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Summary: β‐Phenylethylamine (β‐PEA) is a trace amine with chemical proximity to biogenic amines and amphetamines. It is an endogenous agonist of trace amine‐associated receptors (TAARs) that acts as a neuromodulator of classic neurotransmitters in the central nervous system. At high concentrations, β‐PEA contracts smooth muscle, and a role for TAARs in these responses has been postulated. The high dietary intake of trace amines has been associated with such symptoms as hypertension and migraine, especially after the intake of foods containing such compounds. In gastrointestinal tissues, TAAR expression was reported, although the effect of β‐PEA on gastric contractile behaviour is unknown. Here, isolated strips that were obtained from the rat gastric fundus were stimulated with high micromolar concentrations of β‐PEA. Under resting tonus, β‐PEA induced contractions. In contrast, when the strips were previously contracted with KCl, a relaxant response to β‐PEA was observed. The contractile effect of β‐PEA was inhibited by 5‐hydroxytryptamine (5‐HT) receptor antagonists (i.e., cyproheptadine and ketanserin) but not by the TAAR1 antagonist EPPTB. In gastric fundus strips that were previously contracted with 80 mmol/L KCl, the relaxant effect of β‐PEA intensified in the presence of 5‐HT receptor antagonists, which was inhibited by EPPTB and the adenylyl cyclase inhibitor MDL‐12,330A. The guanylyl cyclase inhibitor ODQ did not alter the relaxant effects of β‐PEA. In conclusion, β‐PEA exerted dual contractile and relaxant effects on rat gastric fundus. The contractile effect appeared to involve the recruitment of 5‐HT receptors, and the relaxant effect of β‐PEA on KCl‐elicited contractions likely involved TAAR1. [ABSTRACT FROM AUTHOR]

Objective Justicia pectoralis is a plant useful for the treatment of respiratory diseases. Here, we studied the antiasthmatic properties of a standardized extract of J. pectoralis (Jp). Methods Ovalbumin ( OVA)-sensitized rats were actively challenged with saline or OVA to study airway hyper-responsiveness after oral treatment with saline or Jp. The ability of Jp to inhibit hyper-reactivity was evaluated in isolated trachea mounted in isolated organ bath chamber. Key findings Using KCl or carbachol as contractile agents, tracheal rings of OVA-challenged rats contracted with higher magnitude than trachea of rats challenged with saline. Such hyper-responsive phenotype of OVA-challenged tissues decreased with Jp administration. In Ca+-free medium, Jp or its major constituent coumarin inhibited preferentially the contractions induced by Ca2+ addition in tissues of OVA-challenged rats stimulated with KCl or acetylcholine. In tissues depleted of their internal Ca+ stores in the presence of thapsigargin, Jp inhibited the contraction induced by capacitative Ca2+ entry. By gavage, Jp abolished the increase caused by challenge with OVA on the levels of IL-1β and TNF-α in the bronchoalveolar fluid and also impaired the changes in gene expression of canonical transient receptor proteins. Conclusions Jp has antiasthmatic properties in an experimental model that reproduces tracheal hyper-reactivity. [ABSTRACT FROM AUTHOR]

Context: The labdenic diterpene labd-8(17)-en-15-oic acid (labd-8) isolated from a methanolic extract of Moldenhawera nutans Queiroz & Alkin (Leguminosae) has hypotensive and tachycardiac properties in normotensive rats. A part of the hypotensive effect was due to a reduction in the sympathetic nerve drive to vessels, an event admittedly enhanced in spontaneously hypertensive rats (SHRs). Objectives: We assessed whether the cardiovascular effects induced by labd-8 could be enhanced in SHRs. Materials and methods: For in vivo experiments, arterial and venous catheters were implanted under anesthesia for blood pressure recording and drug administration, respectively. For in vitro experiments, thoracic aorta rings were suspended in organ baths containing warm (37 °C) perfusion medium that was continuously bubbled with carbogen. Results: Intravenous injection of labd-8 (1, 3, 5, and 10 mg/kg) induced similar dose-dependent hypotension and tachycardia in both SHRs and Wistar-Kyoto rats (WKY). In SHRs, only the tachycardia response to labd-8 was significantly reduced by pretreatment with methylatropine or propranolol. However, both cardiovascular effects of labd-8 were reduced by hexamethonium while remained unchanged by l-NAME. In isolated aortic preparations from SHRs, labd-8 (1-1000 µg/mL) relaxed potassium-induced contractions with an IC50 (geometric mean [95% confidence interval]) value (536.5 [441.0-631.9] µg/mL) significantly greater than that (157.6 [99.1-250.5] µg/mL) obtained in preparations from WKY rats. Conclusion: In SHRs, the hypotension induced by labd-8 is associated with a reflex tachycardia and seems mediated partly through withdrawal of sympathetic vasomotor tone and partly through an active vasorelaxation. Its magnitude was not enhanced when compared with WKY rats likely because of impaired vasorelaxant effects of labd-8 in preparations from SHRs. [ABSTRACT FROM AUTHOR]

