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Biomedical subjects

R M Gaion

Publications and source records attributed to R M Gaion.

At least 55 records · Page 3Linked to original sources
PubMed1985

A caffeine analogue (1,3,7-trimethyl-6-thioxo-2-oxopurine) with a negative inotropic and chronotropic effect.

Cardiac effects of thio-xanthine derivatives, S-caffeine and S-theophylline, were studied on isolated guinea-pig atria and on partially purified cardiac cAMP phosphodiesterase enzymes. Theophylline and caffeine were taken as reference compounds. On electrically driven left atria S-caffeine (0.01-1 mmol/l) decreased contractile tension in a concentration dependent manner. On spontaneously beating atria, the same concentrations of S-caffeine showed negative inotropic as well as negative chronotropic effects. On electrically driven left atria, S-theophylline (0.01-1 mmol/l) increased heart contractile tension but, at higher concentrations, a reversal of the stimulating effect was observed. Both S-caffeine and S-theophylline inhibited bovine heart cAMP phosphodiesterase activity to a comparable extent. Their inhibitory potencies were about three and nine times higher than those of theophylline or caffeine but consistently lower than that of IBMX. The results show that the replacement of O with S in the methylxanthine molecule drastically modifies the effects induced by the drugs on cardiac function without changing those on cAMP phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Antilipolytic activity of tiadenol-nicotinate in isolated fat cells: a comparison with its parent drugs.

Tiadenol-nicotinate is an ester in which two molecules of nicotinic acid are linked to one molecule of tiadenol. In the present study the antilipolytic activity of tiadenol-nicotinate was evaluated in isolated rat fat cells and a direct comparison was made with the parent drugs. Basal lipolysis was not affected by tiadenol-nicotinate or by nicotinic acid, but it was reduced by a high concentration of tiadenol (10(-3) M) alone or associated with a double concentration of nicotinic acid. Tiadenol-nicotinate (10(-5)-10(-3) M) was very effective in antagonizing the lipolytic action of epinephrine (10(-6) M) and of theophylline (3 X 10(-4) M). The latter drugs were equally sensitive to the inhibitory effect of tiadenol, while nicotinic acid reduced the action of theophylline more than the effect of the catecholamine. Neither of the parent drugs was as effective as tiadenol-nicotinate at this level. However, nicotinic acid potentiated the antilipolytic effect of tiadenol, thus making it possible to reach an inhibitory effect quantitatively similar to or even higher than the effect of tiadenol-nicotinate. These results show that tiadenol-nicotinate is a potent antilipolytic agent in vitro and that its effect may be due to hydrolysis of the ester and release of the parent drugs. The possible therapeutic value of tiadenol-nicotinate is discussed.

Adipose Tissue↗
PubMed1984

Prostacyclin and lipolysis in rat fat cells.

In rat fat cells incubated for 15 min at 37 degrees and pH 8.5, glycerol release was highly stimulated both by norepinephrine and by theophylline. Prostacyclin (PGI2) (10(-8)-10(-7)M) did not alter the basal rate of glycerol release but potentiated the lipolytic effect of 2 X 10(-6)M norepinephrine. The rate of norepinephrine-induced glycerol release was increased by PGI2 during 10 min of incubation and then maintained for the next 5 min. Lipolysis induced by concentrations of norepinephrine which produced maximal effects was not altered by PGI2. PGI2 (10(-7)-10(-6)M) also potentiated the effect of 5 X 10(-4)M theophylline on glycerol release, but antagonized the stimulation induced by a maximally effective concentration of the methylxanthine (2 X 10(-3)M). Incubation of the cells with norepinephrine in the presence of 2 X 10(-4) or 5 X 10(-4)M theophylline caused a loss of the potentiating effect of PGI2 on norepinephrine-induced lipolysis. In the presence of 10(-3)M theophylline, the lipolytic action of norepinephrine was inhibited by PGI2. In fat cells incubated with adenosine deaminase (0.5 U/ml), 2.5 X 10(-7)M PGI2 did not alter the response to 5 X 10(-4)M theophylline and inhibited the effect of norepinephrine both in the absence and in the presence of theophylline. The present results show that, under appropriate experimental conditions, PGI2 may act as a lipolytic agent in isolated fat cells and that some kind of interaction exists between stimulation of methylxanthine-sensitive adenosine receptors and stimulation of PGI2 receptors.

