RESUMEN
Isatin (indole-dione) is an endogenous indole that exibits a wide range of biological and physiological activity. The influence of isatin derivatives 5-nitroisatin and arbidol (an antiviral preparatation) on spermine NONO-induced activation of human platelet soluble guanylyl cyclase was investigated. 5-nitroistnin and arbidol had no effect on basal activity, but synergistically increased in a concentration-dependent manner the spermine NONO-induced activation of this enzyme. 5-Nitroisatin and arbidol, like YC-1, sensitized guanylyl cyclase towards nitric oxide (NO) and produced a leftward shift of the spermine NONO concentration response curve. At the same time both compounds used did not influence the activation of guanylyl cyclase by YC-1 and did not change the synergistic increase of spermine NONO-induced activation of soluble guanylyl cyclase in the presence of YC-1. This suggests that 5-nitroisanin and arbidol did not compete with YC-1. Addition of isatin did not change the synergistic increase in the spermine NONO-induced guanylyl cyclase activation by 5-nitroisatin and arbidol and did not influence a leftward shift of spermine NONO concentration response curve produced by these compounds. These data suggest lack of competitive interaction between isatin and both its derivatives used.
Asunto(s)
Antivirales/farmacología , Plaquetas/enzimología , Guanilato Ciclasa/metabolismo , Indoles/farmacología , Isatina/análogos & derivados , Isatina/farmacología , Óxido Nítrico/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Adulto , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Guanilil Ciclasa Soluble , Espermina/farmacologíaRESUMEN
Isatin (indole-dione-2,3) is an endogenous indole that exhibits a wide spectrum of biological and pharmacological activities. Physiologically relevant concentrations of isatin (ranged from 1 nM to 10 M) did not influence basal activity of soluble human platelet guanylate cyclase (sGC), but caused a bell-shaped inhibition of the NO-activated enzyme. Inhibition of the NO-dependent activation by isatin did not depend on a chemical nature of the NO donors. The inhibitory effects of ODC (a heme-dependent inhibitor of sGC) and isatin were non-additive suggesting that the inhibitory effect of isatin may involve the heme binding domain (possibly heme iron) and experiments with hemin revealed some isatin-dependent changes in its spectrum. Isatin also inhibited sGC activation by the allosteric activator YC-1. It is suggested that the bell shaped inhibition of the NO-dependent activation of sGC by isatin may be attributed to complex interaction of isatin with the heme binding domain and the allosteric YC-1-binding site of sGC.
Asunto(s)
Plaquetas/enzimología , Guanilato Ciclasa/antagonistas & inhibidores , Isatina/farmacología , Óxido Nítrico/metabolismo , Adulto , Regulación Alostérica/efectos de los fármacos , Plaquetas/citología , Activadores de Enzimas/farmacología , Furanos/farmacología , Guanilato Ciclasa/metabolismo , Hemo/metabolismo , Humanos , Indazoles/farmacología , Masculino , Estructura Terciaria de ProteínaRESUMEN
The influence of antibiotics laevomycetin and tetracycline and the antivirus agent oxolin on the activity of human platelet soluble guanylate cyclase, the stimulation of the enzyme by NO-donors (sodium nitroprusside (SNP) and spermine nanoate (spermine NONO)) and the combination of spermine NONO and YC-1 was investigated. All preparations used in the concentration range 0,1-10 mM had no effect on the basal activity of guanylate cyclase but potentiated the SNP-induced activation of this enzyme. All preparations used synergistically increased (similar to YC-1) spermine NONO-induced activation of soluble guanylate cyclase. At the same time these compounds did not produce the leftward shift of spermine NONO concentration response curve characteristic for YC-1. Moreover, all compounds used did not influence the leftward shift of spermine NONO concentration response curve obtained in the presence of YC-1. This demonstrated that there was no competition between YC-1 and the drugs for interaction with the enzyme. The revealed regulatory phenomen of laevomycetin, tetracycline and oxolin to increase synergistically NO-dependent activation of soluble guanylate cyclase may cause additional pharmacological effects during prolong treatment by these drugs. This fact is necessary taking into account.
Asunto(s)
Plaquetas/efectos de los fármacos , Cloranfenicol/farmacología , Guanilato Ciclasa/metabolismo , Óxido Nítrico/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Tetraciclina/farmacología , Tetrahidronaftalenos/farmacología , Antibacterianos/farmacología , Antivirales/farmacología , Plaquetas/metabolismo , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Guanilato Ciclasa/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Indazoles/farmacología , Donantes de Óxido Nítrico/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Guanilil Ciclasa SolubleRESUMEN
The influence of adrenochrome and YC-1 on spermine NONO-induced activation of human soluble guanylyl cyclase was investigated. Adrenochrome (0.1-10 microM) had no effect on the basal activity, but it potentiated in concentration-dependent manner the spermine NONO-induced activation of this enzyme. Adrenochrome, like YC-1, sensitized guanylyl cyclase towards nitric oxide (NO) and produced the leftward shift of spermine NONO concentration responce curve. Addition of adrenochrome decreased the YC-1-induced leftward shift of spermine NONO concentration response curve. Adrenochrome also inhibited (by 63%) the enzyme activation by YC-1. These data demonstrates the possible competition between adrenochrome and YC-1. Thus, synergistic activation of NO-stimulated guanylyl cyclase activity by adrenochrome represents a new biochemical effect of this compound and indicates that adrenochrome may act as an endogenous regulator of NO-dependent stimulation of soluble guanylyl cyclase. This new property of adrenochrome, similar to YC-1, is necessary taking into account, especially under conditions of overproduction of adrenochrome in organism.
Asunto(s)
Adrenocromo/metabolismo , Activadores de Enzimas/farmacología , Guanilato Ciclasa/metabolismo , Indazoles/farmacología , Óxido Nítrico/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Plaquetas/enzimología , Sinergismo Farmacológico , Activación Enzimática , Humanos , Técnicas In Vitro , Donantes de Óxido Nítrico/farmacología , Guanilil Ciclasa Soluble , Espermina/análogos & derivados , Espermina/farmacologíaRESUMEN
The influence of polyamines (putrescine, spermidine, spermine) on the activity of human platelet soluble guanylate cyclase and stimulation of the enzyme by sodium nitroprusside, YC-1 and their combination was investigated. All polyamines used stimulated the guanylate cyclase activity and potentiated its activation by sodium nitroprusside. The stimulatory effects of sodium nitroprusside and putrescine (or spermine) were additive; spermidine produced a synergistic activation and increased the additive effect. All polyamines investigated inhibited the activation of the enzyme by YC-1 and decreased the synergistic activation of sodium nitroprusside-stimulated guanylate cyclase activity by YC-1 with approximately the same efficiency. The revealed ability of polyamines investigated to potentiate and synergistically increase (similar to YC-1, but less effective) NO-dependent activation of soluble guanylate cyclase represents a new biochemical effect of these compounds, which should be taken into consideration, especially due to the endogenous nature of polyamines. The data obtained suggest, that the specific functions of polyamines in the processes of cell growth and diffentiation may be also related to the ability of these compounds to activate soluble guanylate cyclase and increase cGMP level.