Assessment of thorotrast redistribution in liver tissue of the rat.
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Biomedical subjects
Publications and source records attributed to W Riedel.
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Rabbits in a warm environment reacted to i.v. injections of 10 mg/kg propylthiouracil (PTU) with an immediate fall of serum triiodothyronine (T3) concentration, associated with decreases of respiratory rate and cutaneous blood flow. Simultaneously renal blood flow increased, while arterial blood pressure fell slightly. A rise in the animals' core temperature by 1.1 degree C, on average, contributed to the impression that PTU mimicked the stimulation of the normal thermoregulatory response pattern of cold defence. The cardiorespiratory responses to PTU were found to be augmented 6-8 days after thyroidectomy, but were completely abolished 16-20 days after thyroidectomy or chronic PTU treatment. In chronically thyroidectomized rabbits, i.v. injections of T3, but not of T4, elicited panting and cutaneous vasodilatation. The acute effects of injecting i.v. bacterial endotoxin (LPS) into rabbits in a warm environment consisted of cutaneous vasoconstriction and a decrease in respiratory rate, i.e. in an autonomic cold defence response, which was associated with a sustained increase in serum T3 concentration and caused core temperature, T3 serum concentration decreased again, whilst simultaneously the autonomic activity pattern changed to that of heat defence, comprising a rise in respiratory rate and skin vasodilatation. The results suggest the hypothesis that, similarly to a decrease of serum T3, LPS activates neurones in the CNS which secrete the thyrotropin-releasing hormone (TRH). This, in turn, elicits cardiorespiratory adjustments similar to those observed in the cold, while the opposite response occurs if these TRH secreting neurones are inhibited.
As a prerequisite for quantifying the non-radiation effect of Thorotrast, nonradioactive and radioactive aquasols with identical physicochemical properties and with biophysical behavior comparable to that of Thorotrast were developed and produced for a second long-term animal experiment. Comparative investigations with hafnium and zirconium (zirconotrast) dioxide aquasols showed the latter to be most appropriate considering the size of both the dispersoids and the aggregates in the liver tissue. The average particle diameters of ThO2, ZrO2 and HfO2 proved to be values of 9.3 nm, 15 nm and 45 nm, respectively. The size of the aggregates shows a slight dependence on the applied amount but no dependence on the duration of body burden of the colloid. The aggregate diameters in the 600 microliters group turned out to be 9.6 microns, 14.4 microns and 5.3 microns, respectively. Radioactive zirconotrast was prepared by radiochemical incorporation of 230Th and 228Th at dose rates which produce accumulated doses in the liver of rats equivalent to those of commercial 230Th enriched Thorotrast after 1.5 yr. Five different colloids were prepared with alpha-energy emission rates increased by factors of 1, 2.5, 5, 10 and 25 compared to Thorotrast and then injected into rats.
Our first long-term animal experiment made use of 1920 female Wistar rats divided into 20 groups of 96 animals each. These were injected at 12 weeks of age with different volumes and different dosages of Thorotrast which was enriched with 230Th to enhance the alpha-energy emission rate. The purpose of the study was to evaluate the effects due to the colloidal substance and the radiation. In the main experiment, 12 groups of rats were injected intravenously with 60, 120 and 300 microliters Thorotrast. 230Th was added to some Thorotrast preparations so that the total alpha-energy emission rate varied by factors of 1, 2, 5 and 10 relative to normal Thorotrast. Two groups were injected with 12 and 60 microliters of 50-fold enriched Thorotrast. One group was given 600 microliters of normal Thorotrast. In addition, we had 5 control groups, 1 NaCl and 4 Dextrin groups. The latter were injected with 60, 120, 300 or 600 microliters of Dextrin. The first animals died 8 months after injection, and the last 11 animals were killed 41 months after starting the experiment. The number of animals that developed a hepatic or splenic tumor increased by a factor of 10 in the highest dose-rate groups compared to controls. Our results demonstrated a linear correlation between the dose-rate and the number of primary hepatic and splenic tumors. It appeared that the volume of injected Thorotrast, by itself, had little influence on the number of tumors. However, at a constant dose-rate of 10, a 50-fold increase in the volume of Thorotrast (12-600 microliters) decreased the minimal tumor-appearance time by about 250 days.
Hypothalamic heating in dogs with depleted peripheral adrenergic transmitter stores by means of chronic application of reserpine elicits increase of hindpaw blood flow. The vasodilator response is not affected by alpha- and beta-adrenergic or cholinergic blocking substances, nor by histamine-, or prostaglandin-antagonists. Dopamine and ergometrine produce cutaneous vasoconstriction which is antagonized or prevented by haloperidol. The hypothalamic vasodilator response is abolished after intra-arterial injection of haloperidol, after lumbar sympathetic chain section, or by high doses of hexamethonium. The results indicate neurogenic non-adrenergic control of skin blood flow in thermoregulation possibly acting through inhibition of dopaminergic vasoconstrictor mechanisms.
