The effects of methylxanthines, papaverine, dipyridamole and imipramine on lipolysis and phosphodiesterase activity of rat adipose tissue were investigated. Lipolysis in isolated fat cells was stimulated by theophylline and caffeine whereas papaverine, dipyridamole and imipramine had no substantial effect on the basal lipolytic rate. Lipolysis induced by noradrenaline was potentiated by theophylline, but blocked by papaverine, dipyridamole and imipramine at concentrations between 0.02 to 0.2 mM. These agents also depressed lipolysis induced by theophylline and dibutyryl cyclic AMP and reduced the lipolytic activity of homogenates of adipose tissue. The activity of phosphodiesterase assayed over a wide range of substrate concentrations revealed two different Michaelis constants. Both types of phosphodiesterase were inhibited by theophylline, papaverine, dipyridamole and imipramine in a competitive manner, the low Km enzyme being more sensitive for inhibition than the high Km enzyme. On both types of phosphodiesterase papaverine and dipyridamole proved to be 10 to 100 times more potent inhibitors than theophylline and imipramine. To explain the antilipolytic effect of phosphodiesterase inhibitors it is assumed that they do not only affect substrate binding of cyclic AMP to phosphodiesterase but also displace cyclic AMP from the binding site on protein kinase, thus acting as inhibitors of the activation process within the lipolytic system.
The amount of K+-release from phalloidin poisoned rat livers is lower at 10° than at 40°C. In the region of normal body temperature, the K+-loss starts immediately after the application of the cyclopeptide. At 20°C the beginning of K+-release is delayed, but the total K+-release is similar at 20° and 40°C.
After irreversible inhibition of monoamine oxidase (MAO) in rats with hydrazine derivatives (3-amino-2-oxazolidinone, furazolidone, benmoxine) and the non-hydrazine pargyline, recovery of enzyme activity occurred at rates which were characteristic for the organ investigated and independent of the chemical structure of the irreversible inhibitor. The respective half times were the same in homogenates and in mitochondria and amounted to about 10 days in the brain and 3 to 4 days in the liver; in the small intestine, mucosal MAO activity recovered with a half time of 0.5 days, whereas in the residual intestinal layers a half time of about 4 days was found.\3-Tranylcypromine is not an irreversible inhibitor: the half times of MAO recovery were 3.6 days in the brain and 2.4 days in the liver.
After a single i.v. administration of 50 mg/kg of Trimethoprim (TM) to rats in late pregnancy, a diffusion equilibrium of the folic acid inhibitor in the foetal organs is reached after 30–60 min. The TM levels in maternal as well as in foetal organs can have an inhibitory effect on folic acid reductase activity.
The technique of Sephadex gel filtration was employed to characterize the effect of some sulfonylurea compounds, ioglycamic acid, and suramin on the binding of phenprocoumon to bovine serum albumin.
Hemisection of the brains of rats was performed at a level slightly rostral to the mesencephalo-diencephalic junction. In chronic experiments (7 to 14 days after the lesion) a considerable decrease in 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels was found in the ipsilateral hemiforebrain. In acute experiments (3 to 6 h after the lesion) the effect of the lesion on synthesis and metabolism of 5-HT was investigated by estimating tryptophan, 5-hydroxytryptophan (5-HTP), 5-HT and 5-HIAA levels in different parts of the brain. In order to get an insight into the different steps in 5-HT metabolism inhibitors of enzymes or transport were used (Ro 4-4602 [N-(dl-seryl)-N1-(2,3,4-trihydroxybenzyl) hydrazine], pargyline, and probenecid). The effect of l-tryptophan loading was also investigated.
In 10 patients the time course of specific activity in plasma, and the excretion rates in urine and feces after oral and intravenous administration of 12α-3H-4‴-methyldigoxin were studied. The determined biological half life of radioactivity in plasma averaged 43 h and corresponds with the renal excretion velocity (50 h). 32.5 ± 5.0 and 31.5 ± 6.3% of the dose were found in feces and 59.7 ± 1.3 and 52.9 ± 1.8% were excreted in urine within 7 days after intravenous and oral administration, respectively. These results together with the observed plasma concentrations suggest a rapid and almost complete absorption of 4′-methyldigoxin.
The effect of 5-hydroxytryptamine (5-HT) was studied on the nictitating membrane (isolated, or in situ in the pithed cat) and on strips of spleen capsule of the cat.
The influence of phenylbutazone (Butazolidin®) on the growth of mouse fibroblasts (L 929) in-vitro was studied. The substance was added in concentrations of 190, 364 and 667 μg/ml to cultures in media containing different amounts of serum ranging from 10 to 50%. The inhibition of cell growth was found to be proportional to the concentration of phenylbutazone. Furthermore, the inhibition of growth was found to be inversely proportional to the serum content of the media.
The effects of wide concentration ranges of furosemide, ethacrynic acid, and chlorothiazide on glucose formation by rat kidney cortex slices were investigated from fructose, pyruvate, lactate, and α-ketoglutarate and partly at two different pH.
