Biomedical subjects
Publications and source records attributed to H J Mest.
Intracerebroventricular administration of PGI2 or PGE2 reduced aconitine-induced cardiac arrhythmia in rats. PGF2 alpha had no antiarrhythmic effect under the same conditions. The ED50 values of PGI2 and E2 were 0.25 microgram/kg and 1.1 microgram/kg, respectively. Central mechanisms may participate in the antiarrhythmic effect of these PGs.
1. PG E2 (2.10(-8) g/ml) produces a positive inotropic effect and lengthens the duration of the action potential at the level of 50% and 90% of repolarization. 2. PG F2 alpha acts negatively inotropic and shortens the action potential at the level of 75% and 90% of repolarization. 3. PG F2 alpha (2.10(-8) g/ml) increases both the electrotropic and inotropic vagal effects, PG E2 (2.10(-8) g/ml) decreases them. 4. PG E2 improves the electromechanical coupling, PG F2 alpha reduces it.
Prostacyclin (PGI2) produces an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 of PGI2 was 0.7 microgram/kg and the maximum antiarrhythmic effect 54 per cent. The equi-effective doses of PGE2 and PGF2alpha were higher (ED50 of PGF2alpha = 1.2 microgram/kg, ED50 of PGE2 = 2.7 microgram/kg). However, PGF2alpha and PGE2 had a maximum antiarrhythmic effect of 80 per cent in this model.
Tachyarrhythmias and extrasystoles produced an increase of PGE and PGF2alpha in canine coronary sinus blood (CSB). After application of aconitine the PG efflux was nearly unchanged before arrhythmia occurred. However, the PG efflux increased after arrhythmia had occurred.
Antiarrhythmic effects of the Prostaglandin (PG) precursors arachidonic and Linoleic acid were demonstrated on three models of experimental arrhythmias, whereas the fatty acids linolenic and oleic acid proved to be ineffective in these models. In ouabain-induced arrhythmias infusions of arachidonic acid (1, 0 mg/kg/min) caused a strong antiarrhythmic effect in 80 percent of the animals. On the same model linoleic acid showed a maximum effct in 40 percent of the animals. BaCl2-induced arrhythmias were abolished by arachidonic and linoleic acid in 60 percent and 66 percent of the rabbits, respectively. Pretreatment by indomethacin reduced the antiarrhythmic effects of linoleic acid from 40 percent to 9 percent on ouabain-induced arrhythmias in cats. The results suggest a participation of PG synthesis in the antiarrhythmic effect of PG precursors.
The antiarrhythmic effect of PGE2 as compared with the adrenergic beta-receptor blocking substance propranolol and the unspecific antiarrhythmic agent ajmaline was examanined on catecholamine-induced arrhythmias of the guinea-pig after preliminary sensibilisation by means of chloroform. Prophylactic administration of the tested substances resulted in a decrease in severity of arrhythmia by 91% after propranolol, by 37% after PGE2 and by 34% after ajmaline. Onset and duration of the arrhythmia were affected only to a negligible degree. The possible mode of action is still under discussion.
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The prostaglandins A1, E1, A2, E2 and F2a were comparatively studied for their antiarrhythmic action using the model of strophanthin arrhythmia of narcotized cats. Infusions of prostaglandins A1, E2 and F2a in doses of 1-5 mug/kg/min for 5 min improved the arrhythmias in 63%, 83% and 81% of the animals, respectively, whereas prostaglandin A2 was effective in 44%, and prostaglandin E1 in only 10% of the cats. Prostaglandins A1 and E2 transiently established a sinus rhythm in 54 and 50%, and prostaglandin F2a in 18% of the animals. The injection of 12 mu9/kg prostaglandin F2a brought about improvement of arrhythmia in 70% of the animals, producing a transient sinus rhythm in 40%. With ajmaline as the standard substance in doses of 0.3 mg/kg/min for 5 min produced an antiarrhythmic effect in 50% of the animals, while injection of 1 mg/kg was effective in 60% of the animals. Effects on the vegetative nervous system are discussed as the possible action mechanism of the prostaglandins.
