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Background: Gomphrena perennis L. is a native plant of South America whose pharmacological properties have not been studied yet. Aim: To evaluate the cardiovascular and intestinal pharmacological effects of Gomphrena perennis L. leaves tincture (GphT) and the mechanisms involved. Experimental procedure: The chromatographic profile of GphT was done. Its ex vivo effects were evaluated by contractile concentration-response curves (CRCs) obtained from the agonist carbachol or calcium found in isolated rat small intestine, as well as in the relaxant CRCs. Cardiac effects were evaluated on isolated rat hearts exposed to ischemia/reperfusion (I/R). Experiments in vivo were performed to evaluate the diuretic activity in conscious rats and the hypotensive effect in anaesthetised rats. Results: Fifteen flavonoids were identified in GphT by HPLC-UV, including diosmin. GphT induced a non-competitive inhibition in both carbachol and calcium CRCs on rat small intestine. The first was not affected by indomethacin. Moreover, GphT, unlike diosmin, relaxed the contracture produced by a high-potassium solution in a dose-dependently way. Neither propranolol nor l-NAME changed it. GphT did not show diuretic activity but induced hypotension insensitive to l-NAME. While GphT perfusion of isolated hearts increased injury consequent to I/R, oral administration was cardioprotective and reversed by l-NAME. However, diosmin did not improve the post-ischemic recovery. Conclusions: This study supports the use of Gomphrena perennis L. tincture as an antispasmodic and hypotensive agent. Moreover, it has been demonstrated to be preventive of post-ischemic cardiac dysfunction. However, diosmin would not be responsible for these effects.
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Nebivolol could prevent dysfunction in patients suffering myocardial ischemia. However, influence of hyperthyroidism is not known. Consequences and mechanisms of nebivolol treatment were investigated in isolated hearts from euthyroid (EuT) and hyperthyroid (HpT) rats. Rats were orally treated during 1 week with 20 mg/kg/day nebivolol (O-Neb), 30 mg/kg/day atenolol (O-Ate), or not treated (C). Isolated perfused hearts were exposed to global ischemia and reperfusion (I/R) inside a flow calorimeter. Left diastolic ventricular pressure, developed contractile pressure (P), and total heat rate (Ht) were continuously measured, while infarct size was measured after 2-h R. EuT-C and HpT-C hearts developed similarly low post-ischemic contractile recovery and economy (P/Ht). Nebivolol totally prevented dysfunction and reduced infarction size in EuT hearts, but partially improved recovery in HpT rat hearts. Contrarily, oral atenolol totally prevented dysfunction in HpT hearts but partially in EuT hearts. Nebivolol effects were reversed by perfusing L-NAME in both conditions, but partially reduced by aminoguanidine in HpT. However, L-NAME increased P and P/Ht recoveries in EuT-C and HpT-C rat hearts, as well as melatonin. Oral nebivolol prevented post-ischemic dysfunction and infarction in EuT hearts due to adrenergic ß1 blockade and activation of iNOS and/or eNOS, but the effect was attenuated in HpT hearts by excessive iNOS-dependent nitrosative pathways.
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Schinus lentiscifolius (Anacardiaceae) is widely used in folk medicine for treating gastrointestinal and emotional complaints but there are no scientific studies that support these uses. This work aims at evaluating the antispasmodic and central effects of S. lentiscifolius as well as the flavonoids presence in the tincture (SchT) and the composition of the essential oil (SchO). SchT inhibited the concentration-response curves (CRC) of carbachol and calcium in a non-competitive way in isolated rat intestine, bladder and uterus. SchT also non-competitively inhibited the CRC of histamine in guinea-pig intestine and the CRCs of serotonin and oxytocin in rat uterus. Isoquercetin and rutin were identified in SchT. The behavioral effects of SchT, SchO and infusion of S. lentiscifolius leaves (SchW) were tested in mice. These extracts showed an anxiolytic-like effect in the novelty-suppressed feeding test, which was reversed by flumazenil except in SchO-treated mice. Only SchO reduced the spontaneous locomotor function in the open field test. Also, SchT and SchW decreased immobility time in both, the tail suspension (TST) and forced swimming tests, while SchO produced the same effect in the TST. d-limonene and α-santalol were the main components found in SchO. The results demonstrated that extracts obtained from S. lentiscifolius leaves were effective as intestinal, urinary and uterine antispasmodics. SchT and SchW exhibited anxiolytic and antidepressant properties without sedation, whereas SchO showed also sedative properties. Therefore, the present study gives preclinical support to the traditional use of this plant for gastrointestinal and depressive or emotional symptoms.
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BACKGROUND AND AIM: Phytoestrogens are traditionally used for cardiovascular risks but direct effects on the ischemic heart remain unclear. Plants with phytoestrogens are used for reducing menopausic symptoms and they could also be cardioprotectives. Here we investigated whether maca (Lepidium meyenii) contains isoflavones and prevents cardiac stunning, in comparison to soy isoflavones. EXPERIMENTAL PROCEDURE: Both products were orally and daily administered to rats during 1 week before exposing isolated hearts to ischemia/reperfusion (I/R). Young male (YM), female (YF) and aged female (AgF) rats treated with maca (MACA, 1 g/kg/day) or soy isoflavones (ISOF, 100 mg/kg/day) were compared to acute daidzein (DAZ, 5 mg/kg i.p.) and non-treated rat groups. Isolated ventricles were perfused inside a calorimeter to simultaneously measure contractile and calorimetrical signals before and during I/R. RESULTS AND CONCLUSIONS: Maca has genistein and daidzein. MACA and ISOF improved the post-ischemic contractile recovery (PICR) and muscle economy (P/Ht) in YM and YF hearts, but not in AgF hearts. DAZ improved PICR and P/Ht more in YM than in YF. The mKATP channels blockade reduced both PICR and P/Ht in DAZ-treated YM hearts, without affecting them in ISOF or MACA-treated YM hearts. In MACA treated YF hearts, the simultaneous blockade of NOS and mKATP channels, or the mNCX blockade reduced cardioprotection. Results show that subacute oral treatment with maca or with soy isoflavones was strongly preventive of cardiac ischemic dysfunction, more than the acute administration of a pure isoflavone (daidzein, genistein). Maca induced synergistic and complex mechanisms which prevented mitochondrial calcium overload.
