RESUMEN
In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine-indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4myc myotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, 12, 14, 15, 16, 19, 27, and 35 demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells. Compound 19 exhibited the highest potency and was selected for in vivo evaluation. A notable reduction of 21.6% (p < 0.01) in blood glucose levels was observed after 5 h of treatment with compound 19 in STZ-induced diabetic rats. Furthermore, pharmacokinetic studies affirmed that compound 19 was favorable to oral exposure with suitable pharmacological parameters. Overall, compound 19 emerged as a promising lead compound for further structural modification and optimization.
Asunto(s)
Diabetes Mellitus Experimental , Dihidropiridinas , Diseño de Fármacos , Transportador de Glucosa de Tipo 4 , Hipoglucemiantes , Indoles , Animales , Transportador de Glucosa de Tipo 4/metabolismo , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Indoles/farmacocinética , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/química , Dihidropiridinas/farmacología , Dihidropiridinas/síntesis química , Dihidropiridinas/química , Dihidropiridinas/uso terapéutico , Dihidropiridinas/farmacocinética , Ratas , Masculino , Relación Estructura-Actividad , Glucemia/análisis , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Línea Celular , Ratas Sprague-DawleyAsunto(s)
Antiinflamatorios , Dihidropiridinas , Modelos Animales de Enfermedad , Células HaCaT , Factor de Necrosis Tumoral alfa , Animales , Ratones , Factor de Necrosis Tumoral alfa/metabolismo , Humanos , Dihidropiridinas/farmacología , Dihidropiridinas/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Acetato de Tetradecanoilforbol/toxicidad , Inflamación/tratamiento farmacológico , Queratinocitos/efectos de los fármacos , Queratinocitos/patologíaRESUMEN
The current study aimed to investigate the anti-atrial fibrillatory (AF) effects of a combination of valsartan and a calcium channel blocker (cilnidipine or amlodipine) in Dahl salt-sensitive (Dahl S) rats. Seven-week-old male Dahl S rats were fed an 8% salt diet. Six weeks later, valsartan (60 mg/kg, Val group), cilnidipine + valsartan (10 + 60 mg/kg, CV group), amlodipine + valsartan (3 + 60 mg/kg, AV group), or vehicle was orally administered daily for 5 weeks. Echocardiography and atrial electrophysiological evaluations were performed on the last day of treatment. Blood pressure in each drug treatment group was lower than in the Vehicle group. The duration of AF induced by atrial burst stimulation was shorter in the Val group (3.2 ± 1.6 s) than in the Vehicle group (11.2 ± 6.0 s), which was further shortened in the CV and AV groups (1.1 ± 0.3 and 1.3 ± 0.3 s, respectively). Left ventricular ejection fraction and left ventricular fractional shortening were greater in the CV and AV groups than those in the Vehicle group. Urinary albumin excretion in the CV group was the lowest among the drug-treated groups. The results collectively suggest that the combination of a calcium channel blocker with valsartan could be useful in terms of its anti-AF action as well as for improving cardiac and renal functions.
Asunto(s)
Presión Sanguínea , Bloqueadores de los Canales de Calcio , Dihidropiridinas , Ratas Endogámicas Dahl , Valsartán , Animales , Valsartán/farmacología , Dihidropiridinas/farmacología , Masculino , Bloqueadores de los Canales de Calcio/farmacología , Presión Sanguínea/efectos de los fármacos , Fibrilación Atrial/tratamiento farmacológico , Quimioterapia Combinada , Riñón/efectos de los fármacos , Ratas , Amlodipino/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacosRESUMEN
Despite the availability of various 11C-labeled positron emission tomography (PET) tracers for assessing P-glycoprotein (P-gp) function, there are still limitations related to complex metabolism, high lipophilicity, and low baseline uptake. This study aimed to address these issues by exploring a series of customized dihydropyridines (DHPs) with enhanced stability and reduced lipophilicity as alternative PET tracers for P-gp dysfunction. Compared with verapamil and the rest DHPs, dimethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1) exhibited superior cellular uptake differences between the human gastric cancer cell line SGC7901 and its drug-resistant counterpart. [18F]1 is successfully synthesized using a novel "hot-Hantzsch" approach in 22.1 ± 0.1 % radiochemical yields. MicroPET/CT imaging demonstrated that the uptake of [18F]1 in the brains of P-gp blocked mice increased by > 3 times compared to the control group. Additionally, [18F]1 displayed favorable lipophilicity (log D = 2.3) and excellent clearance characteristics, making it a promising tracer candidate with low background noise and high contrast.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Dihidropiridinas , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Dihidropiridinas/química , Dihidropiridinas/síntesis química , Dihidropiridinas/farmacología , Humanos , Animales , Radioisótopos de Flúor/química , Ratones , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Línea Celular Tumoral , Estructura Molecular , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacología , Relación Estructura-Actividad , Distribución TisularRESUMEN
The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.
