RESUMEN
Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells from various stresses is the heat-shock response which results in the induction of the synthesis of heat-shock proteins (HSPs or stress proteins). A large body of information supports that stress proteins--many of them molecular chaperones--are crucial for the maintenance of cell integrity during normal growth as well as during pathophysiological conditions, and thus can be considered "homeostatic proteins." Recently emphasis is being placed on the potential use of these proteins in preventing and/or treating diseases. Therefore, it would be of great therapeutic benefit to discover compounds that are clinically safe yet able to induce the accumulation of HSPs in patients with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamine derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboximidoil-chloride maleate, Bimoclomol, facilitates the formation of chaperone molecules in eukaryotic cells by inducing or amplifying expression of heat-shock genes. The cytoprotective effects observed under several experimental conditions, including a murine model of ischemia and wound healing in the diabetic rat, are likely mediated by the coordinate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applications.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/biosíntesis , Corazón/efectos de los fármacos , Proteínas de Choque Térmico/biosíntesis , Imidas/farmacología , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Piridinas/farmacología , Transcripción Genética/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Línea Celular , Diabetes Mellitus Experimental/fisiopatología , Embrión de Mamíferos , Proteínas HSP70 de Choque Térmico/genética , Células HeLa , Corazón/fisiología , Corazón/fisiopatología , Trastornos de Estrés por Calor , Humanos , Técnicas In Vitro , Luciferasas/biosíntesis , Masculino , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Proteínas Recombinantes de Fusión , Piel/efectos de los fármacos , Piel/patología , TransfecciónRESUMEN
GYKI-23 107 is a new antiarrhythmic substance with local anaesthetic activity. Its specific pharmacological and cardiovascular effects were studied in vivo and its efficacy was compared with that of lidocaine and mexiletine. GYKI-23 107 was effective against chemically (aconitine and ouabain) induced arrhythmias after both parenteral and oral administration. In aconitine-induced arrhythmia in mice the new compound was more active than either mexiletine or lidocaine after i.p. treatment. In ouabain-induced arrhythmia in dogs, the ED50 of GYKI-23 107 was approximately half that of mexiletine after i.v. injection. GYKI-23 107 and mexiletine produced similar elevation of the fibrillation threshold in anaesthetized cats. After oral pretreatment, GYKI-23 107 showed protective effects against coronary ligation-induced arrhythmia in conscious rats. The circulatory side-effects of GYKI-23 107 in anaesthetized and conscious dogs and cats were milder then those of mexiletine. In the antiarrhythmic dose range there were no adverse cardiovascular actions.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Propilaminas/uso terapéutico , Aconitum , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/inducido químicamente , Gatos , Fenómenos Químicos , Química , Perros , Femenino , Hemodinámica/efectos de los fármacos , Lidocaína/uso terapéutico , Masculino , Mexiletine/uso terapéutico , Ratones , Ouabaína , Propilaminas/farmacología , RatasRESUMEN
GYKI-32 887 reveals an antihypertensive action, similar to that of the known ergoline derivatives, in conscious SH-rats, in anesthetized normotensive rats, and in cats. It exerts its action first of all by stimulation of the central DA-receptors and by this it reduces the sympathetic activity. The hypotensive effect cannot be detected after icv administration, but both the hypotension and bradycardia can be antagonized by sulpiride administered either icv or iv.