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 NG-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. [ABSTRACT FROM AUTHOR]

Physical exercise, mainly after vigorous activity, may induce gastrointestinal dysmotility whose mechanisms are still unknown. We hypothesized that physical exercise and ensuing lactate-related acidemia alter gastrointestinal motor behavior. In the present study, we evaluated the effects of short-term exercise on gastric emptying rate in awake rats subjected to 15-min swimming sessions against a load equivalent to 5% of their body weight. After 0, 10, or 20 min of exercise testing, the rats were gavage fed with 1.5 ml of a liquid test meal (0.5 mg/ml of phenol red in 5% glucose solution) and euthanized 10 min postprandially to measure fractional gastric dye recovery. In addition to inducing acidemia and increasing blood lactate levels, acute exercise increased (P < 0.05) gastric retention. Such a phenomenon presented a positive corre-lation (P < 0.001) between blood lactate levels and fractional gastric dye recovery. Gastric retention and other acidbase-related changes were all prevented by NaHCO3 pretreatment. Additionally, exercise enhanced (P < 0.05) the marker's progression through the small intestine. In anesthetized rats, exercise increased (P < 0.05) gastric volume, measured by a balloon catheter in a barostat system. Compared with sedentary control rats, acute exercise also inhibited (P < 0.05) the contractility of gastric fundus strips in vitro. In conclusion, acute exercise delayed the gastric emptying of a liquid test meal by interfering with the acid-base balance. [ABSTRACT FROM AUTHOR]

Arteriovenous anastomoses disrupt cardiovascular and renal homeostasis, eliciting hemodynamic adjustments, resetting the humoral pattern, and inducing cardiac hypertrophy. Because acute circulatory imbalance alters gut motor behavior, we studied the effects of arteriovenous fistula placement on the gastric emptying (GE) of a liquid meal in awake rats. After laparotomy, we created an aortocaval fistula (ACF) by aorta and cava wall puncture with a 21-, 23-, or 26-gauge needle. The ACF was not created in the control group, which underwent sham operation. After 12, 24, or 48 h, mean arterial pressure, heart rate, and central venous pressure were continuously recorded, and cardiac output was estimated by thermal dilution. The rats were then gavage fed a test meal (i.e., phenol red in glucose solution), and fractional dye retention was determined 10, 20, or 30 min later. The effect of prior bleeding on ACF-induced GE delay, the role of neuroautonomic pathways, and changes in plasma hormone levels (i.e., angiotensin II, arginine vasopressin, atrial natriuretic peptide, corticosterone, and oxytocin) were evaluated. When compared with the sham-operated group, ACF rats exhibited arterial hypotension, higher (P < 0.05) heart rate, central venous pressure, and cardiac output values and increased (P < 0.05) gastric dye retention, a phenomenon prevented by bilateral subdiaphragmatic vagotomy and hexamethonium treatment. Pirenzepine also impaired the occurrence of gastric delay in subjects with ACF. In addition to causing hyperkinetic circulation, ACF placement delayed the GE of liquid in awake rats, an effect that likely involves a parasympathetic pathway. [ABSTRACT FROM AUTHOR]