Asunto(s)
Antimaláricos , Dihidropiridinas , Plasmodium falciparum , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Dihidropiridinas/farmacología , Dihidropiridinas/química , Dihidropiridinas/síntesis química , Relación Estructura-Actividad , Plasmodium falciparum/efectos de los fármacos , Animales , Ratones , Estereoisomerismo , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Calcium channel blockers (CCBs) are widely used antihypertensive agents due to their effectiveness in reducing blood pressure (BP), along with their good tolerability and evidence of reducing hypertension (HTN)-related cardiovascular and renal diseases. Cilnidipine, a unique dihydropyridine calcium antagonist, exhibits potent inhibitory action on both N-type and L-type voltage-dependent calcium channels. With excellent oral absorption and a prolonged duration of action, it demonstrates a significant antihypertensive effect. It effectively reduces BP both systolic and diastolic while providing renal, neurological, and cardiovascular protection. Unlike L-type CCBs, cilnidipine does not increase pulse rates (PRs) and is associated with reduced occurrence of pedal edema. Cilnidipine is an effective treatment choice for individuals with mild to moderate essential HTN, whether it is administered alone or in conjunction with other treatment modalities.
Asunto(s)
Antihipertensivos , Bloqueadores de los Canales de Calcio , Dihidropiridinas , Hipertensión , Dihidropiridinas/uso terapéutico , Dihidropiridinas/farmacología , Humanos , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Canales de Calcio Tipo N/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Canales de Calcio Tipo LRESUMEN
Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through ß-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1-filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.
Asunto(s)
Dihidropiridinas , Dinaminas , Gotas Lipídicas , Hígado , Animales , Dinaminas/metabolismo , Humanos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/efectos de los fármacos , Ratones , Células Hep G2 , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Dihidropiridinas/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Dinámicas Mitocondriales/efectos de los fármacos , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacosRESUMEN
BACKGROUND: Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties. AIM: This study aimed to find novel MDR modulators to effectively combat multidrug resistance in cancer cells. OBJECTIVE: We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells. METHODS: Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate. RESULTS: Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity and restoration of cancer cell sensitivity towards the used anticancer drug. CONCLUSION: Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos , Proliferación Celular , Dihidropiridinas , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Dihidropiridinas/farmacología , Dihidropiridinas/química , Dihidropiridinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Resistencia a Antineoplásicos/efectos de los fármacos , Relación Estructura-Actividad , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Estructura Molecular , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009-17.7 µM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.
Asunto(s)
Fármacos Anti-VIH , Dihidropiridinas , VIH-1 , Simulación del Acoplamiento Molecular , Inhibidores de la Transcriptasa Inversa , Triazoles , VIH-1/efectos de los fármacos , Triazoles/química , Triazoles/farmacología , Triazoles/farmacocinética , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Dihidropiridinas/química , Dihidropiridinas/farmacología , Dihidropiridinas/farmacocinética , Relación Estructura-Actividad , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Animales , Masculino , Descubrimiento de Drogas , Estructura Molecular , RatonesRESUMEN
Activated microglia contribute to many neuroinflammatory diseases in the central nervous system. In this study, we attempted to identify an anti-inflammatory compound that could suppress microglial activation. We performed high-throughput screening with a chemical library developed at our institute. We performed a luciferase assay of nuclear factor-kappa B (NF-κB) reporter stable HT22 cells and identified a compound that was confirmed to inhibit the anti-inflammatory response in BV2 microglial cells. The selected dihydropyridine derivative can suppress the expression response of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF), as well as NF-κB phosphorylation and nuclear translocation, and reduce the intracellular calcium level. Thus, our identified compound has a potential role in suppressing microglial activation and may contribute to the development of a new therapeutic molecule against neuroinflammatory diseases.