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Hypothyroidism is considered a cardiac risk factor, but there is controversial evidence about its effects on coronary disease. The aim of this work was to evaluate the influence of hypothyroidism in rat hearts exposed to 2 degrees of stunning due to ischemia and reperfusion (I/R) as well as the underlying mechanisms. Hypothyroid (HypoT) rats were obtained by drinking 0.02% methimazole during 15 days. Isolated hearts were perfused and introduced in a flow calorimeter to measure contractile performance (P), total heat rate (Ht), and muscle economy (P/Ht). Hearts were exposed to 2 models of I/R, moderate and severe (respectively 20 or 30 minutes I/45 minutes R). Moreover, free cytosolic and mitochondrial calcium changes were measured by confocal fluorometry on cardiomyocytes. Comparison to euthyroid (EuT) hearts was done. Hypothyroidism was cardioprotective, but HypoT hearts were more sensitive than EuT hearts to the preischemic blockade of mitochondrial transporters mNCX and mKATP channels. Moreover, the postischemic recovery of P and P/Ht in HypoT hearts was strongly reduced by inhibition of the cellular pathways of PI3K/Akt and protein kinase C (PKC), and it was increased by nitric oxide synthase (NOS) inhibition. However, physiological concentrations of adrenaline reduced the cardioprotection of HypoT, but oral treatment with 20 mg/kg/day carvedilol prevented it. Results show that hypothyroidism reduces the mitochondrial Ca2+ overload during I/R by mKATP channel activation and Ca2+ extrusion through mNCX, while the PI3K/Akt and PKC pathways are involved in that cardioprotection. Contrarily, NOS activation and adrenaline blunt such cardioprotection, but carvedilol prevented the adrenergic dysfunction. These results would explain why hypothyroidism is a clinical risk factor in angor patients under adrenergic exacerbation but reduced the incidence of acute episodes of coronary syndrome in hospitalized patients. Results suggest that a treatment with carvedilol could be a potential therapeutic agent to prevent cardiac postischemic dysfunction in hypothyroid patients.
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Metabolismo Energético , Hipotiroidismo/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Animales , Señalización del Calcio , Modelos Animales de Enfermedad , Femenino , Frecuencia Cardíaca , Hipotiroidismo/patología , Hipotiroidismo/fisiopatología , Preparación de Corazón Aislado , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Contracción Miocárdica , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Óxido Nítrico Sintasa/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Canales de Potasio/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Intercambiador de Sodio-Calcio/metabolismoRESUMEN
AIMS: Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischaemia/reperfusion (I/R)-induced cell death. In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation. METHODS AND RESULTS: We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban (PLN)-deficient-S2814D knock-in (SDKO) mice resulting from crossbreeding S2814D with phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the strains were arrhythmic before ischaemia. Upon cardiac I/R, WT, and S2814D hearts exhibited abundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablation increased infarct size compared with WT and S2814D hearts. Mechanistically, the enhanced SR Ca2+ sequestration evoked by PLN ablation in SDKO hearts prevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2+ waves into non-propagated and non-arrhythmogenic events (mini-waves). Conversely, the increase in SR Ca2+ sequestration did not reduce but rather exacerbated I/R-induced SR Ca2+ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2+ uptake is ineffective in preventing the enhanced SR Ca2+ leak of PLN ablated myocytes from either entering into nearby mitochondria and/or activating additional CaMKII pathways, contributing to cardiac damage. CONCLUSION: Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.
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Arritmias Cardíacas/enzimología , Proteínas de Unión al Calcio/deficiencia , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Mitocondrias Cardíacas/enzimología , Infarto del Miocardio/enzimología , Daño por Reperfusión Miocárdica/enzimología , Miocitos Cardíacos/enzimología , Potenciales de Acción , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Señalización del Calcio , Proteínas de Unión al Calcio/genética , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Frecuencia Cardíaca , Preparación de Corazón Aislado , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Cardíacas/patología , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/patología , Fosforilación , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/enzimología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismoRESUMEN
OBJECTIVES: Low-flow ischemia (LFI) is consequent to coronary disease and produces cardiac stunning during reperfusion (R). Energetic performance and mechanisms of Ca2+ handling during LFI/R are not known. Moreover, cardioprotection of the phytoestrogen genistein (Gen) remains to be demonstrated in LFI/R. The aim was to study the mechanisms of the stunning consequent to LFI/R and the effects of Gen on both sexes. METHODS: Rat ventricles were perfused inside a calorimeter to measure maximal pressure development (P) and total heat rate (Ht) before and during exposition to LFI/R. The mechanisms of stunning were evaluated with selective drugs. KEY FINDINGS: Female hearts (FH) developed higher postischemic contractile recovery (PICR) and muscle economy (P/Ht) than males (MH). Cardioprotection was sensitive to blockade of mKATP channels, UCam and NOS. Perfusion of 20 µmol/l Gen reduced PICR and P/Ht during LFI/R in FH, and dysfunction was increased by mNCX blockade with mPTP opening. However, intraperitoneal 5 mg/kg Gen (Gen-ip) was cardioprotective in both sexes, and the beneficial effect of Gen-ip was blocked by 100 µmol/l 5-HD. CONCLUSIONS: FH are more protected than MH against the LFI/R dysfunction, which involves mitochondrial Ca2+ loss; Gen-ip was more cardioprotective in MH than in FH, mainly by activation of the mKATP channels.