Adipose Tissue↗
PubMed1984

Prostacyclin-induced contraction of guinea-pig ileum: influence of drugs affecting calcium flux in the smooth muscle.

The contraction of guinea-pig terminal ileum induced by prostacyclin (PGI2) (20 nM) was inhibited by verapamil (0.01-1 microM) and by nifedipine (0.1-100 nM) in a concentration-dependent manner. Both drugs reduced the basal tone of the preparations only at the highest concentration tested. Papaverine (3-30 microM) reduced the basal tone as well as the PGI2-induced contractions at all the concentrations tested. The results show that extracellular calcium influx and possibly calcium mobilization from intracellular stores in smooth muscle cells are involved in the contractile response of the ileum to PGI2.

Animals↗
PubMed1984

Dual effect of (-)-N6-phenylisopropyl adenosine on guinea-pig trachea.

The effect of (-)-N6-phenylisopropyl adenosine (PIA), a metabolically stable P1-receptor agonist, was investigated on guinea-pig isolated trachea. PIA showed two opposite effects: contraction, evident at low concentrations (10(-7) to 2-5 X 10(-6) M), and relaxation at higher doses. Relaxation by PIA was antagonized in an apparently competitive manner by two antagonists of extracellular (P1) adenosine receptors: theophylline (Theo) and 8-phenyltheophylline (PT). Contraction by PIA was not inhibited by methylxanthines and was not mediated by stimulation of cholinergic or histaminergic systems. Inhibitors of arachidonic acid cascade acting at different levels, i.e. indomethacin, nordihydroguaiaretic acid (NDGA) and BW755C, all inhibited the contraction by PIA, while they potentiated the relaxation in a concentration-dependent manner. Mepacrine, an inhibitor of phospholipase A2, inhibited the contraction by PIA, but did not affect the relaxation. These results indicate that the contractile effect induced by PIA is supported by an indirect mechanism involving the release of arachidonic acid derivatives (via P2-purinoceptor?). Thus the balance between the two opposite effects of adenosine on tracheal tone is possibly modulated by the prostaglandin turnover.

Adenosine↗
PubMed1984

The role of adrenergic, purinergic and opiate receptors in the control of prostacyclin-induced contraction in the guinea-pig ileum.

The interactions between prostacyclin (PGI2) and adrenergic, opiate, purinergic receptor agonists and antagonists were studied in isolated segments of guinea-pig ileum by recording the changes in isometric tension. The contractile response of these preparations to PGI2 was rapid and qualitatively similar to the effect of acetylcholine. Noradrenaline (30-300 nM) reduced the effect of PGI2 (20 nM) in a concentration-dependent manner. The inhibitory action of noradrenaline on PGI2-induced contractions was prevented by the alpha-blocker phentolamine and unaffected by the beta-blocker D(--)INPEA. Morphine (10,50 nM) antagonized the response of the ileum to PGI2 and naloxone prevented this inhibition. Also N6-phenylisopropyladenosine (PIA) (10,50 nM) inhibited the effect of PGI2, which was restored when theophylline was added before PIA. The present results indicate that presynaptic alpha-adrenergic, opiate and purinergic receptor stimulation operates a negative control on the effect of PGI2 in guinea-pig ileum.

Animals↗
PubMed1984

Influence of amiodarone on oral digoxin bioavailability in healthy volunteers.

The aim of the present work was to evaluate the possible influence of amiodarone on some basic parameters of acute oral digoxin kinetics. A single oral dose of digoxin (0.50 mg) was administered to six healthy volunteers both before and at the end of a 7-day treatment with with amiodarone. This treatment caused a clear-cut rise in peak serum digoxin levels (Cmax) from 2.92 +/- 1.09 to 5.87 +/- 1.68 ng/ml (p less than 0.005) and a decrease of the peak time (Tmax) in four out of the six subjects. The area under the serum concentration-time curve (AUC) was increased by amiodarone with a high individual variability (30.71 +/- 6.15 vs 40.63 +/- 10.04 ng X h X ml-1). Also the 72-hour recovery of the glycoside in the urine was higher (258.77 +/- 68.41 vs 357.62 +/- 62.98 micrograms; p less than 0.01), while renal clearance (Clr) was not altered. These results show that amiodarone increases digoxin bioavailability by a mechanism which appears to be independent of changes in drug elimination.

Administration, Oral↗
PubMed1984

Cholinergic mechanism of sodium nicotinate-induced contractions in rat and guinea-pig descending colon.

