The authors studied the effect of administration of thyroid hormones on the beta-adrenergic receptors of rat adenohypophyseal cells. The administration of triiodothyronine and thyroxine was followed by an increase in specific binding for 3H-dihydroalprenolol. No significant differences were found in cyclic adenosine monophosphate levels before and after isoprenaline stimulation. The significance of changes in these receptors for the hyperplastic reaction after oestrogens is discussed with reference to the inhibitory effect of the thyroid hormones on hyperplasia of the adenohypophyseal cells after the administration of oestradiol.

Experiments using a cytochemical method showed the presence of a specific precipitate of the adenylate cyclase (AC) reaction on the sarcolemma and in the subsarcolemmal cisternae and junctional sarcoplasmic reticulum in rat cardiomyocytes. The localization of AC in the given organelles draws attention to the mutual association between Ca2+ ions and cAMP in the modulation of cardiac contractions. Trifluoperazine (TFP) and chlorpromazine (CHP) are known as phenothiazine derivatives inhibiting cellular enzymatic processes dependent on calmodulin and Ca2+. AC is one of these enzyme systems. The administration of TFP and CHP (both in a dose of 0.1 and 3 mmol.1(-1)) did not affect the cytochemical localization of the enzyme. Quantitative determination of 125I-cAMP by RIA showed that CHP inhibited AC activity in both concentrations. TFP, on the other hand, did not inhibit AC activity in 0.1 mmol.1(-1) concentration and actually stimulated its activation in 3 mmol.1(-1) concentration. The different action of the phenothiazine derivatives on AC activity can be attributed partly to the different affinity of TFP and CHP for calmodulin and partly to interaction of the inhibitor-calmodulin complex with the phosphodiesterase (PDE) system.

Patients with essential hypertension have 3.2 fold and patients with chronic uraemia 11.7 fold higher serum concentrations of endogenous digitalis-like activity than normotensives (76.3 +/- 9.3 nM). Upon haemodialysis this serum activity drops to almost normal values. A low molecular factor could be partially purified from 4000 l haemofiltrate.

Inhibition of the Na(+)-K+ pump by digitalis compounds has been reported to increase intracellular Na+ and Ca2+ concentrations and to stimulate Na(+)-H+ exchange. The activity of endogenous digitalis-like compounds, proposed to promote natriuresis and to raise blood pressure, has been found to be increased in volume expansion and hypertension. The enhanced cytosolic [Ca2+] present in platelets from hypertensive patients may thus originate from inhibition of the Na(+)-K+ pump by endogenous inhibitors, enhanced mobilization of internal Ca2+ stores due to phospholipase C activation and/or structural membrane defects. In unstimulated platelets from essential hypertensives, the increase in [Ca2+]i depends on external Ca2+, thereby underlining the importance of Ca2+ influx. The observation that [Ca2+]i was also enhanced in erythrocytes (p = 0.03) demonstrates that intracellular stores are not required for this rise. Plasma digitalis-like activity was positively correlated with platelet [Ca2+]i (inhibition of renal Na+,K(+)-ATPase, competition with ouabain binding, p less than 0.01). Platelet [Ca2+]i also rose during chronic digoxin administration (p less than 0.02) but not after acute in vitro ouabain treatment. The alkalinisation of platelet cytosol (p = 0.005) also agrees with the stimulation of the Na(+)-H(+)-exchange. In conclusion, these results are compatible with a participation of endogenous Na(+)-K+ pump inhibitors in the control of cytoplasmic [Ca2+] and cell excitability.

Protein kinase C activity in the lysate of erythrocytes of patients with essential hypertension (EH) and spontaneously hypertensive rats (SHR) was found to be increased by 1.6-2.0 times as compared with normotensive controls. Membrane cytoskeleton alterations observed in the erythrocytes of patients with EH and SHR were revealed in decreased average erythrocyte volume, increase of cup-shaped cell formation, and increase of basal phosphorylation of band 4.9 protein. In addition, the rate of Na(+)-H+ exchange in erythrocytes of EH patients and SHR was increased by 1.9-fold. In vitro treatment of erythrocytes of healthy donors and Wistar-Kyoto rats (WKY) with protein kinase C activator (12-O-tetradecanoylphorbol-13-acetate) leads to similar changes of cell shape, cell volume, band 4.9 protein phosphorylation and Na(+)-H+ exchange, as well as to an increase of diS-C3-(5) fluorescence. It may be assumed that alterations of these parameters revealed in primary hypertension are caused by increased activity of protein kinase C.

