RESUMEN

We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson's disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.

Asunto(s)

Antioxidantes/farmacología , Benzodiazepinas/farmacología , Encéfalo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Niacina/análogos & derivados , Oxidopamina/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Masculino , Mitocondrias/metabolismo , Niacina/farmacología , Prueba de Campo Abierto/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Células PC12/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Wistar

RESUMEN

The etiology of Parkinson's disease is not completely understood and is believed to be multifactorial. Neuronal disorders associated to oxidative stress and mitochondrial dysfunction are widely considered major consequences. The aim of this study was to investigate the effect of the synthetic arylidenmalonate derivative 5-(3,4-dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (KM-34), in oxidative stress and mitochondrial dysfunction induced by 6-hydroxydopamine (6-OHDA). Pretreatment (2 h) with KM-34 (1 and 10 µM) markedly attenuated 6-OHDA-induced PC12 cell death in a concentration-dependent manner. KM-34 also inhibited H2O2 generation, mitochondrial swelling, and membrane potential dissipation after 6-OHDA-induced mitochondrial damage. In vivo, KM-34 treatment (1 and 2 mg/Kg) reduced percentage of asymmetry (cylinder test) and increased the vertical exploration (open field) with respect to untreated injured animals; KM-34 also reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in substantia nigra pars compacta. These results demonstrate that KM-34 present biological effects associated to mitoprotection and neuroprotection in vitro, moreover, glial response and neuroprotection in SNpc in vivo. We suggest that KM-34 could be a putative neuroprotective agent for inhibiting the progressive neurodegenerative disease associated to oxidative stress and mitochondrial dysfunction.

Asunto(s)

Antioxidantes/uso terapéutico , Catecoles/uso terapéutico , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Oxidopamina/toxicidad , Trastornos Parkinsonianos/prevención & control , Animales , Antioxidantes/farmacología , Catecoles/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Mitocondrias/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Células PC12 , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Ratas , Ratas Wistar

RESUMEN

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1ß levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.

Asunto(s)

Astrocitos/patología , Benzodiazepinas/uso terapéutico , Infarto Encefálico/tratamiento farmacológico , Encéfalo/patología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Neuronas/patología , Niacina/análogos & derivados , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Benzodiazepinas/farmacología , Infarto Encefálico/líquido cefalorraquídeo , Infarto Encefálico/patología , Región CA3 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/metabolismo , Región CA3 Hipocampal/patología , Muerte Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/metabolismo , Gliosis/patología , Infarto de la Arteria Cerebral Media/líquido cefalorraquídeo , Interleucina-10/líquido cefalorraquídeo , Interleucina-1beta/líquido cefalorraquídeo , Masculino , Neuronas/efectos de los fármacos , Niacina/farmacología , Niacina/uso terapéutico , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Resultado del Tratamiento , Ácido gamma-Aminobutírico/líquido cefalorraquídeo

RESUMEN

Ischemic stroke is a major cause of death and disability worldwide. Thrombolysis by tissue plasminogen activator is the only pharmacological treatment approved for clinical practice, but has a narrow therapeutic window and poor efficacy when the cell death cascade is activated. Numerous drugs that are thought to protect neurons against injury have previously failed in human trials despite showing efficacy in experimental models of stroke. Herein, we reviewed the main pre-clinical results of the neuroprotective effects of JM-20, a new hybrid molecule, against brain ischemia. JM-20 appears to protect the brain from ischemic damage by interfering with several elements of the ischemic cascade: antiexcitotoxic, anticalcic, antioxidant, antiapoptotic, and anti-inflammatory. Its ability to protect not only neurons but also glial cells together with its ability to target and preserve mitochondrial function makes JM-20 a promising molecule that may be able to shield the whole neurovascular unit. The multimodal and multi-cell action of JM-20 may explain the high degree of protection observed in a rat model of brain ischemia, as assayed through histological (hematoxylin-eosin, and luxol fast blue staining), neurochemical (glutamate and aspartate levels in cerebrospinal fluid), mitochondrial functionality and behavioural (neurological scale) analysis at doses of 4 and 8mg/kg. Furthermore, the wide therapeutic window of JM-20 of 8h also suggests that this molecule could be of potential interest in situations where brain perfusion is compromised.

