RESUMEN
The effects of the Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the cardioselective beta 1-adrenergic blocking agent atenolol (AT) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two hours after single oral administration, atenolol (150 mg/kg) did not change hexobarbital sleeping time, while nifedipine (50 mg/kg) and diltiazem (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadministration of atenolol with diltiazem or with nifedipine significantly prolonged hexobarbital sleep by 205 and 283%, respectively. Administered alone, atenolol decreased the ethylmorphine-N-demethylase (EMND) activity, but the amidopyrine-N-demethylase (APND) activity was not changed in any of the treated groups. Atenolol and nifedipine significantly increased aniline-4-hydroxylase (AH) activity and this effect was also observed with the combinations AT + NF and AT + DL. The NADPH cytochrome P-450 reductase activity was significantly decreased by nifedipine and diltiazem. Only nifedipine increased the total content of cytochrome P-450 (by 23.8%). Atenolol and diltiazem tended to increase the content of cytochrome b5 which was increased by nifedipine by 97.6%. The same effect was observed with the combinations AT + NF and AT + DL. The results suggest that NF, AT + NF and AT + DL produced the manifested changes in hepatic oxidative metabolism. The decreased EMND activity by atenolol, however, and the prolongation of hexobarbital sleeping time by nifedipine, diltiazem and their coadministration with atenolol did not correlate with enhanced microsomal P-450 and b5 content.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Hígado/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Oxidorreductasas/efectos de los fármacos , Aminopirina N-Demetilasa/efectos de los fármacos , Aminopirina N-Demetilasa/metabolismo , Anilina Hidroxilasa/efectos de los fármacos , Anilina Hidroxilasa/metabolismo , Animales , Atenolol/administración & dosificación , Atenolol/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos b5/efectos de los fármacos , Citocromos b5/metabolismo , Diltiazem/farmacología , Quimioterapia Combinada , Etilmorfina-N-Demetilasa/efectos de los fármacos , Etilmorfina-N-Demetilasa/metabolismo , Hexobarbital/farmacología , Hipnóticos y Sedantes/farmacología , Hígado/enzimología , Masculino , Microsomas Hepáticos/enzimología , NADPH-Ferrihemoproteína Reductasa/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Nifedipino/farmacología , Oxidorreductasas/metabolismo , Ratas , Ratas WistarRESUMEN
The effects of two Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the nonselective beta-adrenergic blocking agent propranolol (PR) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two h after single oral administration PR (50 mg/kg) did not change HB sleeping time, while NF (50 mg/kg) and DL (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadmistration of PR with DL or with NF significantly prolonged HB sleep by 240.7 and 129%, respectively. Only NF increased aniline 4-hidroxylase (AH) activity (by 92%) and the total P-450 content (by 24%). PR and NF increased cytochrome b5 content and this effect was also observed with the combinations PR + NF (by 109%) and PR + DL (by 102%). The NADPH cytochrome P-450 reductase activity was significantly decreased by NF and DL and after their combination with PR. The ethymorphine-N-demethylase (EMND) and amidopyrine-N-demethylase (APND) activities were not changed. The effects of PR, NF and DL administrated alone or in combination on liver oxidative metabolism are considered as possible mechanisms of drug interactions.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Hígado/efectos de los fármacos , Propranolol/farmacología , Aminopirina N-Demetilasa/efectos de los fármacos , Aminopirina N-Demetilasa/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos b5/efectos de los fármacos , Citocromos b5/metabolismo , Diltiazem/farmacología , Etilmorfina-N-Demetilasa/efectos de los fármacos , Etilmorfina-N-Demetilasa/metabolismo , Hexobarbital/farmacología , Hipnóticos y Sedantes/farmacología , Hígado/enzimología , Masculino , NADPH-Ferrihemoproteína Reductasa/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Nifedipino/farmacología , Ratas , Ratas Wistar , Sueño/efectos de los fármacosRESUMEN
