The effects of flavonoids in experimental sepsis: A systematic review and meta-analysis.

Sepsis is a host's dysregulated immune response to an infection associated with systemic inflammation and excessive oxidative stress, which can cause multiple organ failure and death. The literature suggests that flavonoids, a broad class of secondary plant metabolites, have numerous biological activities which can be valuable in the treatment of sepsis. This study aimed to review the effects of flavonoids on experimental sepsis, focusing mainly on survival rate, and also summarizing information on its mechanisms of action. We searched in the main databases up to November 2022 using relevant keywords, and data were extracted and analyzed qualitatively and quantitatively. Thirty-two articles met the study criteria for review and 29 for meta-analysis. Overall, 30 different flavonoids were used in the studies. The flavonoids were able to strongly inhibit inflammatory response by reducing the levels of important pro-inflammatory mediators, for example, tumor necrosis factor-alpha and interleukin-1ß, oxidative stress, and showed antibacterial and anti-apoptotic actions. The meta-analysis found an increase of 50% in survival rate of the animals treated with flavonoids. They appear to act as multi-target drugs and may be an excellent therapeutic alternative to reduce a number of the complications caused by sepsis, and consequently, to improve survival rate.

Limonene, a food additive, and its active metabolite perillyl alcohol improve regeneration and attenuate neuropathic pain after peripheral nerve injury: Evidence for IL-1ß, TNF-α, GAP, NGF and ERK involvement.

BACKGROUND: Limonene (LIM) and its main metabolite perillyl alcohol (POH) are ingredients found in food with promising chemical entities due to their pharmacological profile. In this study, we hypothesized that LIM and POH are two molecules capable of accelerating the regenerative process and alleviating neuropathic pain. METHODS: Animals were treated daily (LIM, POH and saline) for 28 days and during this period evaluated for mechanical hyperalgesia, astrocyte participation by immunofluorescence for GFAP, and ELISA was used to quantify IL-1ß and TNF-α in the spinal cord. Western blot analysis of the following proteins was also performed: GFAP, GAP-43, NGF and ERK. For motor deficit analysis, tests were performed to assess hind paw muscle strength and footprints through gait (SFI). RESULTS: Both POH and LIM accelerated the regenerative process and improved motor deficits comparing to positive control; however, POH was more effective, particularly between the 2nd and 3rd week after the nerve injury, increasing GAP-43, NGF and the phosphorylated ERK immunocontent. Moreover, POH and LIM were able to reduce hyperalgesia and astrocytosis. CONCLUSIONS: Both substances, LIM and POH, improved the regeneration process and sensory and motor function recovery in the PNI model in mice by mitigating the inflammatory reactions and up-regulating the neurotrophic process.

Pharmacological Properties of Vochysia Haenkeana (Vochysiaceae) Extract to Neutralize the Neuromuscular Blockade Induced by Bothropstoxin-I (Lys49 Phospholipase A2) Myotoxin.

Purpose: Bothrops snakes are responsible for more than 70 % of snakebites every year in Brazil and their venoms cause severe local and systemic damages. The pharmacological properties of medicinal plants have been widely investigated in order to discover new alternative treatments for different classes of diseases including neglected tropical diseases as envenomation by snakebites. In this work, we have investigated the ability of Vochysia haenkeana stem barks extract (VhE) to neutralize the neuromuscular effects caused by Bothropstoxin-I (BthTX-I), the major phospholipase A2 (PLA2) myotoxin from B. jararacussu venom. Methods: The biological compounds of VhE were analysed under thin layer chromatography (TLC) and its neutralizing ability against BthTX-I was assessed through twitch-tension recordings and histological analysis in mouse phrenic nerve-diaphragm (PND) preparations. The antimicrobial activity of VhE was assessed against S. aureus, E. coli and P. aeruginosa strains. The aggregation activity of VhE was analysed under protein precipitation assay. Results: VhE showed the presence of phenolic compound visualized by blue trace under TLC. VhE abolished the neuromuscular blockade caused by BthTX-I applying the pre-toxin incubation treatment and partially neutralized the BthTX-I action under post-toxin incubation treatment; VhE contributed slightly to decrease the myotoxicity induced by BthTX-I. The neutralizing mechanism of VhE may be related to protein aggregation. VhE showed no antimicrobial activity. Conclusion: V. haenkeana extract which has no antimicrobial activity exhibited neutralizing ability against the neuromuscular blockade caused by BthTX-I and also contributed to decrease its myotoxicity. Protein aggregation involving phenolic compounds may be related in these protective effects.

