Biomedical subjects
Publications and source records attributed to R Korbut.
Rat brain slices released spontaneously and after challenge with A23187 LTC4-like radioimmunoactivity. Total cat brain ischemia followed by short postischemic reperfusion period resulted in the increased release of lipid peroxides and PGE2 but not in LTC4-like substance by brain slices. In lumbar cerebrospinal fluid of patients with completed stroke presence of LTC4-like material was observed.
Twenty-one patients with arteriosclerosis obliterans of lower extremities were treated with beta-pyridylcarbinol (Ronicol) for five weeks. The long-term therapy with beta-pyridylcarbinol did not influence platelet aggregability. Activation of the fibrinolytic system was observed. This fibrinolytic effect of Ronicol was abolished in patients treated with aspirin. In most cases a slight clinical improvement was seen, manifested by elongation of pain-free walking distance and increased blood flow in affected limbs. It is concluded that the therapeutic effect of Ronicol in humans may be partly mediated by the release of endogenous prostacyclin.
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Beta-pyridylcarbinol (Ronicol) when injected (1,2-1,4 mg/kg i.v.) into four patients with arteriosclerosis obliterans caused a release of an unstable disaggregatory substance into arterial blood of those patients. This release was not observed in other two patients who had been pretreated with aspirin (1,8 g p.o.daily). It is postulated that some of pharmacological properties of nicotinic acid derivatives are mediated through the release of endogenous PGI2-like substance.
The influence of platelets and platelet membranes on the generation of prostacyclin (PGI2) and thromboxane A2 (TXA2) by isolated rat lung and porcine aortic endothelial cell, as measured by RIA of their stable end-products, 6-oxo-PGF1 alpha and TXB2 respectively, was studied. After introduction of either aspirin-treated platelets or membranes from aspirin-treated platelets to the perfusate, a 5-fold increase in the amount of 6-oxo-PGF1 alpha and TXB2 in the perfusate was observed. Treatment of the lung with aspirin produced a 50% reduction in the platelet-stimulated release of PGI2 and TXA2. Treatment of the lung with the phospholipase inhibitor, mepacrine, significantly reduced the platelet-stimulated release of PGI2 and TXA2. Incubation of endothelial cells with untreated platelet membranes did not alter the generation of PGI2. These results suggest that platelet-stimulated release of PGI2 and TXA2 occurs via mechanical stimulation of phospholipase A2, liberating arachidonic acid.
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It was shown in in vitro experiments that etmozin at a concentration of 100 micrograms/ml significantly suppressed (by 21%) platelet aggregation induced by ADP, but it had no effect on platelet aggregation induced by arachidonic acid. In in vivo experiments etmozin was found to cause a marked suppression of tendon collagen-induced platelet aggregation in the doses 2-5 mg/kg having antiarrhythmic activity. Under suppressed platelet aggregation induced by indomethacin, the prostaglandin biosynthesis blocker etmozin displayed no antiaggregation effect. It is suggested that etmozin effects on ADP release from platelets play the main role in the mechanism of its antiaggregation action.
The influence of hyperventilation on the spontaneous generation of prostacyclin and thromboxane A2 by isolated rat lungs was studied. Both prostacyclin and thromboxane A2, as measured by RIA of their stable end-products, 6-oxo-PGF1 alpha and TXB2 respectively, were continuously released into the perfusate. However, the concentration of prostacyclin in the perfusate was higher than thromboxane A2. Under normal ventilation at a rate 40-50 breaths/min, the ratio between these two compounds was 5:1. Increasing the rate of respiration to 100 breaths/min preferentially stimulated the release of prostacyclin. During hyperventilation-stimulated release of prostacyclin and thromboxane A2. Hydroperoxy-fatty acids and tranylcypromine inhibited only the release of prostacyclin but did not affect the generation of thromboxane A2. Our findings confirm that the lung generates prostacyclin predominantly, and provide direct evidence that respiratory movements are involved in generation of pulmonary prostacyclin and thromboxane A2.