The effect of nitrendipine on desensitization of beta-adrenoceptors induced by isoprenaline was investigated using rat lungs. Rats were treated with saline, isoprenaline, nitrendipine, or nitrendipine + isoprenaline. After 7 days of treatment, tracheas were isolated and the dissociation constant (Kb) for the propranolol-beta-receptor complex was determined. Lung parenchymal tissue was used to study the binding characteristics of beta-adrenoceptors. The Kb value for the propranolol-beta-receptor complex was found to be up to 6.4-fold higher in trachea isolated from isoprenaline-treated rats (32 +/- 5.4 nM) than from control rats (4.9 +/- 1.2 nM); the Kb value for trachea from isoprenaline + nitrendipine-treated rats was 7.0 +/- 1.2 nM. A 31% reduction in the number of beta-adrenoceptors as compared to those of the control group was observed in the isoprenaline-treated group while the number of the beta-adrenoceptors in the isoprenaline + nitrendipine-treated group was significantly increased as compared to that of the isoprenaline-treated group.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Isoproterenol/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Nitrendipino/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Simpatomiméticos/antagonistas & inhibidores , Tráquea/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Animales , Carbacol/farmacología , Interacciones Farmacológicas , Isoproterenol/farmacología , Pulmón/metabolismo , Masculino , Parasimpaticomiméticos/farmacología , Propranolol/farmacología , Ratas , Ratas Wistar , Receptores Adrenérgicos beta/metabolismo , Simpatomiméticos/farmacología , Tráquea/metabolismoRESUMEN
This study was designed to examine the calcium channel blockers flunarizine and nitrendipine for their ability to prevent electroconvulsive shock (ECS)- or clonidine-induced deterioration of the inhibitory avoidance performance (step-down) in rats. Flunarizine (10 mg/kg) and nitrendipine (40 mg/kg) were found to prevent the ECS- or clonidine-provoked amnesia after oral administration for 12 days. The mechanisms of action of the two drugs are considered. The results of this study further suggest that calcium antagonists might be useful in the treatment of cognitive disorders.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Flunarizina/farmacología , Memoria/efectos de los fármacos , Nitrendipino/farmacología , Agonistas alfa-Adrenérgicos/toxicidad , Animales , Reacción de Prevención/efectos de los fármacos , Clonidina/toxicidad , Electrochoque/efectos adversos , Masculino , Memoria/fisiología , Ratas , Ratas WistarRESUMEN
The effects of the beta-adrenoceptor blocker pindolol and the calcium antagonist verapamil administered alone or in combination on retention in step-down- and shuttle-box-trained rats and on the biogenic monoamine levels in the frontal cortex and hippocampus were examined. The chronic oral treatment with pindolol impaired retention in step-down- and shuttle-box-trained rats, decreasing the dopamine (DA) and noradrenaline (NA) levels and increasing the serotonin (5-HT) levels in the cortex and hippocampus. Verapamil did not influence retention in step-down- and shuttle-box avoidance situation and the biogenic monoamine levels in the frontal cortex and hippocampus. It should, however, be noted that the chronic oral treatment with verapamil completely abolished the retention-impairing effect of pindolol, restoring to normal DA, NA and 5-HT levels. These findings might be of interest to clinical practice and suggest the necessity for using a combination of beta-blockers with Ca2+ antagonists in case of prolonged treatment of cardiovascular diseases.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Reacción de Prevención/efectos de los fármacos , Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Memoria/efectos de los fármacos , Animales , Encéfalo/metabolismo , Dopamina/metabolismo , Antagonismo de Drogas , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Norepinefrina/metabolismo , Pindolol/farmacología , Ratas , Ratas Wistar , Serotonina/metabolismo , Verapamilo/farmacologíaRESUMEN
The latency time and escape ability of rats with learned helplessness behavior were studied after 1, 6 and 14 days of oral treatment with beta-adrenergic blockers propranolol (1 and 3 mg/kg) and acebutolol (10 and 30 mg/kg). A dose-dependent significant decrease in latency time and increase in number of avoidances was established after single, 6 and 14 days propranolol treatment. The selective beta 1-blocker acebutolol did not change the escape characteristics. These results suggest a greater impact of beta 1- than beta 2-adrenergic receptors for escape performance after unescapable foot shock, i.e., learned helplessness behavior.