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Cardiotónicos/uso terapéutico , Metabolismo Energético/fisiología , Genisteína/uso terapéutico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevención & control , Reperfusión Miocárdica/métodos , Animales , Calcio/metabolismo , Cardiotónicos/farmacología , Metabolismo Energético/efectos de los fármacos , Femenino , Genisteína/farmacología , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Blepharocalyx salicifolius (Kunth) O. Berg (Myrtaceae) is a tree native to Argentina and Uruguay that grows and is cultivated along the riverside of the Rio de la Plata. The leaves of this plant species, locally known as "anacahuita" are used in South America to prepare infusions for the empiric treatment of cough and bronchospasm, as well as diarrhoea and other intestinal disorders. Although previous phytochemical studies have been performed with the essential oil extracted from Blepharocalyx salicifolius, pharmacological evidence supporting its traditional use is still lacking. AIM OF THE STUDY: To experimentally evaluate the pharmacological properties of Blepharocalyx salicifolius based on its traditional use. The studies were performed with tincture (T-Bs) and essential oil (EO-Bs) prepared from its leaves, in isolated rat trachea, intestine and heart preparations. METHODS: The ex-vivo effects of T-Bs and EO-Bs were evaluated with the agonists carbachol (CCh) and calcium chloride (Ca2+) in the contractile concentration-response curves (CRC) of the isolated intestine. The muscle relaxant effect of EO-Bs was evaluated in the isolated trachea and compared with the effect achieved with papaverine as a positive control. The T-Bs and EO-Bs cardiac effects were analysed by perfusion of an isolated rat heart before a period of ischemia/reperfusion (stunning model). The antitussive effect of both T-Bs and EO-Bs was evaluated in mice exposed to ammonia using codeine as a positive control. RESULTS: Both T-Bs and EO-Bs induced a non-competitive inhibition of the CCh-CRC in the rat intestine, with IC50 values of 170.3 ± 48.5µg T-Bs/mL (n = 6) and 5.9 ± 1.6µg EO-Bs/mL (n = 6), respectively. EO-Bs also inhibited non-competitively the Ca2+-CRC, with IC50 value of 1.8 ± 0.3µg EO-Bs/mL (n = 8). A similar effect was obtained with the main active component of the EO-Bs 1,8-cineole. In isolated trachea, EO-Bs induced the relaxation of the CCh-contracted tissue (1.7 ± 0.2µg EO-Bs/mL, n = 11) up to a maximal relaxation that was 1.9 times higher than that of papaverine. In the isolated heart, EO-Bs induced a poor negative inotropic response, and did not improve the contractile and energetic recovery after ischemia and reperfusion. In the mouse cough model, EO-Bs (90mg/Kg) was as effective as codeine (30mg/Kg) in reducing cough frequency. CONCLUSIONS: The results indicate that the preparations from Blepharocalyx salicifolius leaves were effective as central antitussive, bronchodilating and antispasmodic agents, suggestive of a mechanism associated with the inhibition of Ca2+ influx into smooth muscle. The EO-Bs displayed only a poor ability to reduce cardiac inotropism, and was devoid of any cardioprotective properties. Thus, the present study validates the traditional use of this South American plant for asthma, cough and bronchospasm, shedding new light into its potency and putative mechanism of action.
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Medicina Tradicional/métodos , Myrtaceae/química , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Animales , Antitusígenos/administración & dosificación , Antitusígenos/aislamiento & purificación , Antitusígenos/farmacología , Broncodilatadores/administración & dosificación , Broncodilatadores/aislamiento & purificación , Broncodilatadores/farmacología , Calcio/metabolismo , Cardiotónicos/administración & dosificación , Cardiotónicos/aislamiento & purificación , Cardiotónicos/farmacología , Tos/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Concentración 50 Inhibidora , Masculino , Ratones , Aceites Volátiles/administración & dosificación , Aceites Volátiles/aislamiento & purificación , Parasimpatolíticos/administración & dosificación , Parasimpatolíticos/aislamiento & purificación , Parasimpatolíticos/farmacología , Extractos Vegetales/administración & dosificación , Hojas de la Planta , Ratas , Ratas Sprague-Dawley , América del SurRESUMEN
BACKGROUND: The sweetener and hypoglycemic properties of stevioside (STV) are well known, as the main component of the plant Stevia rebaudiana. Given its extensive use in diabetic patients, it was of interest to evaluate its effects on the most frequent cardiovascular disease, the coronary insufficiency. PURPOSE: To study whether STV could be cardioprotective against ischemia-reperfusion (I/R) in a model of "stunning" in rat hearts. STUDY DESIGN: A preclinical study was performed in isolated hearts from rats in the following groups: non-treated rats whose hearts were perfused with STV 0.3 mg/ml and their controls (C) exposed to either moderate stunning (20 min I/45 min R) or severe stunning (30 min I/45 min R), and a group of rats orally treated with STV 25 mg/kg/day in the drink water during 1 week before the experiment of severe stunning in the isolated hearts were done. METHODS: The mechano-calorimetrical performance of isolated beating hearts was recorded during stabilization period with control Krebs perfusion inside a calorimeter, with or without 0.3 mg/ml STV before the respective period of I/R. The left ventricular maximal developed pressure (P) and total heat rate (Ht) were continuously measured. RESULTS: Both, orally administered and perfused STV improved the post-ischemic contractile recovery (PICR, as % of initial control P) and the total muscle economy (P/Ht) after the severe stunning, but only improved P/Ht in moderate stunning. However, STV increased the diastolic pressure (LVEDP) during I/R in both stunning models. For studying the mechanism of action, ischemic hearts were reperfused with 10 mM caffeine-36 mM Na+-Krebs to induce a contracture dependent on sarcorreticular Ca2+ content, whose relaxation mainly depends on mitochondrial Ca2+ uptake. STV at 0.3 mg/ml increased the area-under-curve of the caffeine-dependent contracture (AUC-LVP). Moreover, at room temperature STV increased the mitochondrial Ca2+ uptake measured by Rhod-2 fluorescence in rat cardiomyocytes, but prevented the [Ca2+]m overload assessed by caffeine-dependent SR release. CONCLUSIONS: Results suggest that STV is cardioprotective against I/R under oral administration or direct perfusion in hearts. The mechanism includes the regulation of the myocardial calcium homeostasis and the energetic during I/R in several sites, mainly reducing mitochondrial Ca2+ overload and increasing the sarcorreticular Ca2+ store.