In segments of rat descending colon 34.5 microM Na-nicotinate-induced rhythmic contractions that were late in onset, long lasting and reversible. The Na-nicotinate contractile effect was unaffected by 100 microM hexamethonium, whereas it was rapidly blocked by 30 nM scopolamine and inhibited by treating the samples with 20 microM hemicholinium-3, or 40 microM tetrodotoxin or 60 microM procaine, by incubation at 20 degrees C for 60 min or by removing CaCl2 from the incubation medium. In segments of rat descending colon exogenous acetylcholine induced an initial peak in developed tension followed by long lasting rhythmic contractions. Low indomethacin concentrations (from 3 to 60 microM) suppressed both Na-nicotinate and acetylcholine-initiated rhythmic contractile activity while a higher indomethacin concentration (0.6 mM) was required to abolish the acetylcholine-evoked first major contraction. Also in segments of guinea-pig descending colon 34.5 microM Na-nicotinate induced a contractile effect that was abolished by 30 nM scopolamine and almost completely absent in tissue samples treated with 20 microM hemicholinium-3 or exposed to low temperature. The data presented indicate that in segments of rat descending colon Na-nicotinate contractile activity is triggered by acetylcholine release from postganglionic nerve endings and that this cholinergic, calcium-dependent action appears to be modulated by a contemporary release of prostaglandin-like material. In addition, indication is given that this indirect mechanism can be responsible of the Na-nicotinate contractile action at the intestinal level in different animal species.

Acetylcholine↗
PubMed1983

Effect of diamide on isolated guinea pig atria.

Diamide [(diazinedicarboxylic acid-bis (dimethylamide)] 50 micrograms/ml induced a positive inotropic and chronotropic effect on spontaneously beating atria from normal and reserpine pretreated guinea pigs and a positive inotropic action on electrically driven left atria. Cumulative addition of diamide 600 micrograms/ml caused a systolic standstill of atria. D(-) INPEA 2 micrograms/ml, a beta-adrenergic blocking agent, antagonized the positive chronotropic action of diamide 50 micrograms/ml while it did not affect the positive inotropic action caused by diamide. In isolated atria perfused with Ca2+ free medium and recovered by stepwise addition of calcium chloride, the calcium level required to restore normal activity was 1.04 mmol/1 while it was 0.52 mmol/l in the presence of diamide. Ruthenium red 10 micrograms/ml, a specific inhibitor of calcium transport in mitochondria, antagonized diamide-induced recovery of the cardiac activity in calcium poor medium. Two different mechanisms, that involve calcium movements and beta-receptor, have been proposed for diamide action on heart muscle.

Animals↗
PubMed1983

The role of prostacyclin in modulating cholinergic neurotransmission in guinea-pig ileum.

The mechanism of action of prostacyclin (PGI2) on isolated segments of guinea-pig terminal ileum was studied by recording the changes in isometric tension. In these preparations PGI2 (1 nM-1 microM) caused a concentration-dependent increase in muscle tension. This effect was rapid and short-lasting. PGI2-induced contractions were inhibited by atropine and potentiated by physostigmine. Hemicholinium-3 reduced the response to PGI2 and the inhibition was quantitatively comparable at any PGI2 concentration tested. Tetrodotoxin as well as low temperature (20 degrees C) abolished and beta-bungarotoxin reduced the effect of PGI2. Hexamethonium decreased the response to submaximal, but not to maximal PGI2 concentrations. PGI2 potentiated the twitch response of the ileum to electrical stimulation. In the presence of tetrodotoxin, PGI2 did not alter the effect of a sub-maximal concentration of acetylcholine (ACh). The present results give indirect evidence for the ability of PGI2 to facilitate ACh release from intramural nerves possibly by increasing the excitability of cholinergic cell bodies.

Acetylcholine↗
PubMed1983

Age related changes in the antilipolytic effects of nicotinic acid in rat adipose tissue.