Isolated perfused cat lungs secreted spontaneously a PGI2-like substance that relaxed a strip of bovine coronary artery. The presence of PGI2 was confirmed by the identification of 6-oxo-PGF1 alpha by GC-MS. Both bioassay and mass fragmentography showed that PGI2 was released at a rate of 4 - 12 ng/ml. Generation of PGI2 by the perfused cat lungs was stimulated by angiotensin II (3 - 10 ng/ml). The above results along with our in vivo experiments point to the lung as an important source of endogenous PGI2 in the body.
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When infused intravenously into anaesthetized cats angiotensin II (1--4 micrograms/kg) released into the circulation an unstable substance that caused de-aggregation of platelet clumps, relaxed a strip of bovine coronary artery, and its release was blocked by aspirin and indomethacin. Because of these characteristics this substance is likely to be prostacyclin. Catecholamines and phenylephrine did not induce the release of prostacyclin. It is suggested that a chemical modification of the molecule of angiotensin II may render a peptide with little hypertensive properties which will be an activator of prostacyclin biosynthesis.
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The antithrombotic effect of dipyridamole is through phosphodiesterase inhibition and depends on stimulation of platelet cyclic A.M.P. by circulating prostacyclin in the bloodstream. Low doses of aspirin selectively inhibit platelet cyclooxygenase and potentiate the antithrombotic effects of dipyridamole and theophylline. High doses of aspirin also prevent prostacyclin formation, thereby abolishing the effects of dipyridamole. Thus, the antithrombotic effectiveness of the combination of aspirin and dipyridamole depends critically on the doses used.
In vivo anti-platelet de-aggregatory activity of exogenous prostacyclin is enhanced after its passage through the pulmonary circulation of anaesthetized cats, probably because of a concomitant generation of endogenous prostacyclin by the lungs. Evidence is also presented that perfused lungs of guinea pigs and rats spontaneously release considerable amounts of prostacyclin. It is therefore postulated that a continuous biosynthesis of prostacyclin by pulmonary endothelium is a general physiological phenomenon, while the generation of thromboxane A2 by lungs occurs in response to pathological stimuli. Coronary and cerebral arteries are supposed to benefit from this hormonal function of the lungs.
Aortic strips from atherosclerotic rabbits or Achilles tendons from healthy rabbits were superfused with blood (3 ml/min) from anaesthetized and heparinized cats, while blood was returned to the venous system of animals. The superfused tissues gained in weight because of deposition of platelet thrombi on their surface. This gain in weight was continuously monitored and quantified. Forty minutes after intravenous administration of indomethacin (14 mg/kg), aspirin (7 mg/kg) or nictindole (2 mg/kg) the formation of platelet depostis was reduced by half. Three hours after i.v. administration of each drug at a dose of 20 m;/kg the remaining anti-platelet activities were 92% for aspirin, 59% for indomethacin and 18% for nictindole as compared to their antithrombotic action, which was recorded 40 min after their administration. Thrombogenesis was also prevented by a direct infusion of nictindole (50 ng/ml) or indomethacin (2000 ng/ml) into a stream of superfusing blood. Thereby our method enables us to quantify in vivo anti-aggregating potency of drug, to estimate the duration of this action, and to compare their in vitro and in vivo aggregation-inhibitory activities.
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In the mixed venous blood of anaesthetized, heparinized cats prostacyclin de-aggregated platelet thrombi, which were formed on the surface of blood-superfused collagen strips or on the surface of blood-superfused aortic strips from atherosclerotic rabbits. The reversal of platelet aggregation by prostacyclin was still achieved 3 hrs after the formation of platelet clumps. After an intravenous injection of prostacyclin the ID50 for its de-aggregatory action was 7.5 microgram/kg. Theophylline ethyl-diamine (aminophylline), at a dose of 3 mg/kg i.v., did not reverse platelet aggregation but it enhanced the duration of the de-aggregatory action of prostacyclin; it had little effect on the hypotensive action of prostacyclin. It is concluded that prostacyclin disintegrates platelet clumps long after they are formed in heparinized blood in vivo and that its anti-platelet action, but not hypotensive action, is selectively potentiated by a phosphodiesterase inhibitor. The above experimental data indicate the possibility of the combined use of theophylline and prostacyclin in arterial thrombosis.