Asunto(s)
Acebutolol/farmacología , Antagonistas Adrenérgicos beta/farmacología , Conducta Animal/efectos de los fármacos , Desamparo Adquirido , Propranolol/farmacología , Estrés Fisiológico/complicaciones , Acebutolol/administración & dosificación , Antagonistas Adrenérgicos beta/administración & dosificación , Animales , Reacción de Prevención/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dosificación Letal Mediana , Masculino , Propranolol/administración & dosificación , Ratas , Ratas WistarRESUMEN
Male Wistar rats were exposed to Pb2+ or Zn2+ and to Pb2+ + Zn2+, receiving Pb(CH3COO)2 or/and ZnSO4 with drinking water for 30 days. Cumulative concentration-effect curves for carbachol were obtained in ileum and trachea isolated from control and heavy metal-treated rats. The effect of the Ca2+ channel blockers on the carbachol-induced contractions was studied by addition of increasing concentrations of verapamil or nitrendipine to the bath solution 20 min. prior to carbachol. The results showed that exposure of rats to heavy metals in doses which did not change the body weight and behaviour, altered the contractile responses to carbachol. The sensitivity to carbachol was higher in preparations from the ileum of Zn(2+)-exposed rats as compared to controls, while a tendency towards decreasing this sensitivity was observed in ileal preparations from Pb(2+)-treated animals. The concentration-effect curves for carbachol in ileal preparations from Pb2+ + Zn(2+)-treated rats did not differ from those in the preparations from untreated rats. The inhibitory effect of the Ca2+ channel blockers on the contractility of ileal and tracheal preparations from treated rats was weaker as compared to that in controls.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Carbacol/farmacología , Plomo/toxicidad , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Zinc/toxicidad , Animales , Combinación de Medicamentos , Masculino , Músculo Liso/efectos de los fármacos , Nitrendipino/farmacología , Ratas , Ratas Wistar , Verapamilo/farmacologíaRESUMEN
Subchronic (30 days) exposure of rats to Co(NO3)2 or NiSO4 (20 mg.kg-1) in drinking water caused suppression of the isolated vas deferens contractile responses to exogenous adenosine 5'-triphosphate (ATP), noradrenaline, and l-phenylephrine, shifting the concentration-response curves to the relevant agonist to the right. Both metals facilitated the alpha 1-adrenoceptor antagonistic effects of prazosin, which resulted in increased pA2 values for the drug (9.68 +/- 0.13 in controls vs. 10.15 +/- 0.12 in Co(2+)-treated preparations and 12.60 +/- 0.67 in Ni(2+)-treated preparations). The inhibitory effect of clonidine on the contractions in response to low-frequency electrical field stimulation (EFS) in metal-treated preparations was decreased with pD2 values: 10.52 +/- 0.04 in controls, 9.56 +/- 0.13 in Co(2+)-treated preparations and 9.92 +/- 0.16 in Ni(2+)-treated preparations. The monophasic contractile responses to low-frequency EFS (0.1 Hz, 1 ms, 80 V) as well as the first phase of the biphasic contractions after high-frequency long-lasting EFS (300 pulses, 0.1 ms, 40 V, at 4, 8 or 20 Hz) were significantly increased in both groups of heavy metal-treated preparations. Therefore, subchronic exposure to Co2+ or Ni2+ leads to changes in pre- and postjunctional mechanisms underlying the sympathetically mediated contractile activity of isolated rat vas deferens.