The rate of delta mu H+ --induced erythrocyte Na+/H+ exchange is increased in both patients with essential hypertension (EH) and spontaneously hypertensive rats (SHR). The increase of Na+,K(+)-cotransport was revealed in erythrocytes of SHR only. This alteration as well as a decrease of mean cell volume were observed in both young and old erythrocytes of SHR. The moderate shrinkage of rat (but not human) erythrocytes results in an increase of the rate of Na+,K(+)-cotransport. The more pronounced shrinkage of rat (but not human) erythrocytes induces the Na+/H+ exchange. These reactions are accompanied by phosphoinositide response. Activator of protein kinase C (TPA) increases delta mu H+ --induced Na+/H+ exchange both in human and rat erythrocytes but it does not modify phosphoinositide metabolism. No differences were observed in the rate of Na+/H+ exchange between TPA-treated erythrocytes of SHR and WKY. We assume that the activation of protein kinase C increases Na+/H+ exchange in primary hypertension. Increased Na+/H(+)-cotransport revealed in an experimental model of primary hypertension is probably due to the decrease of erythrocyte volume.

In a strain of mice called DI +/+ Severe, nephrogenic (or vasopressin-resistant) diabetes insipidus is caused by an inability of the antidiuretic hormone (ADH, or vasopressin) to increase the water permeability of the renal collecting system. That inability, in turn, arises from abnormally high activity of the enzyme cAMP-phosphodiesterase, specifically of the isozyme type III (PDE-III), which hydrolyzes cAMP and prevents the intracellular buildup of this second messenger. Two rather specific inhibitors of PDE-III, rolipram and cilostamide, used either in vitro or in vivo, reverse the deficiencies in DI +/+ Severe mice by increasing intracellular cAMP and water permeability toward or to their normal values. These results have implications for the treatment of nephrogenic diabetes insipidus in human patients.

The problem of space flights called for the need to construct ground-base models which imitate or simulate some reactions of the organism to the complex of spaceflight factors, mainly to microgravity. In this review the processes and models simulating flight factors and their advantages and disadvantages are described. The authors have supplemented the models used until now by a new modification of suspension hypokinesia, so-called safety-pin suspension. This model appears to be simple and inexpensive. It causes relatively weak traumatic stress and this may be demonstrated by daily weighing of the animals.

The anticonvulsant effects of two doses of clonazepam (CZP, Rivotril Roche, 0.1 and 1 mg/kg i.p.) were studied on model motor seizures induced by strychnine, bicuculline, 3-mercaptopropionic acid and metrazol in male laboratory rats (Wistar strain). In the first part the effects of different doses of the convulsants were investigated and for interaction with CZP doses were chosen after which more than 70% of the animals displayed generalized tonic-clonic convulsions (a grand mal seizure). Strychnine induced this type of seizure only: two doses (2 and 3 mg/kg s.c.) were used. CZP reduced the incidence of convulsions only after the larger dose, but plain solvent (propylene glycol, ethanol, water) was equally effective. The other substances first induced a seizure of minimal (mainly clonic) convulsions and only later a grand mal seizure. CZP was highly effective against bicuculline (3 mg/kg s.c.) and metrazol (100 mg/kg s.c.), but was less so against 3-mercaptopropionic acid. The effect on grand mal seizures was more pronounced in every case than on minimal seizures. The decisive role in the anticonvulsant effect of CZP is played by the mechanisms by which the convulsants induce epileptic manifestations. CZP is most effective against substances acting on the supramolecular complex GABA receptor (benzodiazepine receptor) chloride ionophore (bicuculline and probably metrazol).

The authors evaluated the migratory and proliferative properties and the chromosome number of cultivated male and female smooth muscle cells (SMC) obtained by the explanation method from the thoracic aorta of rats of a conventional and a specific pathogen-free (SPF) breed. It was found that male SMC, in most cases, began to migrate from the explants sooner than female SMC and that they migrated from a higher total number of explants. The time needed for the number of cells in the culture to double (doubling time) was practically the same for male and female SMC, but male SMC attained a higher maximum population density. Male SMC cultures (2nd passage) contained cells with a hyperploid chromosome number, whereas female SMC were diploid. It was also found that SMC from conventional rats, in which the presence of pathogens could be presumed, displayed higher migratory and proliferative capacity than the SMC of SPF rats. The capacity of the SMC of male rats for migration and proliferation could have been potentiated by the effect of a different composition of the intercellular matrix and a different chromosome number, and in conventional rats by the presence of pathogens.

The authors studied the question of the completeness of ventilation of an additional dead space in the form of a tube 3 cm in diameter and with a volume of 600 ml. Seven young volunteers were examined while breathing with and without the tube, seated at rest and during a two-grade exercise load on a bicycle ergometer. The criterion of ventilation of the tube was enlargement of the dead space by 600 ml during breathing through the tube. The functional dead space was always calculated from the tidal volume and the CO2 concentration in mixed expired air and in an end-tidal sample, using the Bohr equation. In every case, the tube was found to be completely ventilated by breathing, both under resting conditions and during exercise. In breathing during the bicycle exercise, the ratio of the functional dead space to tidal volume fell from 0.3 to 0.19 and a similar decrease was recorded in breathing through the tube.