Asunto(s)

Benzodiazepinas/farmacología , Isquemia Encefálica/prevención & control , Niacina/análogos & derivados , Animales , Evaluación Preclínica de Medicamentos , Fármacos Neuroprotectores/farmacología , Niacina/farmacología

RESUMEN

Free radicals are important mediators in a number of neurodegenerative diseases and molecules capable of scavenging reactive oxygen species (ROS) may be a feasible strategy for protecting neuronal cells. In this sense, polyphenols have been studied for their antioxidant effects, KM-34 (5-(3, 4-dydroxyl-benzylidene)-2, 2-dimethyl-1, 3-dioxane-4, 6-Dione) is a novel synthetic catechol with potential neuroprotective and antioxidant properties. We have assessed the antioxidant (as scavenging and iron-chelating compound) and neuroprotectant in vitro (in PC12 cell injury induced by H2O2, glutamate or FeSO4/AA) of KM-34. KM-34 was found to be a potent antioxidant, as shown by (i) inhibition of iron induced-brain lipid peroxidation, (ii) inhibition of 2-deoxyribose degradation, (iii) inhibition of superoxide radicals generation (IC50=11.04 µM) and (iv) inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical reduction (IC50=16.26 µM). The overall anti-oxidant action of KM-34 appears to be a combination of a direct reaction with free radicals and chelating the metal ions responsible for the production of ROS. Our work suggests that the antioxidant properties of KM-34 may provide future therapeutic approaches for neurodegenerative disorders.

Asunto(s)

Antioxidantes/farmacología , Catecoles/síntesis química , Catecoles/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas

RESUMEN

This study aims to examine the effects of a new 1,4-dihydropyridine derivative, VdiE-2N, on cell signaling pathways and mitochondrial events in head and neck squamous cell carcinoma (HNSCC) cells, and on a mice model of xenograft tumor growth/cell proliferation. Four HNSCC cell lines (HN13, HN12, HN6, and CAL27), HEK293 cells (human embryonic kidney 293 cells), and human oral healthy mucosa fibroblasts (OHMF) were used for in vitro assessment of cell viability (resazurin assay) and invasion capacity (modified Boyden chamber assay), and mitochondrial membrane potential (JC-1 fluorescence assay), morphology (transmission electron microscopy), and number of mitochondria (MitoTracker® imaging). SET and pDRP1 proteins were analyzed by immunofluorescence, and proteins involved in cell death/survival pathways were analyzed by Western blotting. HN12 xenograft tumors were established in the flank of Balb/c nude mice, and their characteristics and sensitivity to VdiE-2N were determined by immunohistochemistry and histology. VdiE-2N decreased cell viability in HNSCC cells (IC50 = 9.56 and 22.45µM for HN13 and HN12 cells, respectively) more strongly than it decreased cell viability in OHMF and HEK293 cells (IC50 = 32.90 and > 50µM, respectively). In HN13 cells, VdiE-2N dissipated mitochondrial membrane potential and altered the mitochondria size, shape, and number in a concentration-dependent manner, as well as it induced apoptosis and reduced their invasion capacity. Treatment of mice bearing xenograft tumors with VdiE-2N significantly diminished proliferation of cancer cells. Therefore, VdiE-2N induces HNSCC cell death in vitro through mitochondria-mediated apoptotic pathways and dampens tumor growth in vivo, thus supporting a potential anti-cancer effect.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/patología , Dihidropiridinas/química , Dihidropiridinas/farmacología , Neoplasias de Cabeza y Cuello/patología , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc/genética , Neoplasias de Cabeza y Cuello/irrigación sanguínea , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Tamaño Mitocondrial/efectos de los fármacos , Invasividad Neoplásica , Neovascularización Patológica/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Cerebral ischemia is the third most common cause of death and a major cause of disability worldwide. Beyond a shortage of essential metabolites, ischemia triggers many interconnected pathophysiological events, including excitotoxicity, oxidative stress, inflammation and apoptosis. Here, we investigated the neuroprotective mechanisms of JM-20, a novel synthetic molecule, focusing on the phosphoinositide-3-kinase (PI3K)/Akt survival pathway and glial cell response as potential targets of JM-20. For this purpose, we used organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD) to achieve ischemic/reperfusion damage in vitro. Treatment with JM-20 at 0.1 and 10 µM reduced PI incorporation (indicative of cell death) after OGD. OGD decreased the phosphorylation of Akt (pro-survival) and GSK 3ß (pro-apoptotic), resulting in respective inhibition and activation of these proteins. Treatment with JM20 prevented the reduced phosphorylation of these proteins after OGD, representing a shift from pro-apoptotic to pro-survival signaling. The OGD-induced activation of caspase-3 was also attenuated by JM-20 treatment at 10 µM. Moreover, in cultures treated with JM-20 and exposed to OGD conditioning, we observed a decrease in activated microglia, as well as a decrease in interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α release into the culture medium, while the level of the anti-inflammatory IL-10 increased. GFAP immunostaining and IB4 labeling showed that JM-20 treatment significantly augmented GFAP immunoreactivity after OGD, when compared with cultures exposed to OGD only, suggesting the activation of astroglial cells. Our results confirm that JM-20 has a strong neuroprotective effect against ischemic injury and suggest that the mechanisms involved in this effect may include the modulation of reactive astrogliosis, as well as neuroinflammation and the anti-apoptotic cell signaling pathway.