Asunto(s)
Cobalto/administración & dosificación , Contracción Muscular/efectos de los fármacos , Níquel/administración & dosificación , Receptores Adrenérgicos/efectos de los fármacos , Receptores Purinérgicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Conducto Deferente/fisiología , Adenosina Trifosfato/farmacología , Animales , Estimulación Eléctrica , Masculino , Norepinefrina/farmacología , Fenilefrina/farmacología , Ratas , Ratas Wistar , Conducto Deferente/efectos de los fármacos , Yohimbina/farmacologíaRESUMEN
Male Wistar rats were exposed to subtoxic doses of Co2+ or Ni2+, receiving Co(NO3)2 or NiSO4 with drinking water for 30 days. No significant differences in the body weight and no visible changes in the behaviour of the controls and experimental animals were established. Cumulative concentration-effect curves for carbachol were obtained in ileum and trachea isolated from control and Co(2+)- or Ni(2+)-treated rats. The effect of the Ca2+ antagonists on the carbachol-induced contractions was studied by adding increasing concentrations of verapamil or nitrendipine to the bath solution 20 min prior to carbachol. The results showed that exposure of rats to subtoxic doses of Co(NO3)2 or NiSO4 altered the contractile responses to carbachol. The changes in the pD2 values and the shift to the left of the concentration-effect curves suggest a higher sensitivity to carbachol in preparations from the ileum of Co(2+)- or Ni(2+)-exposed rats. The tracheal strips isolated from control and heavy metal-treated rats showed a less potent sensitiveness to carbachol as compared to the ileal segments. An opposite tendency for decreased cholinergic reactivity was observed in tracheal strips from Co(2+)- and Ni(2+)-treated animals. The inhibitory effect of the Ca(2+)-antagonists on the contractility of ileal preparations from Co(2+)-treated rats increased at all concentrations of verapamil and at the highest concentration of nitrendipine, but decreased at lower concentrations of nitrendipine. The effect of verapamil on the preparations from Ni(2+)-exposed rats was unchanged or even decreased at higher verapamil concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Carbacol/farmacología , Cobalto/farmacología , Músculo Liso/efectos de los fármacos , Níquel/farmacología , Nitrendipino/farmacología , Verapamilo/farmacología , Animales , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Tráquea/efectos de los fármacosRESUMEN
The effects of subchronic (30 days) drinking water exposure of rats to ZnSO4 or Pb(CH3COO)2 alone or in combination on the adrenergically-mediated contractile responses of isolated vas deferens were studied. The contractile effects of the alpha 1, alpha 2-adrenoceptor agonist noradrenaline (NA) and to the alpha 1-adrenoceptor agonist 1-phenylephrine (1-PhE) were decreased after zinc exposure, whereas after lead exposure or lead plus zinc exposure they were not changed. The contractile responses to field electrical stimulation (FES, 0.1 Hz, 1 msec, 80 V) were diminished in amplitude in all metal-treated preparations as compared to controls. The yohimbine-induced restoration of the clonidine inhibited contractions in response to FES was decreased in both lead- and zinc-treated preparations, the EC50 for yohimbine being 0.018 +/- 0.001 microM in control preparations, 0.073 +/- 0.019 microM in lead-treated preparations and 0.056 +/- 0.021 microM in zinc-treated preparations. The calcium-channel blocker verapamil was found to inhibit at low concentrations and to increase at higher concentrations the FES-induced contractile responses in preparations from zinc-exposed rats. The inhibitory effect of cumulatively applied nitrendipine on the FES-induced contractions was increased in both lead- and zinc-treated smooth muscles, but was not altered in the preparations from lead plus zinc-treated rats. Therefore, subchronic exposure to subtoxic doses of lead of zinc led to different changes in the adrenergically-mediated contractility of isolated vas deferens. The changes induced by zinc exposure were not observed after lead plus zinc exposure. All these findings might be of pharmacological, toxicological or clinical importance.
Asunto(s)
Plomo/farmacología , Músculo Liso/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Sulfatos/farmacología , Conducto Deferente/efectos de los fármacos , Compuestos de Zinc/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 2 , Animales , Clonidina/farmacología , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Nitrendipino/farmacología , Norepinefrina/farmacología , Fenilefrina/farmacología , Ratas , Ratas Wistar , Conducto Deferente/fisiología , Verapamilo/farmacología , Yohimbina/farmacología , Sulfato de ZincRESUMEN
1. The relationship between endothelin-1(ET-1)-induced effects on the contractile responses of epididymal portion of rat vas deferens elicited by field electrical stimulation (FES: 80 V, 1 msec, 0.1 Hz) and the effects of the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine were studied. 2. ET-1 (0.01 nM-0.1 microM) concentration-dependently increased the FES-induced contractions. 3. ET-1 (0.1 nM-0.1 microM) reversed the inhibitory effect of clonidine on the FES-evoked contractions whereas ET-1 applied before clonidine exerted a dual effect on the clonidine-induced inhibition of the FES-evoked contractions. 4. The ET-1-induced enhancement of FES-induced contractions was potentiated in the presence of 1 microM yohimbine and was not observed at all in the presence of 10 microM yohimbine. Yohimbine, applied at concentrations of 1 and 10 microM exerted similar blocking effects on the alpha 1-adrenoceptor agonistic effects of phenylephrine. However, yohimbine at a concentration of 10 microM markedly potentiated the contractile effect of exogenous adenosine 5'-triphosphate (ATP), 30 microM. Tetrodotoxin abolished this effect of yohimbine. 5. The results presented here suggest the existence of modulating interactions between the ET-1-evoked increase of FES-induced contractions of rat vas deferens and the alpha 2-adrenoceptor drugs clonidine and yohimbine.