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This study investigated the cardiovascular responses to the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in spontaneously hypertensive rats (SHRs). In anesthetized SHRs, intravenous (i.v.) bolus injections of EOAC (1-20 mg/kg) or NP (1-10 mg/kg) elicited dose-dependent hypotensive and bradycardiac effects, which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by EOAC and NP both at 10 mg/kg was absent after left ventricle injection, fully abolished by bilateral vagotomy and perineural treatment of both cervical vagus nerves with capsaicin (250 μg/mL) while remained unaltered by i.v. pretreatment with capsazepine (1 mg/kg) or ondansetron (30 μg/kg). In conscious SHRs, NP (5 and 10 mg/kg, i.v.) evoked rapid hypotensive and bradycardiac effects (phase 1) that were fully abolished by methylatropine (1 mg/kg, i.v.) pretreatment. In rat endothelium-containing mesenteric preparations, increasing concentrations (0.1-1000 μg/mL) of EOAC and NP relaxed the phenylephrine-induced contraction in a concentration-dependent manner. It is concluded that NP induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. This effect does not appear to involve activation of either vanilloid TPRV1 or 5-HT3 receptors located on vagal sensory nerves. The phase 2 hypotensive response to i.v. NP seems to result, at least in part, from its direct vasodilatory effect on the peripheral smooth muscle. All in vivo and in vitro effects of EOAC are mostly attributed to the actions of its main constituent NP. [ABSTRACT FROM AUTHOR]

This study was undertaken to assess the effects of eugenol (EUG) on tracheal muscle (TM) and the putative mechanisms underlying these effects. Cumulatively increasing concentrations (1-1000 μ m) of EUG did not affect the resting tonus of TM. However, EUG (1-2000 μ m) reduced the contractions induced by electrical field stimulation (IC50 = 842.3 ± 52.7 μ m), an effect that was unaltered by either 10 μ m montelukast (IC50 = 816.1 ± 70.1 μ m) or 2 μ m indomethacin (IC50 = 693.1 ± 170.8 μ m). EUG also completely relaxed the sustained contractile responses to 80 mM K+ (IC50 = 597.3 ± 60.6 μ m) and 1 μ m carbamoylcholine (IC50 = 571.3 ± 148.8 μ m), an effect that was unaltered by indomethacin (2 μ m). Under Ca2+-free conditions, EUG reduced the ACh-induced contractions (IC50 = 703.4 ± 256.1 μ m), the CaCl2-induced contractions in preparations pretreated with 60 μ m ACh in the presence of nifedipine, and the Ba2+-induced contractions in preparations depolarized with K+. In tracheal preparations maintained in Ca2+-containing solution, EUG (300-2000 μ m) relaxed the contractile response to phorbol dibutyrate (1 μ m), an activator of protein kinase C. It is concluded that in TM, EUG induces a myogenic antispasmodic effect (not modulated by arachidonic acid derivatives) either through various mechanisms almost with the same pharmacological potency or via an action on a step common to all of them. These mechanisms seem to include blockade of voltage- and receptor-operated Ca2+ channels, IP3-induced Ca2+ release from sarcoplasmic reticulum and reduction of the sensitivity of contractile proteins to Ca2+. [ABSTRACT FROM AUTHOR]

Purpose: Ifosfamide (IFS) is often involved in the occurrence of hemorrhagic cystitis due to direct contact of its metabolite acrolein with uroepithelium. It has been shown that COX-2 is involved in this pathogenesis. Thus, we aimed to study the functional changes on the urinary bladder in the putative modifications induced by IFS, as well as the COX-2 role in this process. Materials and methods: IFS-treated rats were evaluated by cystometrography in absence or presence of COX inhibitors indomethacin or etoricoxib or in the presence of mesna. Experiments with isolated strips of urinary bladder obtained from animals with IFS-induced cystitis, either treated or not treated with COX inhibitors or mesna, were performed. Histological analyses, immunohistochemistry for COX-2, and measurement of plasma PGE were also performed. Results: IFS treatment caused severe inflammation of the bladder tissue. Cystometrography recordings of IFS-treated rats revealed bladder with increased micturition frequency and enhanced filling intravesical pressure. Contractility of the isolated smooth muscle from the rat's bladder with IFS-induced cystitis showed decreased force development in response to KCl and CCh. Almost all effects induced by IFS were ameliorated by the use of COX inhibitors or mesna. Enzyme expression in the urinary bladder tissue was positive, and plasma concentration of PGE was increased in IFS-treated animals and decreased significantly in etoricoxib-treated animals. Conclusions: IFS causes important changes in the micturition physiology in rats, and the inhibition of the isoenzyme COX-2 could be an important event that could prevent the detrimental effects elicited by IFS-induced hemorrhagic cystitis. [ABSTRACT FROM AUTHOR]