Neutralising ability of Terminalia fagifolia extract (Combretaceae) against the in vitro neuromuscular effects of Bothrops jararacussu venom.

The ability of Terminalia fagifolia hydroalcoholic extract (Tf-HE) to neutralise the paralysis and myotoxicity induced by Bothrops jararacussu venom was assayed using mouse phrenic nerve-diaphragm (PND) preparation and two varieties of chick biventer cervicis (BC) preparations. Tf-HE 100 µg/mL and 500 µg/mL were tested against 40 and 200 µg of venom/mL in PND and BC preparations, respectively, using pre- and post-venom incubation treatments. The effects of Tf-HE against the myotoxicity caused by venom were evaluated via histological analysis (PND) and creatine kinase (CK) release (BC). Tf-HE was able to reverse the venom paralysis in both preparation types. The contractures to exogenous ACh in BC preparations showed that Tf-HE may act on extrinsic, preserving those intrinsic postsynaptic receptors. There was a positive correlation between CK and morphological changes. The high non-hemolytic saponin content can explain the Tf-HE efficacy against the toxic effects of B. jararacussu venom in vertebrate neuromuscular preparations.

Both anticipatory and compensatory postural adjustments are adapted while catching a ball in unstable standing posture.

The main objective of this study was to analyze the role of balance exercises on anticipatory (APA) and compensatory (CPA) postural adjustments in different conditions of postural stability. Sixteen subjects were required to catch a ball while standing on rigid floor, trampoline and foam cushion surfaces. Electromyographic activities (EMG) of postural muscles were analyzed during time windows typical for APAs and CPAs. Overall there were a reciprocal activation of the muscles around the ankle and co-activations between ventral and dorsal muscles of the thigh and trunk during the catching a ball task. Compared to the rigid floor, the tibialis anterior activation was greater during the trampoline condition (CPA: p = 0.006) and the soleus muscle inhibition was higher during foam cushion condition (APA: p = 0.001; CPA: p = 0.007). Thigh and trunk muscle activities were similar across the conditions. These results advance the knowledge in postural control during body perturbations standing on unstable surfaces.

The Triterpenoid Betulin Protects against the Neuromuscular Effects of Bothrops jararacussu Snake Venom In Vivo.

We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND) preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA) preparation. Venom caused complete, irreversible blockade in PND (40 µg/mL), but only partial blockade (~30%) in EPSTA (3.6 mg/kg, i.m.) after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA) attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ~70% in both preparations). Preincubation of venom with betulin (200 µg/mL) markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom) virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite.

Multivariate Exploratory Analysis of Metals and Phosphorus Concentrations of Leachates Collected Monthly from a Municipal Sanitary Landfill.

Concentrations of 11 elements (P, Cu, Ni, Co, Pb, Ca, Mn, Fe, Zn, Cr and Al) were measured in leachate samples collected monthly from the municipal landfill in Jequié, Bahia, Brazil. P (0.943-23.8 mg L(-1)), Ca (19.90-129 mg L(-1)) and Fe (0.115-2.87 mg L(-1)) were found in the highest levels, while Cu (

Physicochemical characterization and analgesic effect of inclusion complexes of essential oil from Hyptis pectinata L. Poit leaves with ß-cyclodextrin.

The formation of inclusion complexes of Hyptis pectinata essential oil (EOHP), with potent activities such as anti-nociceptive, anti-inflammatory, among others, with ß -cyclodextrin (ß-CD), was obtained by slurry (SC) and paste procedures (PC). The gas chromatography coupled to the mass spectrometry (GC/MS) analysis demonstrated a total of 36.4% monoterpenes and 63.6% sesquiterpenes in the EOHP. The major components of EOHP were identified as (E)- caryophyllene (54.07%). The analysis of samples (PM, PC and SC) by GC/MS involved the surface and the total extracted oils. The GC/MS results suggested important differences between in SC and PC methods indicating the complexation of mono and sesquiterpenoids in different ratios. Furthermore, the thermal analysis techniques suggests the complexation, especially in SC, which show a thermogravimetry/derivative thermogravimetry (TG/DTG) peak at 140-270ºC, probably related to oil loss. Scanning electron microscopy (SEM) images showed reduction size of the samples mainly in the SC product. Additionally, EOHP/ ß-CD improves pharmacological profile of EOHP alone in formalin-induced pain protocol in mice.