Asunto(s)
Clonidina/farmacología , Endotelinas/farmacología , Músculo Liso/efectos de los fármacos , Yohimbina/farmacología , Adenosina Trifosfato/farmacología , Animales , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Fenilefrina/farmacología , Ratas , Ratas Endogámicas , Conducto Deferente/efectos de los fármacosRESUMEN
Some pharmacokinetic interactions between digoxin and amiodarone were studied in experiments on rabbits. An increase of digoxin serum levels was established in amiodarone-treated rabbits (amiodarone 30 mg/kg s.c. for five days alone or together with digoxin). The calculated elimination half-life (t 1/2) and the area under the curve (AUC) of digoxin were increased and the digoxin clearance was decreased, being most pronounced in animals receiving amiodarone-digoxin combination for five days. There were no changes either in digoxin toxicity in amiodarone-treated guinea pigs or in serum levels of T4, T3 and TTH. The possible mechanisms of digoxin-amiodarone interactions are discussed.
Asunto(s)
Amiodarona/farmacología , Digoxina/farmacocinética , Animales , Digoxina/sangre , Digoxina/toxicidad , Interacciones Farmacológicas , Cobayas , Radioisótopos de Yodo , Masculino , Conejos , Tiroxina/sangreRESUMEN
The effects of the organic Ca2+ antagonists nitrendipine, verapamil and diltiazem on the cholinergic contractile responses induced by field electrical stimulation or carbachol (0.1 microM) and on contractions evoked by high concentration KCl (30 mM) were studied in isolated preparations from the guinea-pig ileum. The three Ca2+ antagonists dose-dependently suppressed the contractile responses showing the same order of potency (nitrendipine greater than verapamil greater than diltiazem) with the three different types of stimulation. Comparison of the IC50 values of the Ca2+ antagonists for carbachol-, KCl- and electrically-evoked contractions demonstrated that the carbachol-evoked contractions were most sensitive to the inhibitory action of the antagonists tested. The presynaptic inhibitory effect of (Met)enkephalin (10 nM) on the electrically-evoked cholinergic contractions was only slightly potentiated by high concentrations (1 or 10 microM) of nitrendipine and diltiazem and remained unchanged by verapamil. The results suggest that the Ca2+ antagonists tested block mainly the carbachol-activated L-type Ca2+ channels on the smooth muscle cells, while the effects on the N-type Ca2+ channels are insignificant, except for the high concentrations of nitrendipine and diltiazem.
Asunto(s)
Carbacol/farmacología , Diltiazem/farmacología , Músculo Liso/efectos de los fármacos , Nitrendipino/farmacología , Verapamilo/farmacología , Animales , Estimulación Eléctrica , Encefalina Metionina/farmacología , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Cloruro de Potasio/farmacologíaRESUMEN
1. The binding characteristics (Bmax and Kd) of the alpha-adrenoceptor radioligand [3H] WB4101 in crude membrane fraction (fraction P2) from cerebral cortex were studied after 13-day oral treatment of male Wistar rats with the Ca(2+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin-antagonist trifluoperazine (TFP) (3 mg/kg). 2. A significant reduction of the binding sites (Bmax) for [3H] WB4101 was established after the three Ca(2+)-antagonists as well as after TFP treatment. 3. Different changes in the affinity constant (Kd) of brain adrenoceptors were observed depending on the type of the Ca2+ or CaM-antagonist used: nifedipine did not change the Kd value, verapamil and TFP decreased whereas flunarizine increased the Kd value. 4. Relationships between Ca ions and alpha-adrenoceptor functions are suggested.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Corteza Cerebral/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Trifluoperazina/farmacología , Administración Oral , Animales , Bloqueadores de los Canales de Calcio/administración & dosificación , Calmodulina/antagonistas & inhibidores , Corteza Cerebral/metabolismo , Dioxanos/metabolismo , Flunarizina/administración & dosificación , Flunarizina/farmacología , Masculino , Nifedipino/administración & dosificación , Nifedipino/farmacología , Ratas , Ratas Endogámicas , Receptores Adrenérgicos alfa/metabolismo , Análisis de Regresión , Trifluoperazina/administración & dosificación , Verapamilo/administración & dosificación , Verapamilo/farmacologíaRESUMEN