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Cardiotónicos/farmacología , Diterpenos de Tipo Kaurano/farmacología , Glucósidos/farmacología , Corazón/efectos de los fármacos , Daño por Reperfusión/prevención & control , Animales , Calcio/metabolismo , Femenino , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas , Stevia/químicaRESUMEN
During ischemia and reperfusion (I/R) mitochondria suffer a deficiency to supply the cardiomyocyte with chemical energy, but also contribute to the cytosolic ionic alterations especially of Ca2+. Their free calcium concentration ([Ca2+]m) mainly depends on mitochondrial entrance through the uniporter (UCam) and extrusion in exchange with Na+ (mNCX) driven by the electrochemical gradient (ΔΨm). Cardiac energetic is frequently estimated by the oxygen consumption, which determines metabolism coupled to ATP production and to the maintaining of ΔΨm. Nevertheless, a better estimation of heart energy consumption is the total heat release associated to ATP hydrolysis, metabolism, and binding reactions, which is measurable either in the presence or the absence of oxygenation or perfusion. Consequently, a mechano-calorimetrical approach on isolated hearts gives a tool to evaluate muscle economy. The mitochondrial role during I/R depends on the injury degree. We investigated the role of the mitochondrial Ca2+ transporters in the energetic of hearts stunned by a model of no-flow I/R in rat hearts. This chapter explores an integrated view of previous and new results which give evidences to the mitochondrial role in cardiac stunning by ischemia o hypoxia, and the influence of thyroid alterations and cardioprotective strategies, such as cardioplegic solutions (high K-low Ca, pyruvate) and the phytoestrogen genistein in both sex. Rat ventricles were perfused in a flow-calorimeter at either 30 °C or 37 °C to continuously measure the left ventricular pressure (LVP) and total heat rate (Ht). A pharmacological treatment was done before exposing to no-flow I and R. The post-ischemic contractile (PICR as %) and energetical (Ht) recovery and muscle economy (Eco: P/Ht) were determined during stunning. The functional interaction between mitochondria (Mit) and sarcoplasmic reticulum (SR) was evaluated with selective mitochondrial inhibitors in hearts reperfused with Krebs-10 mM caffeine-36 mM Na+. The caffeine induced contracture (CIC) was due to SR Ca2+ release, while relaxation mainly depends on mitochondrial Ca2+ uptake since neither SL-NCX nor SERCA are functional under this media. The ratio of area-under-curves over ischemic values (AUC-ΔHt/AUC-ΔLVP) estimates the energetical consumption (EC) to maintain CIC. Relaxation of CIC was accelerated by inhibition of mNCX or by adding the aerobic substrate pyruvate, while both increased EC. Contrarily, relaxation was slowed by cardioplegia (high K-low Ca Krebs) and by inhibition of UCam. Thus, Mit regulate the cytosolic [Ca2+] and SR Ca2+ content. Both, hyperthyroidism (HpT) and hypothyroidism (HypoT) reduced the peak of CIC but increased EC, in spite of improving PICR. Both, CIC and PICR in HpT were also sensitive to inhibition of mNCX or UCam, suggesting that Mit contribute to regulate the SR store and Ca2+ release. The interaction between mitochondria and SR and the energetic consequences were also analyzed for the effects of genistein in hearts exposed to I/R, and for the hypoxia/reoxygenation process. Our results give evidence about the mitochondrial regulation of both PICR and energetic consumption during stunning, through the Ca2+ movement.
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Metabolismo Energético , Mitocondrias Cardíacas/metabolismo , Contracción Miocárdica , Daño por Reperfusión Miocárdica/metabolismo , Reperfusión Miocárdica/efectos adversos , Aturdimiento Miocárdico/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Señalización del Calcio , Circulación Coronaria , Humanos , Mitocondrias Cardíacas/ultraestructura , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Aturdimiento Miocárdico/etiología , Aturdimiento Miocárdico/patología , Aturdimiento Miocárdico/fisiopatología , Miocitos Cardíacos/ultraestructura , Factores de Riesgo , Retículo Sarcoplasmático/metabolismo , Factores de TiempoRESUMEN
Although the phytoestrogen genistein (Gen) is considered protective in cardiovascular diseases, its direct effects on stunned hearts after transient ischemia-reperfusion (I/R) are unknown. This report studied the effects of 20 µmol/L Gen on the mechano-calorimetric behaviour during I/R of rat and guinea pig hearts to evaluate the energetics of Ca(2+) homeostasis. Isolated beating hearts were perfused with control Krebs solution inside a calorimeter with or without perfusion of Gen before a transient period of I/R. Left ventricular pressure development (P) and total heat rate (Ht) were continuously measured. At 37°C, Gen did not change post-ischemic contractile recovery (PICR), but it increased the relaxation rate. However, PICR was reduced in hearts of male rats and guinea pigs at 30°C. Total muscle economy (P/Ht) showed the same behaviour as P at each temperature. Inhibition of phosphatases with orthovanadate during Gen perfusion prevented a decrease in PICR in male rat hearts, suggesting that this effect is due to tyrosine kinase inhibition. Reperfusing ischemic hearts with 10 mmol/L caffeine-36 mmol/L Na(+)-Krebs induced contracture dependent on the sarcoreticular Ca(2+) content. Contracture relaxation depends on mitochondrial Ca(2+) uptake and Gen reduced the relaxation rate. Moreover, Gen prevented the increase in Rhod-2 fluorescence (free [Ca(2+)]m) of rat cardiomyocytes. In guinea pig hearts, Gen maintained ischemic preconditioning, but was reduced by 5-hydroxydecanoate, suggesting the participation of mitochondrial adenosine triphosphate (ATP)-dependent K channels. Results suggest that Gen acts on several mechanisms that regulate myocardial calcium homeostasis and energetics during I/R, which differ in a temperature- and sex-dependent manner.