This study investigates the effects of essential oil of Pterodon polygalaeflorus (EOPP) and β-caryophyllene (β-CAR). EOPP and β-CAR relaxed the basal tone of ileum smooth muscle in a concentration-dependent manner (ICs = 394.35 ± 62.12 and 68.65 ± 9.51 μg/mL respectively), an effect that was unaltered by hexamethonium, -nitroarginine methyl ester or indomethacin. Both EOPP and β-CAR evoked a concentration-dependent relaxation of ileum pre-contracted with KCl with an IC value of 107.78 ± 10.47 and 17.35 ± 0.75μg/mL, respectively. EOPP and β-CAR inhibited the contractions induced by acetylcholine (ACh) and by KCl. In ileal preparations, the CaCl-induced contractions were reduced by EOPP (300 μg/mL) and β-CAR (100 μg/mL). Furthermore, CaCl-induced contractions were also reduced by EOPP (300 μg/mL) and β-CAR (100 μg/mL) in ileal preparations pretreated with ACh under Ca-free condition and in the presence of verapamil. EOPP (100 and 300 μg/mL) and β-CAR (30 and 100 μg/mL) reduced the ACh-induced contractions of isolated rat ileum under Ca-free conditions. In the presence of high KCl and Ca-free conditions, EOPP (300 μg/mL) and β-CAR (100 μg/mL) reduced the contractions induced by barium. A similar effect was also observed with verapamil. It is concluded that (i) β-CAR is an important constituent involved in the myorelaxant and antispasmodic effects induced by EOPP; (ii) the inhibitory effect on intestinal contractility is myogenic and seems mainly mediated through an intracellular mechanism. However, the ability of EOPP and β-CAR to decrease Ca influx through cytoplasmic membrane could not be discounted. [ABSTRACT FROM AUTHOR]

1. 1,8-Cineole is a non-toxic small terpenoid oxide believed to have medicinal properties in folk medicine. It has been shown to have various pharmacological effects, including blockade of the compound action potential (AP). In the present study, using intracellular recording techniques, we investigated the effects of 1,8-cineole on the electrophysiological parameters of neurons of the superior cervical ganglion (SCG) in rats. 2. 1,8-Cineole (0.1–6 mmol/L) showed reversible and concentration-dependent effects on various electrophysiological parameters. At 3 and 6 mmol/L, but not at 0.1 and 1 mmol/L, 1,8-cineole significantly diminished the input resistance (Ri) and altered the resting potential (Em) to more positive values. At 6 mmol/L, 1,8-cineole completely blocked all APs within 2.7 ± 0.6 min ( n = 12). In neurons exposed to 3 and 1 mmol/L 1,8-cineole, the effects regarding excitability varied from complete AP blockade to minor inhibition of AP parameters. The depolarization of Em and the decrease in Ri induced by 6 mmol/L 1,8-cineole were unaltered by 200 µmol/L niflumic acid, a well known blocker of Ca2+-activated Cl− currents. 3. Significant correlations (Pearson correlation test) were found between changes in Em and decreases in AP amplitude ( r = –0.893; P < 0.00282) and maximum ascendant inclination ( r = –0.799; P < 0.0173), but not for maximum descendant inclination ( r = 0.598; P < 0.117). Application of current to restore the transmembrane potential equal to control Em values in the presence of 6 mmol/L 1,8-cineole resulted in the partial recovery of AP. 4. The present study shows that 1,8-cineole effectively blocks the excitability of SCG neurons, probably through various mechanisms, one of which acts indirectly via depolarization of the neuronal cytoplasmatic membrane. [ABSTRACT FROM AUTHOR]