Some pharmacokinetic and pharmacodynamic interactions between digoxin and gentamicin were studied in experiments on rabbits, guinea-pigs and cats. An increase of digoxin serum levels and changes in some basic pharmacokinetic parameters of digoxin (t1/2 alpha t1/2 beta, AUC, C1) were found in gentamicin-pretreated rabbits, the changes being dependent on the dose and schedule of administration. The most pronounced changes were those in digoxin kinetics during simultaneous 5-day treatment with digoxin (0.035 mg/kg i.v.) and nontoxic (10 and 2 mg/kg) doses of gentamicin. The toxicity of digoxin in guinea-pigs, assessed by administration of lethal doses of digoxin, was increased only after the highest dose of gentamicin (100 mg/kg), while after nontoxic or close to therapeutic doses (10 and 2 mg/kg) of gentamicin, the digoxin toxicity was either unchanged or even decreased. Digoxin decreased the nerve-muscle blocking effect of gentamicin on cat ischiadicus-gastrocnemius preparation. The possible mechanisms involved are discussed.
Asunto(s)
Digoxina/farmacología , Digoxina/farmacocinética , Gentamicinas/farmacología , Animales , Gatos , Digoxina/toxicidad , Interacciones Farmacológicas , Femenino , Cobayas , Riñón/efectos de los fármacos , Masculino , Unión Neuromuscular/fisiología , Conejos , Transmisión Sináptica/efectos de los fármacosRESUMEN
1. The modulatory action of histaminergic drugs: histamine; 2-(2-aminoethyl)thiazole (H1-agonist); dimaprit (H2-agonist); diphenhydramine (H1-receptor antagonist); and cimetidine (H2-receptor antagonist) on rat vas deferens contractions induced by electrical field stimulation (0.1 Hz, 1 pulse, 1 msec duration, supramaximal voltage) was studied either at different calcium concentrations in the nutrient fluid or after verapamil. 2. Histamine and 2-(2-aminoethyl)thiazole inhibited the electrically-evoked contractions (EEC). This effect was unchanged after verapamil. 3. Diphenhydramine potentiated the EEC. Verapamil added before the H1-receptor antagonist inhibited this action. 4. The effects of agonists and antagonists of H-receptors decreased with the increasing of calcium concentration. 5. The results obtained suggested the existence of heterogeneity of prejunctional H-receptors. The function of histaminergic drugs on adrenergic neurotransmission in field stimulated rat vas deferens is Ca(2+)-dependent.
Asunto(s)
Calcio/metabolismo , Histamina/farmacología , Conducto Deferente/efectos de los fármacos , Animales , Calcio/administración & dosificación , Cimetidina/farmacología , Dimaprit , Difenhidramina/farmacología , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H2/efectos de los fármacos , Tiazoles/farmacología , Tiourea/farmacología , Conducto Deferente/fisiología , Verapamilo/farmacologíaRESUMEN
1. The binding activity of 5-HT1 receptors was studied in membrane fractions from the cerebral cortex and hippocampus of male Wistar rats treated orally for 13 days with the Ca(2+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg) and flunarizine (10 mg/kg) and with the calmodulin antagonist trifluoperazine (3 mg/kg). 2. The binding capacity and affinity of the 5-HT1 receptors in the cerebral cortex were significantly decreased after the treatment with the Ca(2+)-antagonists nifedipine, verapamil and flunarizine. The dissociation constant (Kd) was increased after the treatment with the calmodulin antagonist trifluoperazine. 3. In the hippocampus the 5-HT1 receptor affinity and number of binding sites were significantly reduced after the treatment with all four antagonists tested--nifedipine, verapamil, flunarizine and trifluoperazine, the Kd value being increased insignificantly after the flunarizine treatment. 4. The results obtained afford the suggestion that the reduction of 5-HT1 receptor activity is at least one of the results of the well known Ca(2+)-ions mediated automodulation of 5-HT release. The data confirm the view about the great importance of Ca(2+)-ions for the regulation of membrane neurotransmitter receptor activities.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Calmodulina/antagonistas & inhibidores , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Antagonistas de la Serotonina , Trifluoperazina/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Flunarizina/farmacología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Cinética , Masculino , Nifedipino/farmacología , Ratas , Ratas Endogámicas , Verapamilo/farmacologíaRESUMEN