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Metabolismo Energético/efectos de los fármacos , Genisteína/farmacología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Aturdimiento Miocárdico/metabolismo , Caracteres Sexuales , Animales , Calcio/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , Femenino , Cobayas , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Contracción Miocárdica/efectos de los fármacos , Aturdimiento Miocárdico/complicaciones , Aturdimiento Miocárdico/patología , Aturdimiento Miocárdico/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratas , Daño por Reperfusión/complicaciones , Presión Ventricular/efectos de los fármacosRESUMEN
NEW FINDINGS: What is the central question of this study? Hyperthyroidism is a cardiac risk factor, but thyroid therapy is used on myocardial stunning. What is the consequence of hyperthyroidism for mitochondrial metabolism and Ca(2+) handling of the postischaemic stunned heart? What is the main finding and its importance? Hyperthyroidism reduced stunning and improved muscle economy of the postischaemic rat heart. The activities of the mitochondrial sodium-calcium exchanger and mitochondrial K(+) channel in hyperthyroid rat hearts were different from those in the euthyroid rat hearts. These findings contribute to the understanding of mitochondrial bioenergetics in pathology and support thyroid therapy in the stunning induced by ischaemia. Transient ischaemia and hyperthyroidism are cardiovascular risk factors. Nevertheless, 3,5,3'-triiodothyronine/thyroxine therapy has been used to revert myocardial stunning. We studied the influence of hyperthyroidism on the role played by mitochondria in myocardial stunning consequent to ischaemia-reperfusion. Rats were injected s.c. daily with 20 µg kg(-1) triiodothyronine for 15 days (HpT group). Isolated ventricles from either HpT or euthyroid (EuT) rats were perfused in a calorimeter, and left intraventricular pressure (in millimetres of mercury) and heat release (Ht; in milliwatts per gram) were measured. Stunning was evoked by 20 min of no-flow ischaemia and 45 min reperfusion. The HpT hearts developed higher postischaemic contractile recovery (PICR) and improved total muscle economy (P/Ht) with lower diastolic contracture (ΔLVEDP) than EuT hearts. Release of Ca(2+) from the sarcoplasmic reticulum during reperfusion with 10 mm caffeine in low-[Na(+) ] Krebs solution evoked a higher contracture in EuT than in HpT hearts. Blockade of the mitochondrial sodium-calcium exchanger with clonazepam increased ΔLVEDP and reduced P/Ht and PICR in HpT but not in EuT hearts. The clonazepam-induced dysfunction in HpT hearts was reduced by ciclosporin, suggesting a dependance on activation of the mitochondrial permeability transition pore. Blockade of the mitochondrial Ca(2+) uniporter with Ru360 reduced P/Ht and PICR to â¼10% in both HpT and EuT hearts. Blockade of mitochondrial K(+) channels with 5-hydroxydecanoate increased LVEDP and reduced PICR and P/Ht in HpT hearts, while it only increased LVEDP in EuT hearts. The results suggest that hyperthyroidism prevents the stunning with high dependence on the mitochondrial sodium-calcium exchanger and mitochondrial K(+) channels. Both HpT and EuT hearts showed a similar and critical role of the uniporter. The HpT hearts have a slow sarcoplasmic reticulum Ca(2+) loss and low mitochondrial Ca(2+) uptake.
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Metabolismo Energético , Hiperparatiroidismo/metabolismo , Mitocondrias Cardíacas/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Aturdimiento Miocárdico/prevención & control , Miocitos Cardíacos/metabolismo , Animales , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Señalización del Calcio , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Femenino , Hiperparatiroidismo/inducido químicamente , Hiperparatiroidismo/fisiopatología , Preparación de Corazón Aislado , Masculino , Moduladores del Transporte de Membrana/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Contracción Miocárdica , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Aturdimiento Miocárdico/metabolismo , Aturdimiento Miocárdico/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas Wistar , Recuperación de la Función , Retículo Sarcoplasmático/metabolismo , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Intercambiador de Sodio-Calcio/metabolismo , Factores de Tiempo , Triyodotironina , Función Ventricular Izquierda , Presión VentricularRESUMEN
Pyruvate (Pyr) was proposed as an additive to cold high-K(+)-low-Ca(2+) cardioplegia (CPG) to protect the heart during surgery. We explored whether Pyr and CPG would work synergistically to protect rat hearts from stunning during ischemia-reperfusion (I/R). We measured the heat release and contractility of perfused ventricles during I/R, and the cytosolic and mitochondrial [Ca(2+)] in cardiomyocytes by confocal microscopy. We found that under cold-CPG (30 °C), 10 mmol·L(-1) Pyr reduced the post-ischemic contractile recovery (PICR) as well as muscle economy, when added either before ischemia or during I/R, which was reversed by blockade of UCam. In noncardioplegic hearts, Pyr was cardioprotective when it was present during I/R, more so at 37 °C than at 30 °C, with improved economy. In cardiomyocytes, the addition of Pyr to CPG slightly increased the mitochondrial [Ca(2+)] but decreased cytosolic [Ca(2+)]. The results suggest that Pyr only protects hearts from stunning when present before ischemia and during reperfusion, and that it dampens the cardioprotective properties of CPG. The mechanisms underlying such different behavior depend on the dynamic balance between Pyr stimulation of the energetic state and mitochondrial Ca(2+) uptake. Our results support the use of Pyr in stunned hearts, but not in cold high-K(+) cardioplegia.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Ácido Pirúvico/farmacología , Animales , Calcio/metabolismo , Femenino , Paro Cardíaco Inducido , Ventrículos Cardíacos/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas Endogámicas WKYRESUMEN