Asunto(s)
Presión Sanguínea , Receptores Dopaminérgicos/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Ergolinas/administración & dosificación , Ergolinas/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Endogámicas SHR , Receptores Dopaminérgicos/efectos de los fármacos , Sulpirida/farmacologíaRESUMEN
Using the pithed rat preparation it has been proven that GYKI-12743 exerted its alpha-adrenergic blocking action only at the postsynaptic vascular level in the cardiovascular system. This new molecule failed to antagonize the presynaptic alpha 2-adrenoceptors of the cardiac sympathetic nerve endings. Thereby it was possible to demonstrate the first vasoselective postsynaptic adrenoceptor antagonist which potentially might be interesting in the cardiovascular therapy.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Presión Sanguínea/efectos de los fármacos , Dioxanos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Piridazinas/farmacología , Animales , Azepinas/farmacología , Clonidina/farmacología , Estado de Descerebración , Estimulación Eléctrica , Idazoxan , Fentolamina/farmacología , Fenilefrina/farmacología , Ratas , Ratas Endogámicas , Yohimbina/farmacologíaRESUMEN
The cardiovascular effects of morphine and a potent enkephalin analogue, D-Met2, Pro5-enkephalinamide (D-Met2, Pro5-EA) have been examined in pentobarbitone anesthetized cats with their vagi cut and in awake normotensive and genetically hypertensive rats. In cats both opioids only moderately decreased the blood pressure and the heart rate, but the enkephalin analogue considerably attenuated the carotid occlusion pressor response. Neither substance influenced the blood pressure and the heart rate in normotensive rats, but both induced moderate hypotension and considerable bradycardia in spontaneously hypertensive rats, the potency of D-Met2, Pro5-EA being much stronger than that of morphine. These observations confirm the conclusions from the literature that, under physiological conditions, endorphins play no primary role in the regulation of the cardiovascular functions but they might be mobilized in certain cases of pathological elevation of the blood pressure probably as a part of a compensatory process.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Encefalina Metionina/análogos & derivados , Frecuencia Cardíaca/efectos de los fármacos , Anestesia , Animales , Gatos , Encefalina Metionina/farmacología , Femenino , Masculino , Morfina/farmacología , Naloxona/farmacología , RatasRESUMEN
[1,4]Benzodioxanylmethyl-, [1,4]benzodioxanylmethylaminopropyl- and phenoxyethylaminoethyl-substituted lactams were synthesised and their hypotensive activity was investigated. Some of these compounds show moderate to high hypotensive effect, but they had more toxic and/or side effects than GYKI-12 743.
Asunto(s)
Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Dioxanos/síntesis química , Dioxanos/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , GatosRESUMEN
Effects of bimoclomol, the novel heat shock protein (HSP) coinducer, was studied in various mammalian cardiac and rabbit aortic preparations. Bimoclomol decreased the ST-segment elevation induced by coronary occlusion in anesthetized dogs (56% and 80% reduction with 1 and 5 mg/kg, respectively). In isolated working rat hearts, bimoclomol increased coronary flow (CF), decreased the reduction of cardiac output (CO) and left ventricular developed pressure (LVDP) developing after coronary occlusion, and prevented ventricular fibrillation (VF) during reperfusion. In rabbit aortic preparations, precontracted with phenylephrine, bimoclomol induced relaxation (EC(50)=214 microM). Bimoclomol produced partial relaxation against 20 mM KCl, however, bimoclomol failed to relax preparations precontracted with serotonin, PGF(2) or angiotensin II. All these effects were evident within a few minutes after application of bimoclomol. A rapid bimoclomol-induced compartmental translocation of the already preformed HSPs may explain the protective action of the compound.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Enfermedad Coronaria/complicaciones , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Perros , Electrocardiografía , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Imidas/farmacología , Isquemia/complicaciones , Masculino , Modelos Animales , Contracción Miocárdica/efectos de los fármacos , Piridinas/farmacología , Conejos , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
The neuroprotective effect of BGP-15 against peripheral sensory neuropathy was studied in rats that were exposed to short-term cisplatin or taxol administration. The changes of nerve conduction velocity were determined in situ after treating the Wistar rats with BGP-15 (50, 100, and 200 mg/kg po daily doses throughout the experiment), cisplatin (1.5 mg/kg ip daily dose for 5 days), or taxol (5.0 mg/kg ip daily dose every other day in a 10-day interval) alone or giving the test compound in combination with cisplatin or taxol. Electrophysiological recordings were carried out in vivo by stimulating the sciatic nerve at both sciatic notch and ankle site. Neither motor nor sensory nerve conduction velocity was altered by any dose level of BGP-15 tested. Both anticancer drugs decreased the sensory nerve conduction velocity (SNCV). BGP-15 treatment prevented the impairment of SNCV either in part or totally in the cisplatin- or taxol-treated groups. This neuroprotective potential of BGP-15 could be well correlated with its recently described poly(ADP-ribose) polymerase- inhibitory effect and its ability to protect against the damages induced by the increased level of reactive oxygen species in response to anticancer treatment.