Asunto(s)

Benzodiazepinas/farmacología , Muerte Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Hipocampo/efectos de los fármacos , Niacina/análogos & derivados , Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Animales Recién Nacidos , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Niacina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas Wistar

RESUMEN

JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel benzodiazepine dihydropyridine hybrid molecule, which has been shown to be a neuroprotective agent in brain disorders involving glutamate receptors. However, the effect of JM-20 on the functionality of the glutamatergic system has not been investigated. In this study, by using different in vitro preparations, we investigated the effects of JM-20 on (i) rat brain synaptic vesicles (L-[(3)H]-glutamate uptake, proton gradient built-up and bafilomycin-sensitive H(+)-ATPase activity), (ii) rat brain synaptosomes (glutamate release) and (iii) primary cultures of rat cortical neurons, astrocytes and astrocyte-neuron co-cultures (L-[(3)H]-glutamate uptake and glutamate release). We observed here that JM-20 impairs H(+)-ATPase activity and consequently reduces vesicular glutamate uptake. This molecule also inhibits glutamate release from brain synaptosomes and markedly increases glutamate uptake in astrocytes alone, and co-cultured neurons and astrocytes. The impairment of vesicular glutamate uptake by inhibition of the H(+)-ATPase caused by JM-20 could decrease the amount of the transmitter stored in synaptic vesicles, increase the cytosolic levels of glutamate, and will thus down-regulate neurotransmitter release. Together, these results contribute to explain the anti-excitotoxic effect of JM-20 and its strong neuroprotective effect observed in different in vitro and in vivo models of brain ischemia.

Asunto(s)

Benzodiazepinas/farmacología , Encéfalo/efectos de los fármacos , Ácido Glutámico/metabolismo , Neuronas/efectos de los fármacos , Niacina/análogos & derivados , Vesículas Sinápticas/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Animales , Encéfalo/citología , Encéfalo/metabolismo , Células Cultivadas , Masculino , Neuronas/metabolismo , Niacina/farmacología , Ratas , Ratas Wistar , Vesículas Sinápticas/metabolismo , Sinaptosomas/metabolismo

RESUMEN

Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated the antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria and synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H2O2 generation in both mitochondria and synaptosomes incubated in depolarized (high K(+)) medium at extremely low micromolar concentration and with identical IC50 values of 0.91 µM. JM-20 also repressed glucose-induced H2O2 generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC50 values of 0.395 µM and 2.452 µM, respectively. JM-20 was unable to react directly with H2O2 or with superoxide anion radicals but displayed a cathodic reduction peak at -0.71V, which is close to that of oxygen (-0.8V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca(2+)-induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome c release, which are key pathogenic events during stroke. This molecule also prevented Ca(2+) influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca(2+) observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategies to combat ischemic brain damage.