ETHOPHARMACOLOGY RELEVANCE: Lippia alba (Mill.) N. E. Brown (Verbenaceae) is an aromatic species used in Central and South America as eupeptic for indigestion. In Argentina, it is used by the "criollos" from the Chaco province. There are several chemotypes which differ in the chemical composition of the essential oils. Nowadays, it is experimentally cultivated in some countries of the region, including Argentina. AIM OF THE STUDY: To compare the chemical composition and pharmacology of the essential oils from two chemotypes: "citral" (CEO) and "linalool" (LEO), in isolated rat duodenum and ileum. METHODS: Contractile concentration-response curves (CRC) of acetylcholine (ACh) and calcium in 40mM K(+)-medium (Ca(2+)-CRC) were done in isolated intestine portions, in the absence and presence of CEO or LEO at different concentrations. RESULTS: Likewise verapamil, CEO and LEO induced a non-competitive inhibition of the ACh-CRC, with IC50 of 7.0±0.3mg CEO/mL and 37.2±4.2mg LEO/mL. l-NAME, a NO-synthase blocker, increased the IC50 of CEO to 26.1±8.7mg CEO/mL. Likewise verapamil, CEO and LEO non-competitively inhibited the Ca(2+)-CRC, with IC50 of 6.3±1.7mg CEO/mL, 7.0±2.5mg LEO/mL and 0.24±0.04mg verapamil/mL (pIC50: 6.28). CEO was proved to possess limonene, neral, geranial and (-)-carvone as the major components, while LEO was rich in linalool. CONCLUSIONS: Results suggest that CEO has five times more potency than LEO to inhibit muscarinic contractions. The essential oils of both chemotypes interfered with the Ca(2+)-influx, but with an IC50 about 28 times higher than that of verapamil. Moreover, CEO partially stimulated the NO production. These results show the medicinal usefulness of both Lippia alba chemotypes, thus validating its traditional use, potency and mechanism of action.
Asunto(s)
Lippia/química , Aceites Volátiles , Parasimpatolíticos , Aceites de Plantas , Animales , Argentina , Relación Dosis-Respuesta a Droga , Duodeno/efectos de los fármacos , Femenino , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Medicina Tradicional , Contracción Muscular/efectos de los fármacos , Aceites Volátiles/química , Aceites Volátiles/farmacología , Parasimpatolíticos/química , Parasimpatolíticos/farmacología , Aceites de Plantas/química , Aceites de Plantas/farmacología , Ratas , Ratas Sprague-Dawley , Espasmo/tratamiento farmacológicoRESUMEN
The antispasmodic effects of acqueous extracts (AE) and tinctures (T) of Aloysia polystachya (Griseb.) Moldenke and Aloysia gratissima (Gillies & Hook.) Tronc., Verbenaceae, were studied on rat isolated ileum and duodenum. These plants are used for gastrointestinal disorders and as eupeptic in South America. Both AE non-competitively inhibited the dose-response curves (DRC) of ACh and the DRC of Ca2+ in high-[K+]o, as well as the T. The T of A. polystachya and A. gratissima respectively inhibited the ACh-DRC at the IC50 of 3.15±0.57 and 6.46±2.28 mg leaves/mL. The Ca2+- antagonist activity of both T occurred with IC50 respectively similar to those of the ACh-DRC, and was potentiated by the depolarization produced by 10 mM TEA, a blocker of K+- channels. The spasmolytic effect of T does not involve DA release and binding to D2, since it was not reduced by 10 µ M metoclopramide. Also, T induced dose-dependent relaxation on the tonic contracture produced by high -[K+]o and ACh. By TLC there were detected in the leaves the presence of carvone, and flavonoids such as quercetin and hesperidin. By HPLC there were not found vitexin nor isovitexin, identified in A. citriodora. The monoterpene (-)- carvone non-competitively inhibited the ACh-DRC (pD'2 of 4.0±0.1) and the DRC of Ca2+ (pD'2 of 3.86±0.19), suggesting that the Ca2+- influx blockade is the mechanism of its antispasmodic effect. Results suggest that the antispasmodic effect of A. polystachya and A. gratissima are mostly explained by the non-competitive blockade of Ca+2 influx. It could be associated to the presence of flavonoids, and in the tinctures to some spasmolytic components of the essential oil such as carvone.
RESUMEN
Medicinal plants are useful as a natural therapy to treat minor illnesses, as gastrointestinal disorders or as topic antiinflammatories. Also, they have been increasingly used as a coadjuvant in cronic diseases as hypertension, diabetes or hyperlipidemias. Nevertheless, many of the plants have active principles which are contraindicated or need precaution in certain illnesses as coagulation disorders or in certain states as pregnancy or breastfeeding. In this review we had compiled the side-effects, precautions and interactions with other medicines of many plants which are used in self-medication in our region. A previous population study gave us information on the consumption of medicinal plants in 73 pharmacies of the Buenos Aires province, in Argentina. During a period of one year, there were 37102 self-medicated plants, while only 1532 were prescribed by the physician. Among the most frequently self-medicated plants are Malva sylvestris L., Matricaria chamomile L, and Quassia amara. Among the most frequently prescribed are also "malva" and "chamomile", Tilia cordata Mill. and Valeriana officinalis. Based in the most consumed medicinal plants in our region, we reviewed the risks of such plants and the precautions that should be taken for a rational use. Also, we detected 15 adverse-reactions reported by the pharmacists through a pharmaceutical vigilance program, which are described and analyzed here. The results of the study and other reports suggest that adverse reactions of herbal medicines could be avoided if preventing self-medication, and taking into consideration possible contraindications and interactions.
Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Fitoterapia , Preparaciones de Plantas/efectos adversos , Plantas Medicinales/efectos adversos , Automedicación/estadística & datos numéricos , Sistemas de Registro de Reacción Adversa a Medicamentos , Argentina , Contraindicaciones , Encuestas Epidemiológicas , Interacciones de Hierba-Droga , Humanos , Educación del Paciente como Asunto , Fitoterapia/efectos adversos , Preparaciones de Plantas/administración & dosificación , Preparaciones de Plantas/uso terapéuticoRESUMEN
UNLABELLED: The role of mitochondrial transporters in the cardioprotection of rat hearts exposed to high [K+]-low [Ca2+]-cardioplegia (CPG) and ischemia and reperfusion (I/R) was studied through the mechano-energetic consequences of target drugs. The total heat rate (Ht) and the left intraventricular pressure (LVP) were simultaneously measured in isolated perfused hearts (30 degrees C and 1 Hz) inside a flow-calorimeter during 45 minutes of no-flow I and 45 minutes of R. After stabilization (C) they were pretreated with CPG and 100 microM 5-hydroxidecanoate (5HD, selective mKATP blocker) without and with 10 or 30 microM clonazepam (Clzp, mNCX inhibitor), 30 microM diazoxide (Dzx, selective mKATP opener), 1 microM Ru360 (selective Ca-uniporter blocker), and 0.2 microM cyclosporine-A, (mPTP inhibitor, before I and during R). Before I, 5-hydroxydecanoate in CPG increased the resting heat rate (17.83 +/- 3.55 mW/g) without changing the stunning. Clzp 30 microM + CPG + 5-hydroxydecanoate reduced the postischemic P with diastolic contracture and high Ht. Dzx protected C-hearts from stunning but increased it in CPG hearts with low economy (P/Ht) as well as Ru360. Cyclosporine-A did not modify the stunning of C or CPG ischemic hearts, suggesting that the mPTP was not opened. CONCLUSIONS: Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R. Known protective drugs, such as Dzx and Ru360, which reduce the mitochondrial Ca2+-uptake, increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increased the stunning by inducing mitochondrial Ca2+ overload.
Asunto(s)
Canales de Calcio/metabolismo , Corazón/fisiopatología , Mitocondrias Cardíacas/enzimología , Mitocondrias Cardíacas/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Animales , Agonistas de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Soluciones Cardiopléjicas , Corazón/efectos de los fármacos , Paro Cardíaco Inducido , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Poro de Transición de la Permeabilidad Mitocondrial , Aturdimiento Miocárdico/inducido químicamente , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/agonistas , Ratas , Ratas Sprague-Dawley , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Factores de Tiempo , Presión Ventricular/efectos de los fármacosRESUMEN
The mechanocalorimetric consequences and mechanisms involved in Ca2+ homeostasis during ischemia-reperfusion (I/R) as well as the protective role of cardioplegic pretreatment with high [K+] (25 mmol/L) and low or near-normal [Ca2+] (0.5 or 2 mmol/L) were evaluated in a model of neonatal rat heart. Beating hearts from 10-12-day-old rats were perfused with Krebs solution (2 mmol/L Ca2+) under both isotonic and isometric conditions. During pretreatment, hearts were exposed for 20 min to either Krebs (control) or cardioplegia (CPG) before 15 min ischemia and 45 min reperfusion while being continuously measured for either contractility or total heat rate (Ht) in a flow calorimeter. Contractile recovery after reperfusion in hearts exposed to ischemia only (control) was higher in the isometric hearts under optimal length (87.9% +/- 8.1%) than in the isotonic hearts (57.3% +/- 10.6%). This same behavior was found in hearts pretreated with CPG-0.5 mmol/L Ca2+. Ht in controls was reduced from 11.5 +/- 0.8 mW/g in the initial beating condition to 1.11 +/- 0.33 mW/g during ischemia and was increased to 13.02 +/- 0.93 mW/g (113.8% +/- 5.0% of preischemic) after reperfusion. Hearts pretreated with CPG-0.5 mmol/L Ca2+ showed the same behavior. However, when extracellular calcium ([Ca]o) was increased to 2 mmol/L under CPG, isotonic hearts, but not isometric hearts, significantly increased the contractile recovery to a maximum of 88.7% +/- 10.8% of preischemic levels. Ht was recovered to 92.1% +/- 4.3% of preischemic, suggesting that contractile recovery was less energetically expensive after CPG-2 mmol/L Ca2+ than it was in postischemic hearts exposed to control or CPG-0.5 mmol/L Ca2+. The role of the sarcoplasmic reticulum store was evaluated by pretreating hearts with 10 mmol/L caffeine, which reduced contractile recovery only under isometric conditions or after increasing [Ca]o in CPG under isotonic conditions, suggesting that the contribution of the sarcoplasmic reticulum was dependent on the fibre length or the [Ca]o. The inhibition of the reverse mode of the sarcolemmal Na/Ca exchanger (NCX) and the mitochondrial Ca uniporter (CaU) by KB-R7943 (KBR) at 5 micromol/L in CPG-0.5 mmol/L Ca2+ improved contractile recovery of isotonic hearts, whereas it decreased Ht at the start of reperfusion, suggesting that mitochondria could uptake Ca2+ vía the mitochondrial CaU. Neither the positive inotropism nor Ht were changed by inhibiting the mitochondrial NCX with 10 micromol/L clonazepam in CPG-0.5 mmol/L Ca2+ + 5 micromol/L KBR, which suggests that the mitochondrial NCX does not have a role. Finally, the role of the forward mode of the sarcolemmal NCX was evidenced by the fall in contractile recovery with increased Ht when KBR was increased to 20 micromol/L and added to CPG-2 mmol/L Ca2+ + 10 mmol/L caffeine before I/R. Thus the sarcolemmal NCX was essential for removing the diastolic Ca2+ during the periods of CPG and I/R. In summary, Ca2+ homeostasis during I/R of neonatal rat hearts is different from that of adult rats. High-[K+] CPG protected neonatal hearts only under isotonic conditions, at a near-normal [Ca]o, or by exposure to KBR. Mitochondria were able to uptake Ca2+ via the mitochondrial CaU and reduce the Ca2+ available for contractile recovery. Nevertheless, after increasing [Ca]o in CPG, the sarcoplasmic reticulum had a main role in restoring contractility during reperfusion, as it does in adults. Thus, the degree of maturation of the heart must be taken into account to evaluate the effects of CPG and drugs on I/R.