Intravenous application of arachidonic and linoleic acid induced strong antiarrhythmic effects demonstrated on three models of experimental arrhythmias. In contrast, linolenic and oleic acid were poorly effective. The antiarrhythmic action of the unsaturated fatty acids required 10- to 1000-fold higher doses in comparison with the most effective prostaglandins. Indomethacin decreased the antidysrhythmic action of arachidonic and linoleic acid; PG efficiency remained unaffected. Polyphloretinphosphate markedly reduced the improvement of aconitine arrhythmia by PGs, the decrease of the antidysrhythmic effects of arachidonic and linoleic acid was without statistical significance. The results suggest an important role of PG synthesis for the antiarrhythmic effect of polyunsaturated fatty acids.
The blood pressure active substances noradrenaline, alpha-methyl-dopa, clonidine, dihydralazine, and reserpine were studied 20 min after i.v. administration to rabbits for their action on blood pressure, heart rate, PGE-content and -synthesis in the renal medulla. Noradrenaline caused increase in blood pressure, and distinctly enhanced the PGE content in the renal medulla. alpha-methyl-dopa raised both PGE-content and -synthesis, without changing blood pressure and heart rate. Clonidine and dihydralazine caused a pronounced fall of the blood pressure, but only did dihydralazine lower PGE-synthesis, while no such effect was produced by clonidine. Reserpine, like dihydralazine, decreased PGE-synthesis, without simultaneously lowering blood pressure. Indomethacine, one of the most potent inhibitors of PG-synthesis, has no effect on blood pressure within 20 min. The results argue against the existence of a simple direct correlation between PGE-synthesis rate in the homogenate of rabbit renal medulla and the instantaneous blood pressure.
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The influence of PGI2 and iloprost on the contents of high energy phosphates, cAMP, glycolytic metabolites and on cardiac performance was investigated in open-chest dogs subjected to 3 h of ischaemia, induced by occlusion of the left anterior descending coronary artery. The administration of drugs for 2 h, starting 1 h after the onset of ischaemia, resulted in a normalization and an appreciable reduction in the loss of high energy phosphates in the non-ischaemic and ischaemic left ventricular muscle, respectively, leading to an improvement in the phosphate potential of the cardiac tissue. A reduction in the ischemia-induced rise in cAMP levels was observed, indicating a lower catecholamine overflow in the presence of these drugs. PGI2 and iloprost in the dose employed significantly decreased cardiac preload, which was found to be elevated in the untreated animals after coronary artery ligation. The observed effect of PGI2 and its mimetic on the haemodynamics, as well as on myocardial cAMP and high energy phosphate levels of the heart, may be considered helpful in the phase of temporary imbalance between energy demand and supply during acute ischaemia.
The effect of trapidil (RocornalR) and some of its newly developed derivatives (AR 12456, AR 12463, AR 12465, AR 12464) on the receptor-mediated low density lipoprotein (LDL) binding, uptake and degradation was studied in human skin fibroblasts (HSF) and in human hepatoma cell line Hep G2. Compound AR 12456 influenced this pathway in a selective way: it enhanced the uptake and degradation of 125I-LDL by Hep G2 cells in a dose-dependent manner, but inhibited it in HSF. Scatchard analysis of the saturable LDL binding in Hep G2 indicates that the effect of compound AR 12456 is the result of an increased number of LDL binding sites. Compound AR 12465 was less effective on LDL catabolism. Trapidil and the other derivatives were inactive under the same experimental conditions. When Ar 12456 was preincubated with Hep G2 cells and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. These findings suggest that a metabolite(s) of AR 12456 might be responsible for the enhanced expression of LDL receptors in cultured human cells.