The anticonvulsant effect of geraniol and inclusion complex geraniol: beta-cyclodextrin / El efecto anticonvulsivo de geraniol y la inclusión de geraniol complejo: beta-ciclodextrina

Geraniol (GR) is an acyclic monoterpene alcohol present in essential oils of aromatic plant species used in Brazilian folk medicine for the treatment of epilepsy. The present study was designed to evaluate the anticonvulsant effect of GR and of the inclusion complex geraniol:beta-cyclodextrin (GR:beta-CD). Mice were treated with GR or with GR:beta-CD (50, 100 and 200 mg/kg) 30 min before pentylenetetrazole (PTZ) or strychnine (STN). GR at 200 mg/kg and GR:beta-CD at the doses of 100 and 200 mg/kg significantly increased the latency for the first PTZ-induced convulsion and reduced the percentage of animals that convulsed. The pretreatment of flumazenil did not revert the anticonvulsant effect of GR in the PTZ-induced convulsion model. In the STN-induced convulsion model, the effects of GR were investigated and no difference was found against control. The results demonstrated an anticonvulsant activity of GR in the PTZ-model, which was potentialized by the complexation with beta-CD...

Geraniol (GR) es un alcohol monoterpeno acíclico presentes en los aceites esenciales de las especies de plantas aromáticas utilizadas en la medicina popular brasileña para el tratamiento de la epilepsia. El presente estudio fue diseñado para evaluar el efecto anticonvulsivo del GR y de la inclusión de geraniol complejo: beta-ciclodextrina (GR:beta-CD). Los ratones fueron tratados con GR o con GR:beta- CD (50, 100 y 200 mg/kg) 30 minutos antes de pentylenotetrazole (PTZ) o strichinine (STN). GR a 200 mg/kg y GR:beta-CD en las dosis de 100 y 200 mg/kg aumentó significativamente la latencia para la primera convulsión inducida PTZ-y redujo la porcentaje de animales que convulsionó. El tratamiento previo de flumazenil no revirtió el efecto anticonvulsivo de GR en el modelo de convulsión inducida con PTZ. En el modelo de convulsión inducida com STN, los efectos de GR fueron investigados y no se encontró ninguna diferencia contra el control. Los resultados demostraron una actividad anticonvulsiva de geraniol en el modelo de PTZ, que fue potenciada por la formación de complejos con beta-CD...

An isoflavone from Dipteryx alata Vogel is active against the in vitro neuromuscular paralysis of Bothrops jararacussu snake venom and bothropstoxin I, and prevents venom-induced myonecrosis.

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 µg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 µg/mL) caused irreversible paralysis. Preincubation of TM (200 µg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% ± 5% (mean ± SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA2 of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% ± 1.7% were damaged; n = 4) compared to venom alone (50.3% ± 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% ± 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (-S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom.

Vellozia flavicans Mart. ex Schult. hydroalcoholic extract inhibits the neuromuscular blockade induced by Bothrops jararacussu venom.