Phosphodiesterase type-5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well-known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenafil-induced myorelaxation in rat isolated duodenum, assessing its interaction with nitric oxide (NO) synthase and K+ channel opening. The spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil (0.1–300 μm) in a concentration-dependent manner [mean (95% confidence interval); EC50 = 6.8 (2.7–17.3) μm]. The sildenafil-induced myorelaxation was significantly decreased by the NO synthase inhibitor N-nitro-l-arginine methyl ester [increasing the EC50 value to 41.9 (26.1–67.3) μm]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil-induced myorelaxation. In isolated strips pretreated with BaCl2 (0.2 mm), 4-aminopyridine (4-AP, 3 mm), or glybenclamide (1 μm), the sildenafil-induced EC50 value was significantly increased to 32.8 (19.1–56.4), 27.1 (15.2–48.3) and 20.1 (16.4–24.7) μm, respectively. Minoxidil (50 μm) or diazoxide (100 μm) also significantly attenuated the sildenafil-induced potency. In conclusion, the NO synthase/cyclic nucleotide pathway activation is involved in sildenafil-induced inhibition of spontaneous duodenal contractions. Its pharmacological action seems to be influenced by K+ channel opening, especially the voltage-sensitive ones, being inhibited by 4-AP and KATP channels, sensitive to glybenclamide. [ABSTRACT FROM AUTHOR]

1. Sildenafil citrate (Viagra™; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activityin vitro.2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 µmol/L (95% confidence interval (CI) 2.0–55.3 µmol/L).3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC50 of 16.2 µmol/L (95% CI 9.5–27.6 µmol/L). Sildenafil produced significant additional relaxation of 25.2 ± 8.1% of the CCh-induced contraction, beyond basal tone.4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 µmol/L (95% CI 5.7–16.2 µmol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 µmol/L (95% CI 46.0–182.2 µmol/L) and 78.5 µmol/L (95% CI 37.1–166.3 µmol/L), respectively.5. In preparations treated previously with methylene blue (10 μmol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 µmol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 µmol/L (95% CI 23.9–63.4 µmol/L) and 43.8 µmol/L (95% CI 24.5–78.3 µmol/L), respectively. These values were significantly greater than those obtained with sildenafil alone.6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segmentsin vitro.The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the vasorelaxant effects of the synthetic nitro compound, trans - 4 - methoxy - β - nitrostyrene (T4MN) were studied in isolated small resistance arteries from spontaneously hypertensive rats (SHRs). T4MN caused vasorelaxation in endothelium-intact third-order branches of the mesenteric artery pre-contracted with noradrenaline (NA). This effect was unchanged by indomethacin and atropine but was significantly reduced by endothelium removal, L-NAME, LY294002, glybenclamide, TEA, apamin, TRAM 34, or by the association of apamin and TRAM 34. Pretreatment with the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3- a ]quinoxalin-1-one (ODQ) reduced the T4MN-induced relaxation in endothelium-intact, but not in denuded preparations. Incubation of small resistance arteries with T4MN increased nitric oxide (NO) production, an effect that was blocked by L-NAME. In Ca2+-free medium, T4MN inhibits the contractions induced by (i) NA, (ii) exogenous calcium through receptor- or voltage-operated Ca2+ channels and (iii) those evoked by Ca2+ influx through stores-operated Ca2+ channels activated by thapsigargin-induced Ca2+ store depletion. In contrast, T4MN was inert against the transient contraction induced by caffeine in Ca2+-free medium. In conclusion, T4MN induced effective vasorelaxant effects in isolated small resistance arteries from SHRs. This vasorelaxation seems to be mediated partly by an endothelium-dependent mechanism involving activation of Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca2+ influx from the extracellular milieu and IP 3 -sensitive intracellular Ca2+ release as well as activation of potassium channels. fx1 [ABSTRACT FROM AUTHOR]

Compounds containing a nitro group may reveal vasodilator properties. Several nitro compounds have a NO 2 group in a short aliphatic chain connected to an aromatic group. In this study, we evaluated in rat aorta the effects of two nitro compounds, with emphasis on a putative recruitment of the soluble guanylate cyclase (sGC) pathway to induce vasodilation. Isolated aortic rings were obtained from male Wistar rats to compare the effects induced by 2-nitro-1-phenylethanone (NPeth) or 2-nitro-2-phenyl-propane-1,3-diol (NPprop). In aortic preparations contracted with phenylephrine or KCl, NPeth and NPprop induced vasorelaxant effects that did not depend on the integrity of vascular endothelium. NPeth had a lesser vasorelaxant efficacy than NPprop and only the NPprop effects were inhibited by pretreatment with the sGC inhibitors, 1H-[1,2,4]oxadiazolo[4,3- a ]quinoxalin-1-one (ODQ) or methylene blue. In an ODQ-preventable manner, NPprop inhibited the contractile component of the phenylephrine-induced response mediated by intracellular Ca 2+ release or by extracellular Ca 2+ recruitment through receptor- or voltage-operated Ca 2+ channels. In contrast, NPprop was inert against the transient contraction induced by caffeine in Ca 2+ -free medium. In an ODQ-dependent manner, NPprop inhibited the contraction induced by the protein kinase C activator phorbol 12,13-dibutyrate or by the tyrosine phosphatase inhibitor sodium orthovanadate. In silico docking analysis of a sGC homologous protein revealed preferential site for NPprop. In conclusion, the nitro compounds NPeth and NPprop induced vasorelaxation in rat aortic rings. Aliphatic chain substituents selectively interfered in the ability of these compounds to induce vasorelaxant effects, and only NPprop relaxed aortic rings via a sGC pathway. [ABSTRACT FROM AUTHOR]