Asunto(s)
Calcio , Dihidropiridinas , Microglía , FN-kappa B , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratones , FN-kappa B/metabolismo , Calcio/metabolismo , Línea Celular , Dihidropiridinas/farmacología , Fosforilación/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacosRESUMEN
Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.
Asunto(s)
Bloqueadores de los Canales de Calcio , Canales de Calcio Tipo T , Endotelio Vascular , Nifedipino , Nitrofenoles , Humanos , Masculino , Canales de Calcio Tipo T/metabolismo , Canales de Calcio Tipo T/efectos de los fármacos , Anciano , Bloqueadores de los Canales de Calcio/farmacología , Nifedipino/farmacología , Proyectos Piloto , Método Doble Ciego , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Dihidropiridinas/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Compuestos Organofosforados/farmacología , Acetilcolina/farmacología , Pierna/irrigación sanguínea , Nitroprusiato/farmacología , Persona de Mediana EdadRESUMEN
In this study, we designed, synthesized and characterized a novel series of piperidine-dihydropyridine hybrid compounds and characterized them by 1H-NMR, 13C NMR, mass spectrometry (MS), and elemental analysis. Subsequently, we assessed their inâ vitro anticancer potentials against the human breast adenocarcinoma cell line MCF-7 and the lung cancer cell line A-549. Several of these compounds demonstrated significant activity, with IC50 values ranging from 15.94â µM to 48.04â µM for A-549 and 24.68â µM to 59.12â µM for MCF-7, when compared to the reference drug Cisplatin.Notably, a compound featuring a 3-fluoro substitution in the carboxamide series exhibited robust inhibitory effects, with an IC50 of 15.94±0.201â µM against A-549 cells and an IC50 of 22.12±0.213â µM against MCF-7 cells, respectively. Additionally, a compound containing a cyclobutyl ring displayed potent activity, with an IC50 of 16.56±0.125â µM against A-549 and an IC50 of 24.68±0.217â µM against MCF-7 cells, respectively. Furthermore, molecular docking studies against the Epidermal Growth Factor Receptor (EGFR) (PDB ID: 2J6M) revealed favourable binding scores and interactions, suggesting their potential as promising candidates for further investigation in the context of anticancer drug development.
Asunto(s)
Antineoplásicos , Dihidropiridinas , Humanos , Estructura Molecular , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/química , Dihidropiridinas/farmacología , Proliferación Celular , Línea Celular Tumoral , Diseño de FármacosRESUMEN
Benidipine hydrochloride (BH), a medication frequently used by the hypertension patients, acts as a calcium channel blocker. However, its effects on the macrophages have not been investigated thus far. Our goal was investigating the effect of the benidipine hydrochloride to modulate the J774.2 murine macrophage cells inflammatory activity. Our results suggest that in the absence of a standard stimulating agent (LPS) BH did not stimulate the macrophages to produce pro-inflammatory IL-12p40, TNF-α, GM-CSF and IL-6 cytokines. However, when BH was administrated to the cells in the presence of LPS as stimulating agent, it reduced the production of these pro-inflammatory cytokines. Therefore, it had anti-inflammatory activity. At the clinical setting this study suggests that BH can be utilized as hypertension drug that can suppress the inflammation associated with it.