Pentobarbital induces a regular slow wave activity with a frequency between 5 to 25 Hz and a burst firing pattern of single red nucleus neurons, which is correlated with the slow wave rhythm.
Superior cervical ganglia from 6-day and 4-week-old mice showed increased tyrosine hydroxylase activity when cultured for 48 h in media containing 5 or 15 times the normal potassium concentration. Increased sodium concentration had no such effect. These results suggest that depolarisation of adrenergic neurones may be important in the trans-synaptic regulation of enzyme activity in both adult and neonatal ganglia.
The effect of 0.025 mM hydrocortisone on the response of isolated heart muscle of kittens to (-)-isoprenaline and (-)-noradrenaline was studied. Four effects of the catecholamines were measured on three tissues: frequency of spontaneously beating right atria; isometric tension of driven left atrial strips and papillary muscles (2 and 5 sec intervals, respectively) and velocity of contraction (max dP/dt) on papillary muscles.
Classical hypnotics (barbiturates, paraldehyde, chloral hydrate, piperidinedione derivatives, methaqualone, ethinamate, bromvalurea), transquilizers (benzodiazepine derivatives, meprobamate) and one volatile anesthetic agent (methoxyflurane) regularize the “spontaneous” activity of the CB and RN. The frequency of the drug-induced rhythm depends on the depth of anesthesia.
The effect of pretreatment with 340 μg/g pyrazole i.p., an inhibitor of alcohol dehydrogenase, on the changes in the carbohydrate metabolism of the liver, as produced by 4 mg/g ethanol i.v., was investigated in mice. Pyrazole completely prevented the ethanol-induced rise of the glycerol-1-phosphate content and of the glycerol-1-phosphate/dihydroxyacetone phosphate and lactate/pyruvate ratios and diminished the decrease of the hepatic pyruvate and lactate contents. This suggests, that these changes are mediated by shifts in the hepatic NADH/NAD ratio occurring during alcohol oxidation. The glycogen depleting effect of ethanol was not abolished by pyrazole showing that this effect is brought about—at least in part—by ethanol itself.
The positive inotropic effect of noradrenaline on the guinea-pig papillary muscle is potentiated in the presence of 1×10−5 M tyramine, the concentration of noradrenaline that is necessary to produce a half maximal increase in force of contraction being reduced to about one third. There is no alteration of the maximal inotropic effect since the concentration-effect curve of noradrenaline is simply shifted to the left.
Livers from fed and starved rats were perfused with either rat blood, washed bovine erythrocytes suspended in Eagle minimal essential medium, or the same medium without erythrocytes.
The binding of didesmethylpromazine, promazine N-oxide, 2-hydroxypromazine, promazine sulfoxide, monodesmethylpromazine sulfoxide, didesmethylchlorpromazine, chlorpromazine N-oxide, and chlorpromazine sulfoxide to bovine serum albumin was determined by means of sephadex gel filtration.
Isolated perfused mesenteric artery preparations of genetic (Japanese strain), renal and DOCA/saline hypertensive rats showed a marked increase in reactivity to the vasoconstrictor effect of 5-hydroxytryptamine (5-HT) as compared with normotensive controls. In the arteries of the hypertensive animals, the threshold vasoconstrictor doses of 5-HT were lower, the 5-HT dose-response curves were steeper and their maxima were increased by a factor of 2.5–4.2. These observation only partially fit into the concept that increased vascular reactivity in hypertension is due to an increased wall/lumen ratio of the arterial blood vessels. Pressor responses to 5-HT were also higher in isolated perfused hindquarter and in pithed preparations from renal and DOCA/saline hypertensive rats but not in those from genetic hypertensive rats. In isolated perfused renal artery preparations, the reactivity to 5-HT was equal for normotensive and hypertensive (genetic and DOCA/saline) animals, indicating that not all arteries of hypertensive rats share the increased reactivity to 5-HT. Pretreatment with reserpine slightly reduced the reactivity to 5-HT in arteries from both hypertensive and normotensive rats. Non-vascular smooth muscle of DOCA/saline hypertensive rats, for which isolated gastric strips were used as an example, responded to 5-HT in the same way as that of normotensive rats. Methysergide blocked the pressor responses to 5-HT but did not influence the blood pressure of the hypertensive animals, thus questioning a causal relationship between the increased vascular reactivity to 5-HT and the maintenance of high blood pressure in these three types of experimental hypertension.
In man the oral or intravenous administration of 4‴-methyldigoxin yields metabolites in urine which are soluble either in chloroform or in water. The chromatographic analysis reveals demethylation as the main metabolic reaction in man. In addition to methyldigoxin and digoxin small amounts of digoxigenin-bisdigitoxoside and digoxigenin-mono-digitoxoside can be detected. The water soluble metabolites represent 7% of the radioactivity excreted in 7 days reaching a maximum within the first 8 h.