1-Nitro-2-phenylethene (NPe) induces a more potent vasorelaxant effect in rat aorta than its structural analog 1-nitro-2-phenylethane, but mediated through a different mechanism, independent of soluble guanylate cyclase (sGC) stimulation. We hypothesized that introducing an electron donor into the aromatic moiety might stabilize NPe, enhancing its potency and/or interaction with sGC. Therefore, trans-4-methoxy-β-nitrostyrene (T4MN) was synthesized, and mechanisms underlying its vasorelaxant effects were studied in rat aortic ring preparations. In endothelium-intact preparations, T4MN fully relaxed contractions induced by phenylephrine (PHE) with a potency similar to that of its parent drug, NPe. This vasorelaxant effect that was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, or MDL-12,330 A, but was significantly reduced by tetraethylammonium, 4-aminopyridine, methyl blue, or ODQ. Under Ca 2+ -free conditions, T4MN did not alter contractions evoked by caffeine, but significantly reduced, in an ODQ-preventable manner, those induced by either PHE or extracellular Ca 2+ restoration following depletion of intracellular Ca 2+ stores in thapsigargin-treated aortic preparations. Under the same conditions, T4MN also reduced contractions induced by protein kinase C activator phorbol-12,13-dibutyrate with a potency similar to that evoked by this nitroderivative against PHE-induced contractions. In conclusion, T4MN induces potent vasorelaxation in rat aorta by stimulating the sGC-cGMP pathway through a NO-independent mechanism. Introduction of a methoxy group into the aromatic moiety apparently stabilizes NPe, thereby enhancing its interaction with sGC. [ABSTRACT FROM AUTHOR]

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala. [ABSTRACT FROM AUTHOR]

Previously, we showed that nitro-2-phenylethane is a vasorelaxant constituent of the essential oil of Aniba canelilla . Here, we investigated the mechanisms underlying the vascular effects of 1-nitro-2-phenylethene (NPe), a structural analog of 1-nitro-2-phenylethane obtained synthetically, in rat isolated thoracic aortic preparations. At 0.1–100 μg/mL, NPe similarly relaxed endothelium-intact or endothelium-denuded aortic preparations pre-contracted with 60 mM KCl or with phenylephrine (PHE, 1 μM). Vasorelaxant effects of NPe against PHE-induced contractions remained unaffected following blockade of potassium channels by TEA, and inhibition of either nitric oxide synthase by l -NAME, cyclooxygenase by indomethacin or guanylate cyclase by ODQ. In preparations maintained under Ca 2 + -free conditions, NPe significantly reduced the contractions induced (i) by PHE, but not those evoked by caffeine, (ii) by CaCl 2 in either PHE (in the presence of 1 μM verapamil)- or KCl-stimulated preparations, (iii) by extracellular Ca 2 + restoration in thapsigargin-treated aortic preparations, and (iv) by the activator of protein kinase C phorbol-12,13-dibutyrate or the inhibitor of protein tyrosine phosphatase sodium orthovanadate. It is concluded that NPe induced an endothelium-independent vasorelaxation with potency greater than its structural analog 1-nitro-2-phenylethane. Such action appears to occur intracellularly probably through inhibition of contractile events that are clearly independent of Ca 2+ influx from the extracellular milieu. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigated the mechanisms underlying the vasorelaxant effects of the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in isolated superior mesenteric artery from spontaneously hypertensive rats (SHRs). At 0.1–1000μg/mL, EOAC and NP relaxed SMA preparations pre-contracted with 75mMKCl with IC50 (geometric mean [95% confidence interval]) values of 294.19 [158.20–94.64] and 501.27 [378.60–624.00] μg/mL, respectively); or with phenylephrine (PHE) (IC50s=11.07 [6.40–15.68] and 7.91 [4.08–11.74) μg/mL, respectively). All these effects were reversible and remained unaltered by vascular endothelium removal. In preparations maintained under Ca2+-free conditions, EOAC and NP (both at 600μg/mL) reduced the PHE-, but not the caffeine-induced contraction. In Ca2+-free and high K+ (75mM) medium, the contractions produced by CaCl2 or BaCl2 were reduced or even abolished by EOAC and NP at 100 and 600μg/mL, respectively. EOAC and NP (both at 10–1000μg/mL) also relaxed the contraction evoked by phorbol dibutyrate (IC50 =52.66 [10.82–94.64] and 39.13 [31.55–46.72] μg/mL, respectively). It is concluded that NP has a myogenic endothelium-independent vasorelaxant effects and appears to be the active principle of the EOAC. Vasorelaxant effect induced by both EOAC and NP is preferential to receptor-activated pathways and it appears to occur intracellularly more than a superficial action restricted to the membrane environment such as a simple blocking activity on a given receptor or ion channel. [Copyright &y& Elsevier]