Asunto(s)
Antiinflamatorios , Citocinas , Dihidropiridinas , Lipopolisacáridos , Macrófagos , Animales , Dihidropiridinas/farmacología , Lipopolisacáridos/farmacología , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Antiinflamatorios/farmacología , Línea Celular , Citocinas/metabolismo , Bloqueadores de los Canales de Calcio/farmacologíaRESUMEN
We examined the effects of a dihydropyridine analog, PAK-200, on guinea pig myocardium during experimental ischemia and reperfusion. In isolated ventricular cardiomyocytes, PAK-200 (1 µM) had no effect on the basal peak inward and steady-state currents but inhibited the isoprenaline-induced time-independent Cl- current. In the right atria, PAK-200 had no effect on the beating rate and the chronotropic response to isoprenaline. In an ischemia-reperfusion model with coronary-perfused right ventricular tissue, a decrease in contractile force and a rise in tension were observed during a period of 30-min no-flow ischemia. Upon reperfusion, contractile force returned to less than 50% of preischemic values. PAK-200 had no effect on the decline in contractile force during the no-flow ischemia but reduced the rise in resting tension. PAK-200 significantly improved the recovery of contractile force after reperfusion to about 70% of the preischemic value. PAK-200 was also shown to attenuate the decrease in tissue ATP during ischemia. Treatment of ventricular myocytes with an ischemia-mimetic solution resulted in depolarization of the mitochondrial membrane potential and an increase in cytoplasmic and mitochondrial Ca2+ concentrations. PAK-200 significantly delayed these changes. Thus, PAK-200 inhibits the cAMP-activated chloride current in cardiac muscle and may have protective effects against ischemia-reperfusion injury through novel mechanisms.
Asunto(s)
Dihidropiridinas , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Animales , Cobayas , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Isoproterenol/farmacología , Cloruros/farmacología , Dihidropiridinas/farmacología , Isquemia , Miocitos Cardíacos , Contracción MiocárdicaRESUMEN
La administración crónica de opiáceos induce adaptaciones en las neuronas que dan lugar a la aparición de tolerancia y dependencia a los opiáceos. Se analizaron los cambios en los canales de Ca2 + sensibles a la dihidropiridina (DHP) (de tipo L) asociados con la aparición de tolerancia e hipersensibilidad al efecto antinociceptivo del sufentanil, un agonista de los receptores de opiáceos µ, en el sistema nervioso central (SNC) de la rata. Los estudios autorradiográficos se realizaron con [3H]PN-200-110 (isop ropil 4-(2,1,3-benzoxadiazol-4-il)-1,4-dihidro - 2 , 6-dimetil 5-metoxicarbonilpiridina 3-carboxilato. La infusión s.c. crónica de sufentanil (2 µg . h- 1) durante 7 días, que se ha demostrado que induce tolerancia al efecto antinociceptivo de los opiáceos, produjo un aumento de los sitios de unión de la DHP. Los mayores aumentos de la densidad se localizaron en regiones implicadas en la transmisión y percepción nociceptivas, como el asta dorsal de la médula espinal, el núcleo del rafe dorsal, la sustancia gris central, los núcleos talámicos, y la corteza somatosensorial. Los animales se volvieron hipersensibles al efecto antinociceptivo del sufentanil con la infusión crónica y simultánea de sufentanil (2 µg . h- 1) y nimodipino (1 µg . h- 1) durante 7 días. En esas condiciones, se observó un mayor aumento del número de sitios de unión de la DHP en la médula espinal, la sustancia gris central, el núcleo del rafe dorsal, y la neocorteza somatosensorial, en comparación con el grupo que recibió sufentanil. El presente estudio refuerza el papel de un mayor flujo intracelular del calcio a través de los canales de tipo L en la tolerancia a los opiáceos, mientras que su bloqueo persistente es esencial para la expresión de la hipersensibilidad a los opiáceos (AU)
Asunto(s)
Animales , Masculino , Ratas , Bloqueadores de los Canales de Calcio/farmacología , Sistema Nervioso Central , Dihidropiridinas/farmacología , Sufentanilo/farmacología , Nimodipina/farmacología , Tolerancia a Medicamentos , Hipersensibilidad a las Drogas , Nociceptores , Médula EspinalRESUMEN
Constituyen un grupo importante de medicamentos ampliamente utilzados en la práctica diaria, que farmacológicamente se caracterizan por bloquear los canales lentos del calcio.