BACKGROUND: Snakebite is a significant public health issue in tropical countries. In Brazil, some of the most common snake envenomations are from Bothrops. Bothrops bites trigger local and systemic effects including edema, pain, erythema, cyanosis, infections, and necrosis. Vellozia flavicans is a plant from the Brazilian "cerrado" (savanna) that is popularly used as an anti-inflammatory medicine. Since inflammation develops quickly after Bothrops bites, which can lead to infection, the aim of the present study was to observe possible anti-snake venom and antimicrobial activities of V. flavicans (Vf). METHODS: The chromatographic profile of the main constituents from the Vf leaf hydroalcoholic extract was obtained by thin-layer chromatography (TLC). The anti-snake venom activity was measured by Vf's ability to neutralize the in vitro neuromuscular blockade caused by Bothrops jararacussu venom (Bjssu) in a mouse phrenic nerve-diaphragm model (PND). After a 20 min incubation, preparations of PND were added to Tyrode's solution (control); Vf (0.2, 0.5, 1, and 2 mg/mL); 40 µg/mL Bjssu; pre-incubation for 30 min with Bjssu and 1 mg/mL Vf; and a Bjssu pretreated preparation (for 10 min) followed by 1 mg/mL Vf. Myographic recording was performed, and the contractile responses were recorded. The antimicrobial activity (minimum inhibitory concentration [MIC] and minimum bactericidal concentration [MBC]) was obtained for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis, using gentamicin and vancomycin as positive controls. RESULTS: TLC analysis yielded several compounds from Vf, such as flavonoids (quercetin) and phenolic acids (chlorogenic acid). Bjssu completely blocked the contractile responses of PND preparations, while Vf preserved 97% (±10%) of the contractile responses when incubated with Bjssu. In the PND pretreated with Bjssu, Vf was able to inhibit the neuromuscular blockade progress. MIC and MBC of Vf ranged from 2.5 to 5.0 mg/mL for P. aeruginosa and S. aureus strains, while no antimicrobial activity was observed for E. coli and E. faecalis. CONCLUSIONS: The hydroalcoholic extract from Vf leaves was able to neutralize and decrease the in vitro neuromuscular blockade caused by Bjssu. However, it did not show significant antimicrobial activity against the tested bacteria.

Antidiabetic effect of the Chrysobalanus icaco L. aqueous extract in rats.

Chrysobalanus icaco L. is a medicinal plant popularly known in Brazil as "Grageru" or "Abageru." It is used in African and American continents as medicinal food in the treatment of several diseases, including diabetes. This study used phytochemical screening to determine the antioxidant and α-amylase inhibitor activities of the aqueous extract (AECI) of C. icaco, and evaluated its antidiabetic potential in rodents. Phytochemical screening was performed using colorimetric tests with specific reagents. The in vitro antioxidant activity was evaluated by the scavenging activity of 2,2-diphenyl-1-picril-hydrazyl. The lethality test and behavioral screening was performed using an oral administration of 5 g/kg of AECI. The antidiabetic potential of AECI was evaluated through the oral glucose tolerance test (OGTT) and chronic hypoglycemic test at the doses of 100, 200, and 400 mg/kg (orally). Metformin was used as a reference drug in all tests. Diabetes was induced by injection of alloxan (40 mg/kg; intravenously). Phytochemical screening showed the presence of various compounds, including tannins, flavones, triterpenoids, steroids, saponins, and alkaloids. The in vitro antioxidant test demonstrated that AECI presented potent antioxidant activity. The lethality test and behavioral screening did not show lethality signs. In the OGTT test, AECI administration was not able to inhibit the elevation of glycemia. However, chronically administrated, it was able to cause a significant (P<.05) reduction of glycemia from 335±27 up to 197±15 mg/dL. These results demonstrate that the AECI presents a potential beneficial effect for diabetes.

Assessment of cytotoxicity, fetotoxicity, and teratogenicity of Plathymenia reticulata Benth Barks aqueous extract.

Scientific assessment of harmful interactions of chemicals over the entire reproductive cycle are divided into three segments based on the period: from premating and mating to implantation (I), from implantation to major organogenesis (II), and late pregnancy and postnatal development (III). We combined the segments I and II to assess Plathymenia reticulata aqueous extract safety. In order to investigate reproductive toxicity (segment I), pregnant rats received orally 0.5 or 1.0 g/kg of extract, daily, during 18 days. These concentrations were determined by a preliminary in vitro LD50 test in CHO-k1 cells. A control group received deionized water. The offspring was removed at the 19th day, by caesarean, and a teratology study (segment II) was carried out. The corpora lutea, implants, resorptions, live, and dead fetuses were then counted. Placenta and fetuses were weighted. External and visceral morphology were provided by the fixation of fetuses in Bouin, whereas skeletal analysis was carried out on the diaphanizated ones. The increase in the weights of placenta and fetuses was the only abnormality observed. Since there was no sign of alteration on reproduction parameters at our experimental conditions, we conclude that P. reticulata aqueous extract is safe at 0.5 to 1.0 g/kg and is not considered teratogenic.