Asunto(s)
Animales Recién Nacidos , Calcio/metabolismo , Paro Cardíaco Inducido/métodos , Potasio/farmacología , Animales , Calorimetría , Femenino , Homeostasis , Técnicas In Vitro , Masculino , Contracción Miocárdica , Ratas , Ratas Wistar , Daño por Reperfusión/fisiopatología , Daño por Reperfusión/prevención & controlRESUMEN
The spasmolytic effects of an acqueous extract of cedrón (AEC) were studied on rat isolated duodenums. This plant (Aloysia citriodora Palau, Verbenaceae) is widely used for gastrointestinal disorders and as eupeptic in South America. AEC non-competitively inhibited the dose-response curve (DRC) of Ach (IC50 of 1.34 +/- 0.49 mg lyophilized/mL) and the DRC of Ca(2+) in high-[K(2-)](o) (IC50 of 2.64 +/- 0.23 mg/mL). AEC potentiated the non-competitive inhibition of either 30 micromol/L W-7 (a calmodulin blocker) and 5-15 micromol/L papaverine on the Ca(2+)-DRC. Also, AEC relaxed the contracture produced by high-[K(+)](o) (IC50 of 2.6 +/- 0.2 mg/mL) until 81.0 +/- 3.2% of the maximal effect of papaverine and 78.1+/- 5.0% of the quercetin, the most selective inhibitor of PDE. The AEC relaxation was non-competitively inhibited by 10-30 micromol/L methylene blue and competitively antagonized by 40 mmol/L TEA. The relaxation of 1mg/mL AEC was inhibited by hypoxia, but not that of 2mg/mL. Two flavonoids were identified by HPLC in the AEC: vitexin and isovitexin. Vitexin non-competitively inhibited the Ach-DRC (pD(2') of 5.7 +/- 0.4) but significantly run leftward the DRC of Ca(2+). Isovitexin did not significantly inhibit the DRC of Ach nor Ca(2+). The results suggest that the spasmolytic effect of AEC could be mostly associated to the increase in cGMP (target shared with the PDE inhibitors) and the activation of K(+)-channels. At low concentrations, AEC also inhibits the aerobic metabolism. The flavonoid vitexin is partially responsible for the effect, since it non-competitively inhibits Ach but not the Ca(2+) influx. Isovitexin was devoid of activity on duodenums.
Asunto(s)
Apigenina/farmacología , Duodeno/efectos de los fármacos , Lippia/química , Parasimpatolíticos/farmacología , Acetilcolina/farmacología , Animales , Apigenina/química , Apigenina/aislamiento & purificación , Cloruro de Calcio/farmacología , Relación Dosis-Respuesta a Droga , Duodeno/fisiología , Inhibidores Enzimáticos/farmacología , Femenino , Técnicas In Vitro , Soluciones Isotónicas/farmacología , Masculino , Azul de Metileno/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Papaverina/farmacología , Parasimpatolíticos/química , Parasimpatolíticos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Quercetina/farmacología , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , Tetraetilamonio/farmacología , Agua/químicaRESUMEN
Cecropia pachystachya Mart. is popularly called "ambay" and extensively used in herbal medicine of South America for cough and asthma. In Argentina it grows in neotropical rainforest (Ntr C.p.) and in a temperate region (Tp C.p.). In a previous work we showed their hypotensive properties with different potency and toxicity, and now we studied the Tp C.p. effects in isolated heart from rats and central effects of both plants on the open-field test for mice. Tp C.p. produced a positive inotropic effect on isolated rat hearts, which was not affected by 1 microM propranolol, suggesting that it is not due to a beta-adrenergic effect. In contrast, it was prevented by pretreatment with high [K](o) media, which stimulates the Na,K-ATPase pump, suggesting an inhibition of the pump by "ambay", as digital do. In the open-field test, both Ntr C.p. and Tp C.p. similarly decreased the spontaneous locomotion and exploratory behavior of mice at doses between 180 and 600 mg/kg. Ntr C.p. potentiated the effect of 3 mg/kg diazepam to one similar to 10 mg/kg diazepam, but was not antagonized by 0.5 mg/kg flumazenil. Amphetamine at 5 mg/kg prevented the sedative effect of Ntr C.p. Chromatographic analysis showed that both plants have a qualitatively similar fingerprint but quantitatively differed in at least three components. Although the purpose was not to identify them, both plants have at least 10 compounds. Two of them were in higher amount in Tp C.p. than in Ntr C.p., and then, they could be responsible for the cardiovascular toxicity of Tp C.p. In conclusion, the results suggest that ambay has cardiotonic and sedative properties. The sedative effect could be useful in cough treatment. The extract resulted additive to benzodiazepines but it did not bind to the same site on GABA-A receptor, and it was interfered by the dopamine release produced with amphetamine.