Asunto(s)
Bloqueadores de los Canales de Calcio/clasificación , Dihidropiridinas , Dihidropiridinas/efectos adversos , Dihidropiridinas , Dihidropiridinas/farmacología , Diltiazem , Diltiazem/efectos adversos , Diltiazem , Diltiazem/farmacología , Verapamilo , Verapamilo/efectos adversos , Verapamilo , Verapamilo/farmacologíaRESUMEN
Los bloqueadores de los canales de calcio (dihidropiridinas, verapamilo y diltiazem) son medicamentos de amplio uso en la práctica diaria. Sus principales indicaciones son la hipertensión arterial; la insuficiencia coronaria con angor crónico estable y el síndrome de raynaud. En el último tiempo algunas publicaciones han señalado que el empleo de los calcioantagonistas encerraría el riesgo de aumentar la incidencia de eventos coronarios agudos y de elevar la mortalidad, lo que ha creado inquietud en pacientes y médicos. Aparentemente el riesgo se limita sólo al nifedipino corriente cuando se administra en dosis altas (mayores de 60 mg diarios); indiscriminadamente por vía sublingual (Servicios de urgencia) y a pacientes con infartos miocárdicos agudos o angor inestable. El verapamilo, el diltiazem y los nifedipinos de liberación lenta y acción prolongada no tendrían riesgos
Asunto(s)
Humanos , Bloqueadores de los Canales de Calcio/farmacología , Enfermedades Cardiovasculares/tratamiento farmacológico , Dihidropiridinas/farmacología , Diltiazem/farmacología , Verapamilo/farmacologíaRESUMEN
Con el objetivo de detectar viabilidad en la zona de un infarto del miocardio y/o reserva funcional en el tejido residual, se administró 5 mg orales de isradipina, una nueva dihidropiridina antagonista del calcio, a 12 pacientes con antecedentes de un infarto del miocardio. Se realizó una ventriculografía nuclear en reposo antes y 60 minutos después de la isradipina. La fracción de expulsión ventricular izquierda (FEVI) no excedió en ningún caso del 50 por ciento , por lo que un aumento en la motilidad segmentaria afectada fue indicativa de un miocardio en hibernación, mientras que un aumento en la FEVI a expensas de una zona sin afectación segmentaria fue considerado como reserva miocárdica de una segmento isquémico, pero sin necrosis. La media de frecuencia cardíaca, FEVI, y la velocidad máxima de expulsión y llenado aumentaron significativamente con la isradipina, mientras que la presión arterial y el volumen diastólico final disminuyeron. La mitad de los pacientes mejoraron la motilidad segmentaria y la FEVI global
Asunto(s)
Humanos , Masculino , Circulación Coronaria , Contracción Miocárdica , Dihidropiridinas/farmacología , Frecuencia Cardíaca , Función Ventricular Izquierda , Hipotermia Inducida , Infarto del Miocardio , Miocardio , Presión Sanguínea , Ventriculografía con Radionúclidos , Volumen SistólicoRESUMEN
The role of calcium in drug-induced contractions of rat gastric fundus strips was evaluated by determining the effect of two procedures on the dose-respponse curves of agonists: a) removal of calcium from the nutrient solution and b) blockade of calcium channels with the dihydrophydine isradipine. Gastric strips were obtanied from adult Wistar rats and suspended in Tyrode solution at 37-C for contraction studies. Dose-response curves for carbachol (CCh), serotonin (5-HT), KCl and BaCl2 were constructed under the two conditions descrived above. A complete blockade of contractile effects was observed for 5-HT and KCl 60 min after calcium withdrawal of after using 3 mM (45 min) of the calcium antagonist. A lower dose of antagonist or a shorter incubation in calcium-free solution caused a partial decrease of dose-response curves, added to a 30-fold shift to the right after the calcium antagonist (1mM), or a larger than 100-fold shift 3 min after calcium removal. In contrast, dose-response curves for CCh and BaCl2 were not significantly affected by either type of treatment. It is concluded that 5-HT and KCl utilize extracellular sources of calcium, whereas CCh or BaCl2 depends on a tightly-bound calcium pool in this preparation