Abstract: Previously, it was shown that intravenous (i.v.) treatment with the essential oil of Aniba canelilla (EOAC) elicited a hypotensive response that is due to active vascular relaxation rather than to the withdrawal of sympathetic tone. The present study investigated mechanisms underlying the cardiovascular responses to 1-nitro-2-phenylethane, the main constituent of the EOAC. In pentobarbital-anesthetized normotensive rats, 1-nitro-2-phenylethane (1–10mg/kg, i.v.) elicited dose-dependent hypotensive and bradycardiac effects which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by 1-nitro-2-phenylethane (10mg/kg) was fully abolished by bilateral vagotomy, perineural treatment of both cervical vagus nerves with capsaicin (250µg/ml) and was absent after left ventricle injection. However, pretreatment with capsazepine (1mg/kg, i.v.) or ondansetron (30µg/kg, i.v.) did not alter phase 1 of the cardiovascular responses to 1-nitro-2-phenylethane (10mg/kg, i.v.). In conscious rats, 1-nitro-2-phenylethane (1–10mg/kg, i.v.) evoked rapid hypotensive and bradycardiac (phase 1) effects that were fully abolished by methylatropine (1mg/kg, i.v.). It is concluded that 1-nitro-2-phenylethane induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. The transduction mechanism of the 1-nitro-2-phenylethane excitation of C-fiber endings is not fully understood and does not appear to involve activation of either Vanilloid TPRV1 or 5-HT3 receptors. The phase 2 hypotensive response to 1-nitro-2-phenylethane seems to result, at least in part, from a direct vasodilatory effect since 1-nitro-2-phenylethane (1–300µg/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction in rat endothelium-containing aorta preparations. [Copyright &y& Elsevier]

Abstract: Eugenol is a phenylpropene obtained from the essential oils of plants such as clove and basil which has ample use in dentistry. Eugenol possesses analgesic effects that may be related to the inhibition of voltage-dependent Na+ channels and/or to the activation of TRPV1 receptors or both. In the present study, electrophysiological parameters were taken from the compound action potentials of the isolated rat sciatic nerve and from neurons of the superior cervical ganglion (SCG) impaled with sharp microelectrodes under current-clamp conditions. In the isolated rat sciatic nerve, eugenol inhibited the compound action potential in a concentration-dependent manner. Action potentials recorded from SCG neurons were inhibited by eugenol with an IC50 of 0.31mM. At high concentrations (2mM), during brief applications, eugenol caused significant action potential blockade while it did not interfere with the resting membrane potential or the membrane input resistance. Surprisingly, however, at low eugenol concentrations (0.6mM), during long time applications, a reversible reduction (by about 50%) in the input membrane resistance was observed, suggesting the possible involvement of a secondary delayed effect of eugenol to reduce neuronal excitability. [Copyright &y& Elsevier]