammonium or 5 × 10^?5 mol/L l ‐NAME plus rauwolscine (10^?5, 10^?6 mol/L). The production of nitric oxide (NO) metabolites was determined in human umbilical vein endothelial cells treated with dexmedetomidine.
• 3 Quinacrine dihydrochloride, NDGA and indomethacin attenuated the dexmedetomidine‐induced contraction of endothelium‐denuded rings. Dexmedetomidine (10^?7–10^?6 mol/L)‐induced contractions of endothelium‐denuded rings were enhanced compared with those of endothelium‐intact rings, as were dexmedetomidine‐induced contractions of endothelium‐intact rings pretreated with l ‐NAME or tetraethylammonium. Rauwolscine attenuated dexmedetomidine‐induced contractions in endothelium‐intact rings pretreated with l ‐NAME. Dexmedetomidine (10^?6 mol/L) was found to activate NO production.
• 4 Taken together, the results indicate that dexmedetomidine‐induced contraction of aortic rings involves activation of the lipoxygenase and cyclo‐oxygenase pathways and is attenuated by increased NO production following stimulation of endothelial α₂‐adrenoceptors by dexmedetomidine.

     

Effects of intraventricular administration of neurotensin and somatostatin on thermoregulation in the rat

Intraventricular administration of either neurotensin or somatostatin produced dose-dependent hypothermia in rats at both the low (8°C) and the moderate (22°C) ambient temperatures (T_a). The hypothermia in response to neurotensin was due to decreased metabolism accompanied by cutaneous vasoconstriction, while the hypothermia in response to somatostatin was due to decreased metabolism and cutaneous vasodilitation. In contrast, intraventricular administration of either neurotensin or somatostatin produced dose-dependent hyperthermia at high (30°C) T_a. The hyperthermia induced by neurotensin was due to cutaneous vasoconstriction accompanied by increased respiratory evaporative heat loss, while the somatostatin-induced hyperthermia was due to increased metabolism-and cutaneous vasoconstriction.     

The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

Rationale  3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans. Objectives  The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR). Materials and methods  Sprague–Dawley rats with telemetry implants were administered 40 μmol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (T _A) (HOT; 30 ± 1°C) or an area at room temperature (ROOM; 21.5 ± 1.5°C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation. Results  HOT rats showed higher core temperature (T _C), HR, and locomotor activity than ROOM rats during confinement to a set T _A (P < 0.001). HR responses to MDMA over 6 weeks at both T _As progressively decreased with repeated dosing (P < 0.05). T _C was significantly higher in both 6-week groups compared to the 1-week groups (P < 0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P < 0.05) and 5-hydroxyindole acetic acid (5-HIAA; P < 0.001) decreased significantly irrespective of T _A, while concentrations of dopamine and 5-HT did not change. Conclusion  Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of T _C in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.