In conscious rabbits peripheral cold stimuli decreased respiratory rate and increased cutaneous vasomotor tone while simultaneously renal sympathetic nervous discharge decreased. Peripheral warm stimuli produced the reverse pattern of autonomic effector activity. Injection of a bacterial endotoxin at warm ambient temperature elicited a biphasic fever response. Within the first 60 min cutaneous vasomotor tone increased, simultaneously renal sympathetic activity decreased. Therefore, ear skin vessels dilated and renal sympathetic activity increased by about 100%. Respiratory rate remained depressed during both fever phases. Renal blood flow was investigated in a second series of experiments and showed a negative stimulation but only in the first phase of fever. The results show that renal innervation is involved in the typical thermoregulatory autonomic activity pattern by which temperature homeostasis is preserved. The vasomotor patterns of cold and heat stress developing during fever are compatible with the concept of a changed set-point of the body thermostat. The depressed respiratory rate and the lack of the renal vascular response to the increased nervous activity during the second fever phase and their reversal to normal after acetylsalicylate (ASA) indicate the participation of prostaglandins modifying peripheral and central neurotransmitter mechanisms.
In conscious rabbits with indwelling intracisternal (i.c.) catheters i.c. injection of noradrenaline (range 20 - 2000 ng) elicited dose-related cutaneous vasoconstriction of the ear skin vessels and reduction in renal sympathetic vasoconstrictor activity (integrated mass discharge). In addition there was shivering and a rise in the animals "core" temperature, so that the injections of noradrenaline mimicked the normal thermoregulatory pattern of cooling. In 5 other rabbits with implanted hypothalamic thermodes we studied the responses of the ear temperature, renal sympathetic nerve activity and respiration rate to hypothalamic heating and cooling. The animals were studied: (i) under control conditions; (ii) after i.c. administration of noradrenaline: (iii) 24 h after 6-hydroxydopamine (6-OHDA) when there is marked depletion of CNS noradrenergic transmitter stores. After the drugs the temperature-response curves were displaced from control in approximately parallel fashion with little change in gain. Noradrenaline elicited shifts that were directionally opposite to those produced by 6-OHDA, suggesting that the changes in thermoregulatory properties were specific effects of the transmitter. Previous studies also suggest that the site of modulation of the thermoregulatory response is at bulbospinal levels, at least as far as the renal sympathetic response was concerned.
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In rabbits, 2 populations of sympathetic postganglionic fibres innervating the skin, heart, muscle and kidney could be classified by their different spike heights and their different susceptibility to noradrenaline and angiotensin amide. The ability of the 2 populations to respond to physiological stimuli in a highly differentiated manner leads to the assumption that 2 different systems in the cardiovascular sympathetic outflow exist.
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Single postganglionic neurones to hairy skin and hairless skin of the hindleg were investigated on spinal cord heating and spinal cord cooling in chloralose anesthetized cats. 1. Spontaneously active postganglionic neurones which were classified as vasoconstrictor neurones were depressed by spinal cord heating and excited by spinal cord cooling. The overall response to spinal cord cooling was smaller than that to spinal cord heating. 2. Postganglionic neurones to the hairless skin, which had most likely sudomotor function, responded initially to spinal cord heating with a few impulses or not at all. As judged by the skin potentials recorded from the hairless skin the sweat glands were also only weakly activated at the beginning of the heat stimuli. 3. Six silent postganglionic neurones, 3 each to the hairy skin and to the hairless skin, were excited during spinal cord heating. The response of these neurones consisted of a dynamic and a static component and started at the beginning of the heating stimuli with latencies of less than 10S. The neurones could not be excited by any other stimuli and were classified as cutaneous vasodilator neurones. 4. Quantitative analysis of 4 spontaneously active postganglionic (vasoconstrictor) neurones and 3 silent postganglionic (vasodilator) neurones revealed that the threshold of the responses of these neurones to spinal cord heating was 40-42 degrees C (on the dorsal spinal cord) and that the response increase was maximal at the highest temperatures tested (43-44 degrees C).¿
Warm stimulation of a circumscribed region of the dorsal abdominal wall of the rabbit evoked discharges in splanchnic afferent single fibers. They showed positive temperature coefficients of their static activities and of their dynamic responses to temperature changes. They were not excited by mechanical stimuli. Cooling from static conditions caused a transient inhibition of impulse frequency. Two populations were found, one having a static and dynamic maximum at 46 degrees C, the other one at about 40 degrees C. Both types were found to be C-fibers, with a conduction velocity of 0.6 - 1.1 m/sec.
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