In vitro and in vivo safety evaluation of Dipteryx alata Vogel extract.

BACKGROUND: Dipteryx alata Vogel popularly known as "baru" is an important commercial leguminous tree species from the Brazilian Cerrado, which possess medicinal properties, besides its fruits consumption by animals and humans. The use of the "naturally occurring plants" as herbal remedies and foods mainly from leaves, seeds, flowers and roots of plants or extracts require precautions before ensuring these are safe and efficacious. The objective of this study was to evaluate the safety of D. alata barks extract. METHODS: Vegetal drugs of D. alata barks were submitted to quality control assays and further to the safety assays under 1) in vitro parameter by Salmonella (Ames) mutagenicity, and 2) in vivo parameter on the pregnancy of rats. RESULTS: The extract was non-mutagenic to any of the assessed strains TA97a, TA98, TA100 and TA102 even after metabolic activation (+S9). All in vivo parameters (reproductive ability evaluation, physical development of rat offsprings, and neurobehavioral development assays) showed no changes related to control group. CONCLUSION: D. alata barks extract is neither mutagenic by the Ames test nor toxic in the pregnancy of rats, with no physical-neurobehavioral consequences on the rat offsprings development.

Structural relationships and vasorelaxant activity of monoterpenes.

BACKGROUND AND PURPOSE OF THE STUDY: The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure-activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. METHODS: Contractions of the vessels were induced with 10 µM of phenylephine (Phe) in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively) were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. RESULTS: The results from the present study showed that both oxygenated terpenes (rotundifolone, (+)-limonene epoxide, pulegone epoxide, carvone epoxide, and (+)-pulegone) and non-oxygenated terpene ((+)-limonene) exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. MAJOR CONCLUSION: The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity.

Implementation of the three Rs in the human hazard assessment of Brazilian medicinal plants: an evaluation of the cytotoxic and genotoxic potentials of Dipteryx alata Vogel.

In Brazil, medicinal plants are widely used by the indigenous people, which leads to a constant requirement for toxicity tests to be performed on the plant extracts. Although the current Brazilian Directive 90/2004 on the preclinical toxicity testing of phytotherapeutics recommends only in vivo tests, some Brazilian researchers would like to change this situation by implementing the Three Rs in the toxicological testing of medicinal plants. The present study evaluated the cytotoxic and genotoxic potentials of bark extracts from Dipteryx alata Vogel, a medicinal plant of the Brazilian cerrado, by using CHO-K1 (Chinese hamster ovary) cells. An IC50 value was obtained, which corresponded to 0.16mg/ml of plant extract, and from this the equivalent LD50 was determined as 705mg/kg. In order to determine the genotoxic potential of the sample, the frequency of micronucleus formation was assessed. CHO-K1 cells were exposed, during targeted mitosis, to different concentrations of plant extract and cytochalasin B, in the presence and absence of an appropriate metabolic activation system (an S9 mix). The results obtained indicated that it might be possible to implement the Three Rs in assessing the potential human hazard of medicinal plants. The publication of such data can increase awareness of the Three Rs by showing how to optimise the management of animal use, if in vivo toxicological experiments are required.

In vitro antiophidian properties of Dipteryx alata Vogel bark extracts.

Extracts from Dipteryx alata bark obtained with different solvents (hexane, dichloromethane, ethyl acetate and methanol) were mixed in vitro with Bothrops jararacussu (Bjssu, 40 µg/mL) and Crotalus durissus terrificus (Cdt, 15 µg/mL) snake venoms, and applied to a mouse phrenic nerve-diaphragm preparation to evaluate the possible neutralization of venom effects. Cdt venom neurotoxic effect was not inhibited by any of the extracts, while the neurotoxic and myotoxic actions of Bjssu venom were decreased by the methanolic extract. This inhibition appears to be augmented by tannins. Dichloromethane bark extract inhibited ~40% of Bjssu venom effects and delayed blockade induced by Cdt. The methodology used to determine which extract was active allows inferring that: (i) phenolic acids and flavonoids contained in the methanolic extract plus tannins were responsible mostly for neutralization of Bjssu effects; (ii) terpenoids from the dichloromethane extract may participate in the anti-Cdt and anti-Bjssu venom effects; (iii) a given extract could not inhibit venoms from different species even if those belong to the same family, so it is improper to generalize a certain plant as antiophidian; (iv) different polarity extracts do not present the same inhibitory capability, thus demonstrating the need for characterizing both venom pharmacology and the phytochemistry of medicinal plant compounds.