The hetrazepine derivative WEB 2086 (0.5-2 mg/kg, i.v.), a well known PAF receptor antagonist, was found to reduce the arrhythmogenic effect of PAF in a dose dependent manner on ouabain induced arrhythmias in guinea-pigs. There was no detectable substance-specific influence of WEB 2086 on the threshold doses of ouabain, since in a dose of 2 mg/kg given i.v. it was able to inhibit cardiac rhythm disturbances induced by PAF as well. Guinea-pigs actively sensitized with ovalbumin responded to antigenic challenge with an increased susceptibility to ouabain induced arrhythmias. This arrhythmogenic effect could also be inhibited by WEB 2086. In conclusion, WEB 2086 was found to exert marked protective effects against PAF related cardiac arrhythmias, indicating its potential usefulness for the treatment of cardiac anaphylaxis.
Different mediators released by anaphylaxis seem to be involved in different pathophysiological conditions, including cardiac arrhythmia. Histamine, 5-HT and platelet-activating factor (PAF) could participate in the enhanced arrhythmogenicity during anaphylaxis in guinea-pigs. The threshold dose of ouabain-induced arrhythmia is decreased in actively sensitized guinea-pigs by i.p. administration of ovalbumin. The purpose of the present paper was to investigate the effect of different mediator antagonists. Antagonists of PAF (WEB 2170), histamine (clemastine) and 5-HT (cyproheptadine) in doses of 5.0 mg/kg, 5.0 mg/kg and 0.5 mg/kg, respectively, can increase the threshold dose of ouabain-induced arrhythmias signalling an antiarrhythmic effect. A combination of WEB 2170 and clemastine, each of them in inactive doses (2.0 mg/kg and 1.0 mg/kg, respectively) showed a statistically significant antiarrhythmic effect. A combination of the same dose of WEB 2170 and cyproheptadine (0.1 mg/kg) under the same conditions induced an antiarrhythmic effect, too. BN 52256 is a new antiallergic drug synthesized on the basis of a novel concept of combining inhibitory activity against various inflammatory mediators in one molecule. BN 52256 in doses of 20-80 micrograms/kg exhibited a statistically significant antiarrhythmic effect. BN 52256 needed a 12.5-125 fold lower dose to induce the same antiarrhythmic effect compared to the antagonists of PAF, histamine or 5-HT investigated in this study. Depending on the pathophysiological conditions, different mediators seem to be involved in the occurrence of cardiac arrhythmia. A complex inhibition of these mediators could induce a more specific influence on such kinds of cardiac arrhythmias.
S 872419 A, a specific receptor antagonist of peptide leukotrienes, was tested in the early-phase treatment of chemically burned eye (0.25 mol/l sodium hydroxide) of the rabbit. The drug was topically applied 5 times a day in a 1% solution, controls were the untreated opposite eye. Gross and microscopic investigations indicated that S 872419 A inhibits the inflammatory response of the chemically burned anterior eye segment. The parameters of healing considered (epithelial regeneration, corneal clouding and swelling, infiltration with polymorphonuclear leukocytes) suggest inhibition of lipoxygenase-mediated reactions in the tissue. PGF2 alpha levels were the same in aqueous humour of treated and untreated eyes. Further experiments with S 872419 A and other nonsteroidal drugs should improve the anti-inflammatory therapy of the chemically burned eye.
The administration of the trapidil derivative AR 12465 (5 mg/kg body weight) intraperitoneally to hypercholesterolemic guinea pigs caused a stronger reduction in serum total cholesterol (TC) than trapidil (20 mg/kg, i.p.) or a vehicle injection (saline with 5% ethanol i.p.). The stronger reduction of TC is caused by a lower level in the sum of all beta-migrating lipoproteins and an enhanced level of high-density lipoprotein. The levels of free and esterified cholesterol were not changed in kidney and left cardiac ventricle, but significantly enhanced (P less than 0.05) in the liver of all groups fed a cholesterol-rich diet. The elevation in liver cholesterol was higher in the group treated with AR 12456 than in the group treated with trapidil or with vehicle. The treatment with AR 12456 diminished the ratio TXB2/6-keto-PGF1 alpha for the capacity of aorta to form these prostanoids. In conclusion, our data show that AR 12456 has a strong antilipidemic action in guinea pigs fed a cholesterol-rich diet.