Studies were made of the effect of nifedipine on the enzyme-inducing activity of phenobarbital and beta-naphthoflavone estimated by hexobarbital sleeping time, benzphetamine-N-demethylase (BND), ethoxycumarin-O-deethylase (ECOD) and ethoxyresorufin-O-deethylase. (EROD) activity, as well as by the cytochrome P-450 and cytochrome b5 content. Nifedipine at the dose used (100 mg/kg, orally) prolonged hexobarbital sleeping time and affected neither the BND, ECOD and EROD activity, nor the cytochrome P-450 and cytochrome b5 content. On single application nifedipine exerted a different effect on the phenobarbital- or beta-naphthoflavone-provoked enzyme induction. The phenobarbital-induced BND activity and the cytochrome P-450 content were not changed, while the beta-naphthoflavone-induced EROD activity and cytochrome P-450 and cytochrome b5 content decreased, the ECOD activity remaining unchanged. Nifedipine administered for three days significantly increased the BND activity and the cytochrome P-450 content. The three-day administration of nifedipine plus phenobarbital resulted in a further increase in the BND activity and the cytochrome P-450 content. Consistent with this finding was the potentiation of the phenobarbital-induced shortening of hexobarbital sleep. Nifedipine administered at a single dose, one hour before beta-naphthoflavone had no effect per se but potentiated the enzyme-inducing effect of beta-naphthoflavone on the EROD activity and the cytochrome P-450 content but not on the ECOD activity. These data could be taken into account when considering the possible interactions between nifedipine and other drugs applied at different sequence and duration.
Asunto(s)
Benzoflavonas/farmacología , Nifedipino/farmacología , Fenobarbital/farmacología , Animales , Sistema Enzimático del Citocromo P-450/biosíntesis , Citocromos b5/biosíntesis , Inducción Enzimática/efectos de los fármacos , Hexobarbital/farmacología , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Oxigenasas de Función Mixta/biosíntesis , Ratas , Ratas Endogámicas , Sueño/efectos de los fármacos , beta-naftoflavonaRESUMEN
Some pharmacokinetic interactions between digoxin and amiodarone were studied in experiments on rabbits. An increase of digoxin serum levels was established in amiodarone-treated rabbits (amiodarone 30 mg/kg s. c. for five days administered alone or together with digoxin). The calculated elimination half-life(t1/2) and the area under the curve (AUC) of digoxin were increased and the digoxin clearance was decreased, being most pronounced in animals receiving a combination of amiodarone and digoxin for five days. Changes were observed neither in the digoxin toxicity in amiodarone-treated guinea-pigs nor in the serum levels of T4, T3 and TTH. The possible mechanisms of the digoxin-amiodarone interactions are discussed.
Asunto(s)
Amiodarona/farmacología , Digoxina/farmacocinética , Digoxina/toxicidad , Animales , Chinchilla , Creatinina/sangre , Semivida , Radioisótopos de Yodo , Masculino , Conejos , Radioinmunoensayo , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
1. The binding of [3H]flunitrazepam to benzodiazepine receptors in the cerebral cortex and hippocampus (membrane fraction P2) was studied after 13-day oral treatment of male Wistar rats with the Ca(2+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin (CaM)-antagonist trifluoperazine (TFP) (3 mg/kg). 2. The changes in the binding characteristics of the benzodiazepine receptors in the frontal cortex were studied in vitro after the addition of nifedipine (10(-6) and 10(-5) M) and verapamil (10(-6) and 10(-5) M). 3. A significant decrease of the binding capacity (Bmax) of [3H]flunitrazepam was established after in vivo treatment with the three Ca(2+)-antagonists as well as after TFP, the decrease being much more pronounced in the hippocampus. 4. Changes in the affinity values (Kd) of [3H]flunitrazepam binding were found in neither of the groups. 5. No data for a direct interaction of nifedipine and verapamil with the brain benzodiazepine receptors were obtained in in vitro experiments.