The effect of nicotinic acid on lipolysis was tested in vitro in adipose tissue from three groups of rats, selected according to age: 6-7 weeks, 10-12 weeks and 16-20 weeks old. Although the changes were not statistically significant, the basal release of free fatty acid (FFA) was increased and glycerol was decreased by nicotinic acid (0.01-1 mM); the drug caused a statistically significant increase in basal FFA: glycerol ratio in a concentration-dependent manner. This ratio also increased with age in the absence of drug. (-)-Noradrenaline (10 microM) and theophylline (3 mM) each stimulated lipolysis. When glycerol release was calculated as a percentage increase, the effects of these drugs became more marked with age. By contrast, the highest absolute rate of induced release occurred in adipose tissue from the youngest rats. The lipolytic effect of 10 microM (-)-noradrenaline was generally unaffected by nicotinic acid except in adipose tissue from the oldest rats when the glycerol release was reduced by 1 mM nicotinic acid, although it did not alter FFA:glycerol ratio. The stimulation of glycerol release induced by 3 mM theophylline was not affected by the presence of nicotinic acid in the youngest rats, but the drug elicited a concentration-dependent antilipolytic effect in adipose tissue from 10-12 weeks old rats, which was even more pronounced in the oldest animals. Lower theophylline concentrations (0.6-1 mM) were also sensitive to nicotinic acid inhibition in the 6-7 weeks old rats. In the presence of theophylline, nicotinic acid had no effect on FFA:glycerol ratio. These data show a direct influence of age on the antilipolytic action of nicotinic acid.

Adipose Tissue↗
PubMed1982

Membrane bound guanylate cyclase in rat fat cell plasma membranes: influence of divalent cations on calcium activation.

Rat fat cell plasma membrane preparations were used to study the effect of Mn2+, Mg2+, Ca2+ on guanylate cyclase activity. Among these three cations, Mn2+ was the most effective in activating the enzyme; Mg2+ and Ca2+ were 23% and 10% respectively as effective as Mn2+ in activating the enzyme. Low concentrations of Ca2+ (1 microM) increased the rate of cGMP formation at MgGTP concentrations ranging from 0.3 to 2 mM. This effect was less at higher concentrations of Ca2+ and was independent of the presence of excess Mg2+. Ca2+ (100 microM) had only a marginal stimulatory effect on the MnGTP-dependent enzyme.

Adipose Tissue↗
PubMed1982

Azidofibrate. Synthesis and evaluation of its effects on fat cell lipolysis in vitro.

Synthesis and biological properties of a new ethyl alpha-(p-chlorophenoxy)-isobutyrate (clofibrate) analogue are described. Replacement of the chlorine atom of the parent drug by an azido group has been attempted in order to avoid the proliferative action on liver peroxysomes. The new compound showed a good degree of inhibition of rat fat cell lipolysis and its action, qualitatively different from that of clofibrate, bears some analogy with that of nicotinic acid.

Animals↗
PubMed1982

Xanthone analogues of clofibrate / Synthesis and biological evaluation as antagonists of lipolysis in vitro.

By appropriate superimposing of fenofibrate and fenofibric acid molecules, two xanthone derivatives (closed models) may be obtained. These compounds as well as their four chlorine-free isomers were prepared and tested on adrenaline- and theophylline-induced lipolysis in rat fat cells in comparison with ethyl 2-(4-chlorophenoxy)-2-methylpropionate (clofibrate). Some of these new derivatives besides being good inhibitors of adrenaline effect, as clofibrate is, were also very active in reducing theophylline-induced lipolysis. Very promising for further studies is the chlorine-free 3-isomer (3e). The possible difference in the action mechanism of these compounds as compared with clofibrate and the structure-activity relationships are briefly discussed.

Adipose Tissue↗
PubMed1981

Effect of cyclonicate, a new hypolipemic drug, on lipolysis in vitro.

A new hypolipemic drug, cyclonicate (3,3,5-trimethyl-cyclohexyl nicotinate), was studied and its effects were compared with those of nicotinic acid. Experiments were carried out in vitro on rat adipose tissue on spontaneous lipolysis, and on lipolysis stimulated by noradrenaline, theophylline, dibutyryl cyclic AMP. Cyclonicate, like nicotinic acid, reduced the lipolytic stimulation of theophylline. Its effect was dose-dependent but 10 times lower (IC50 = 1 mM) than that of nicotinic acid. The inhibitory activity of both compounds was higher on theophylline-induced lipolysis than on noradrenaline-stimulated lipolysis. Neither one had any effect on dibutyryl cyclic AMP. In the absence of stimulating drugs, cyclonicate increased the FFA/glycerol ratio, more than nicotinic acid. Moreover, cyclonicate inhibited theophylline-induced FFA release much less than glycerol release, while under the same conditions, nicotinic acid inhibited both FFA and glycerol release. Thus cyclonicate would influence not only triglyceride hydrolysis, but also FFA utilization by adipose tissue.

Adipose Tissue↗