Asunto(s)

Antioxidantes/farmacología , Benzodiazepinas/farmacología , Calcio/toxicidad , Mitocondrias/efectos de los fármacos , Niacina/análogos & derivados , Prosencéfalo/ultraestructura , Sinaptosomas/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Catalasa/farmacología , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Niacina/farmacología , Oligomicinas/farmacología , Oxígeno/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo

RESUMEN

We previously showed that JM-20, a novel 1,5-benzodiazepine fused to a dihydropyridine moiety, possessed an anxiolytic profile similar to diazepam and strong neuroprotective activity in different cell models relevant to cerebral ischemia. Here, we investigated whether JM-20 protects against ischemic neuronal damage in vitro and in vivo. The effects of JM-20 were evaluated on hippocampal slices subjected to oxygen and glucose deprivation (OGD). For in vivo studies, Wistar rats were subjected 90 min of middle cerebral artery occlusion (MCAo) and oral administration of JM-20 at 2, 4 and 8 mg/kg 1 h following reperfusion. Twenty-four hours after cerebral blood flow restoration, neurological deficits were scored, and the infarct volume, histopathological changes in cortex, number of hippocampal and striatal neurons, and glutamate/aspartate concentrations in the cerebrospinal fluid were measured. Susceptibility to brain mitochondrial swelling, membrane potential dissipation, H2O2 generation, cytochrome c release, Ca2+ accumulation, and morphological changes in the organelles were assessed 24 h post-ischemia. In vitro, JM-20 (1 and 10 µM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to OGD. In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions. JM-20 treatment also protected brain mitochondria from ischemic damage, most likely by preventing Ca2+ accumulation in organelles. Moreover, an 8-mg/kg JM-20 dose reduced glutamate and aspartate concentrations in cerebrospinal fluid and the deleterious effects of MCAo even when delivered 8 h after blood flow restoration. These results suggest that in rats, JM-20 is a robust neuroprotective agent against ischemia/reperfusion injury with a wide therapeutic window. Our findings support the further examination of potential clinical JM-20 use to treat acute ischemic stroke.

Asunto(s)

Benzodiazepinas/farmacología , Isquemia Encefálica/tratamiento farmacológico , Aminoácidos Excitadores/metabolismo , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Niacina/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Modelos Animales de Enfermedad , Glucosa/deficiencia , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Mitocondrias/patología , Mitocondrias/fisiología , Niacina/farmacología , Distribución Aleatoria , Ratas Wistar , Técnicas de Cultivo de Tejidos

RESUMEN

Se prepararon cinco hexahidroquinoleínas por una síntesis en un solo paso, a partir de un aldehído aromático, el ß -aminocrotonato de alquilo (enamina) y dimedona en etanol absoluto como disolvente. Se caracterizaron los efectos de las cinco hexahidroquinoleínas sobre la contractilidad en anillos de aorta de conejo y sobre la contractilidad de músculos papilares de ventrículo derecho de rata, de manera comparativa con la clásica nifedipina. Todas las hexahidroquinoleínas inhibieron la actividad contráctil tanto en músculo liso vascular como en músculo cardíaco, y mostraron efectos característicos de compuestos antagonistas del calcio, aunque con menor potencia de acción que la nifedipina. Sin embargo, dos de las hexahidroquinoleínas estudiadas presentaron cierta vasoselectividad, aunque no marcada(AU)

Asunto(s)

Calcio/antagonistas & inhibidores , Dihidropiridinas , Compuestos Químicos

RESUMEN

Se prepararon cinco hexahidroquinoleínas por una síntesis en un solo paso, a partir de un aldehído aromático, el ß -aminocrotonato de alquilo (enamina) y dimedona en etanol absoluto como disolvente. Se caracterizaron los efectos de las cinco hexahidroquinoleínas sobre la contractilidad en anillos de aorta de conejo y sobre la contractilidad de músculos papilares de ventrículo derecho de rata, de manera comparativa con la clásica nifedipina. Todas las hexahidroquinoleínas inhibieron la actividad contráctil tanto en músculo liso vascular como en músculo cardíaco, y mostraron efectos característicos de compuestos antagonistas del calcio, aunque con menor potencia de acción que la nifedipina. Sin embargo, dos de las hexahidroquinoleínas estudiadas presentaron cierta vasoselectividad, aunque no marcada

Asunto(s)

Calcio , Compuestos Químicos , Dihidropiridinas