Bilateral paralysis of the diaphragm can result in normo or hypoventilation, according to the species studied. Our aim was to ascertain the results of bilateral phrenicotomy in the rat and, if hypoventilation should be present, to try to identify its pathophysiology. We used 33 male rats under urethane anaesthesia (1.3 g/kg i.p.). They were divided into three groups: control animals, rats with bilateral phrenicotomy and a group with two doses of pentobarbital (25 mg/kg i.p. each) on top of the urethane anaesthesia. We observed pronounced hypoventilation both in the rats after phrenicotomy and those with pentobarbital. At comparable levels of hypoventilation (PaCO2 = 5.61 +/- 0.28 kPa immediately after phrenicotomy and 5.91 +/- 0.25 kPa after the first dose of pentobarbital; and 7.21 +/- 0.47 kPa 4 hours after phrenicotomy and 7.38 +/- 0.39 kPa after the second dose of pentobarbital) the only difference was a longer relative duration of inspiration in phrenicotomized rats; (0.39 +/- 0.04 and 0.34 +/- 0.04 after phrenicotomy; 0.32 +/- 0.04 and 0.24 +/- 0.05 in rats after pentobarbital). Immediately after phrenicotomy and 2 and 4 hours later, and also after both doses of pentobarbital breathing was stimulated by hypoxia and hypercapnia due to the additional external dead space (0.5 ml) for 5 min. There was no pronounced differences in the ventilatory response to the dead space between the two groups; the response changed from an isocapnic (in control rats and before phrenicotomy or pentobarbital) to an isoventilatory one (four hours after phrenicotomy and after the second dose of pentobarbital). The rats after the second dose of pentobarbital did not, however, survive the added dead space.(ABSTRACT TRUNCATED AT 250 WORDS)

The micropuncture technique and X-ray microanalyses were used to evaluate Na, K, Ca, Mg, Cl and fluid transport in the early distal tubule mediated by low-molecular fractions isolated from the intestine of the hibernating ground squirrel (HSI). Perfusion of intertubular capillaries with a solution containing HSI with a molecular weight of 1-10 kD (0.1 mg.ml-1) decreased the relative reabsorption of fluid, Ca and Mg. The other low-molecular fraction 1-10 kD of m.v. (0.1 mg.ml-1) isolated from the intestine of alert ground squirrels (ASI 1-10) caused no significant changes of the ionic concentration and inulin concentration index in the distal tubule. Fraction 1 with molecular weight 1.2-4.5 kD (0.1 mg.ml-1) obtained by further division of HSI 1-10, decreased the reabsorption of fluid and ions under study. Fractions 2 (m.w. 0.98 kD) and 3 (m.w. 0.89 kD) had no effect on the ion and fluid transport in the same tubule. The addition of naloxone (0.4 mg.ml-1) blocked the action mediated by HSI 1-10 or fraction 1. Thus, the substance(s) capable of regulating Ca, Mg, and fluid transport in the distal tubule likely to be mediated by the opiate-dependent process has a molecular weight of 1.2-4.5 kD.

1. The influence of chronic forelimb immobilization enforcing movement in upright position on blood pressure was studied in monkeys. 2. In the course of 6 months all animals subjected to immobilization became hypertensive due to a parallel increase of systolic and diastolic pressure by about 30%. The hypertension was demonstrable both in awake and anaesthetized animals and persisted even after restitution of a normal movement regime. 3. In the chronic stage (after 15 months), the plasma renin concentration was decreased by 55%, indicating that the renin-angiotensin system activation does not participate in the maintenance of the hypertensive state. The plasma volume was diminished by 18%, while the interstitial fluid volume did not differ significantly from control values. 4. It is concluded that chronic forelimb immobilization in monkeys induces a low-renin hypertension, associated with changes in extracellular fluid compartments resembling the pattern found in the hypovolaemic type of essential hypertension.

Using rats (Wistar strain) of our own breed, we studied dopamine-beta-hydroxylase (E.C. 1.14.17.1) (DBH) activity in the plasma of animals of different ages (in correlation to sex) under normal conditions and after exposure to altitude hypoxia (corresponding to 7000 or 9000 m and lasting 20 min). The enzyme was determined by the method of Kato et al. (1974). We found that the given plasma enzyme activity was significantly higher in females than in males, throughout the whole life-span. In addition, we found that minimum activity was reached on about the 14th and 21st day of postnatal life and again on the 40th day, while maximum activity was recorded at the ages of 5, 30 and 35 days and in adult rats. In adult animals (males and females), exposure to altitude hypoxia was followed by a statistically significant increase in plasma DBH activity, which was much more pronounced in females than in males. In males, 240 min after terminating hypoxia plasma DBH activity had returned to normal, but in females it was still significantly raised; after 48 h, plasma DBH activity in females was identical to the activity before exposure to hypoxia. In rats aged 5 and 35 days, hypoxia evoked a fluctuating response. A decrease in activity immediately after terminating hypoxia was followed at 60 min by a return to normal, but at 240 min there was again a significant decrease. In 21-day-old rats, hypoxia did not induce any significant change in plasma DBH activity (the initial activity level in this group was very low).