Mechanisms underlying the cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in normotensive rats.

Cardiovascular effects of Labd-8 (17)-en-15-oic acid (Labd-8), a labdenic diterpene isolated from methanolic extract of Moldenhawera nutans were investigated in normotensive rats. Additionally, this study examined the role of autonomic nervous system in the mediation of these cardiovascular effects. In pentobarbital-anesthetized rats, bolus intravenous (i.v.) injection of Labd-8 (1-10 mg/kg) induced dose-dependent hypotensive and tachycardiac responses. After cervical bivagotomy, hypotensive responses to Labd-8 were significantly enhanced whereas the tachycardia was completely abolished. In conscious rats, Labd-8 (1-10 mg/kg, i.v.) also decreased blood pressure and increased heart rate in a dose-dependent manner. Pretreatment with methylatropine (1 mg/kg, i.v.) or propranolol (2 mg/kg, i.v.) significantly reduced the tachycardia evoked by Labd-8 without affecting the hypotension. Blockade of ganglionic neurotransmission with hexamethonium (30 mg/kg, i.v.) reduced and abolished the hypotensive and tachycardic effects of Labd-8, respectively. However, hypotensive effects of Labd-8 were not reduced by pretreatment with N(w)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.), a nitric oxide synthase inhibitor. In rat endothelium-containing aorta preparations, Labd-8 (1-1000 micro g/ml) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction [IC(50) (geometric mean +/-95% confidence interval)=313.6 (191.4-513.8) micro g/ml], an effect that remained unaffected [IC(50)=440.8 (225.1-863.3) micro g/ml] by removal of vascular endothelium. These results show that i.v. treatment with Labd-8-induced dose-dependent hypotensive and tachycardiac effects in both conscious and anesthetized rats. The tachycardia is mediated reflexly through inhibition of vagal and activation of sympathetic drive to the heart. The hypotension is mainly due to withdrawal of sympathetic tone to the vasculature and also partly to an active vascular relaxation. Released nitric oxide from vascular endothelial cells is not involved in the mediation of Labd-8-induced hypotension.

Essential oil of Pterodon polygalaeflorus inhibits electromechanical coupling on rat isolated trachea.

The present work studied the effects of the essential oil of Pterodon polygalaeflorus (EOPP), a plant used to treat bronchitis and amigdalytis, on rat airway smooth muscle in vitro. In Ca(2+)-containing medium, EOPP (100-1300 microg/ml) inhibited preferentially high KCl- than 5-HT-induced muscle contractions in a concentration-dependent fashion, but did affect neither basal muscle tension nor ACh-induced contractions. In preparations maintained in either 60 mM K(+) or 10 microM ACh in Ca(2+)-free medium, EOPP (100, 600 and 1300 microg/ml) inhibited maximum contractile response induced by cumulative Ca(2+) addition (0.1-20 mM). Verapamil (10, 30 and 100 microg/ml), a Ca(2+) channel blocker, also inhibited Ca(2+)-induced concentration-effect curve in presence of ACh in Ca(2+)-free medium, whilst it was ineffective to decrease cholinergic contractions in Ca(2+)-containing medium. In presence of 150 mM K(+) in Ca(2+)-containing medium, EOPP (1300 microg/ml) did not reversed ACh-induced contractions. In contrast, under similar conditions, EOPP almost fully relaxed cholinergic contractions of tracheal smooth muscle in Ba(2+)-containing medium. In medium containing 10 mM tetraethylammonium and 2 mM Ba(2+) instead of Ca(2+), both EOPP (1300 microg/ml) and verapamil (approximately 5 microg/ml) significantly decreased ACh-induced contractions. Thus, in rat isolated trachea, EOPP induces inhibitor effects on contractions preferentially triggered by an electromechanical coupling mode.