[Lung metastases from tumors at different sites]. / Metastazi v belite drobove ot tumori s razlichna lokalizatsiia.

A comparative study of necropsy material is carried out for the period of 1974-1983. For these ten years 11603 autopsies are performed. In 222 cases neoplastic processes with different lung metastases are obligatory, which makes 1.8% of total number of cases. The primary sites of these metastases are as follows: tumor of the stomach (26), breast (33), bile duct (10), bile ways (3), liver (13), large intestine (30), incretory glands (31), etc. The morphological evolution shows that the histologic type of the primary tumors varies (carcinomas, malignant lymphomas, teratocarcinomas, sarcomas, neuroblastomas, etc.). In some cases (carcinomas of the kidneys and liver, sarcomas of the bones) the histologic type of the primary tumor is identical to that of the Metastatic processes in the lungs. In some of the lung metastases however there are differences in the histological structure compared to the primary tumors. A clinical morphological comparative study is performed.

[Study of the effect of sclareol glycol diterpene on the 3',5'-AMP level]. / Prouchvane na efektite na diterpena sklareol glikol vurkhu na 3',5'-AMF.

Sclareol glycol (SG) is a semisynthetic diterpene of the labdanic group. SG is tetranorlabdaniol bivalent alcohol 13, 14, 15, 16-tetranorlabdan-8 alpha, 12-diol, obtained from the plant Salvia sclarea L., grown in Bulgaria. The effects of SG were studied on the level of 3',5'-AMP in:mono-layer tissue cultures of the anterior hypophysis of the rat; in hypophysial and brain tissue during in vitro incubation; in liver microsomes of the rat during in vitro incubation and in liver perfusate of the rat. It was established that SG induced an increase in accumulation of 3,5'-AMP in the tissues from the anterior hypophyses of mature and newborn rats, in the sections of brain cortex and cerebellum of mature rats. Similar changes were found by the diterpene forskolin, studied comparatively. SG induced a reduction of accumulation of 3',5'-AMP in liver microsomes and diminished the release of 3',5'-AMP in a liver perfusate of the rat. The increased accumulation of 3',5'-AMP due to SG could be explained by postreceptor stimulation of the enzyme adenylate cyclase, binding directly to its catalytic subunit. The reduced accumulation of 3',5'-AMP in liver microsomes and its diminished release in liver perfusate could be explained either by activation of the inhibitory adenylate cyclase in hepatocytes or by desensitisation of 3',5'-AMP-generating system.

Effect of papaverine analogues on 3', 5'-adenosine monophosphate phosphodiesterase activity in rat brain.

In vitro studies were carried out of some hydrated papaverine analogues on the rat cerebral phosphodiesterase (PD). The potential inhibitory effect of the newly-synthesized drugs (Trifonov, Orahovats, 1978), as well as the effect of papaverine, were studied in a series of concentrations (1 micrometer to 100 micrometers) on brain homogenates. The enzyme activity was determined by the isotope method of Filburn and Karn (1972) at two substrate concentrations (1 and 200 micrometers). Dihydropapaverine was found to have practically no effect. 6'-Iodo-dihydropapaverine is a weaker inhibitor of the enzyme with low Km, compared with 6'-bromo-dihydropapaverine, however, unlike it its effect on PD with high Km is more marked. Among the compounds tested, papaverine is the most powerful inhibitor of the enzyme with low and high Km. The kinetic analysis of PD with low and with high Km, performed after Lineweaver and Burk, has shown hat the inhibition of the enzyme by the studied substance is reversable and of the competitive type. The inhibitory constants of the compounds studied were estimated.

Ontogenetic development of 3,5-adenosine monophosphate phosphodiesterase in guinea pig and rat ileum.

The postnatal development of phosphodiesterases with low and high Michaelis constants in guinea pig and rat ileum was studied. The tow types of phosphodiesterases were found to increase their activity post partum, and this increase was particulary pronounced in the rat. The rise in the enzyme activity took place mainly at the expense of the increase of the phosphodiesterase with high Km. In addition to the quantitative differences in the phosphodiesterase activity of yound and adult animals, considerable age differences were also observed in the sensitivity of the enzyme to inhibitors and activators. These data can contribute to the explanation of the differences in the action of some drugs influencing the phosphodiesterase in young and adult organisms.

[Effect of ionizing radiation on cerebral phosphodiesterase]. / Vliianie na ionizirashtata radiatsiia vurkhu mozuchnata fosfodiesteraza.

The authors examined the influence of x-ray irradiation on phosphodiesterase system in the brain of rats and the sensitivity of the enzyme to inhibitors (caffeine, theophyline, thyopental) and activators (imidozol). The animals (Wistar with weights of 150--200 gm/were irradiated singly with a dose of 737 r. Phosphodiesterase activity (PD) was determined by the method of Filburn and Carn (1972) at two substrate concentrations (1 and 100 microM). X-ray irradiation did not change PD with high Km, while the enzyme with low Km was reduced significantly and transitionaly. Caffeine, theophyline and thyopental inhibited more PD with low Km in the irradiated rats in comparison with the control nonirradiated rats. The activating effect of imidazol on PD with low Km was more marked in irradiated rats. These data could be interpreted in the light of the molecular mechanisms, determining the altered action of some drugs after x-ray irradiation.

Regulation of transsynaptically elicited increase of 3':5'-cyclic AMP by endogenous phosphodiesterase activator.

Experiments with cold exposure confirmed previous studies indicating that the endogenous protein acitvator of phosphodiesterase (PDEA) isolated by Cheung participates in the in vivo regulation of 3':5'-cyclic adenosine monophosphate (cAMP) in adrenal medulla. This activator of cAMP phosphodiesterase (PDE) (3':5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.17) is present in the particulate as well as the soluble fractions of rat brain. It was found that a purified cAMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37), in the presence of ATP and cAMP, stimulates 3-fold the release of PDEA from the particulate fraction of rat brain and adrenal medulla. The substrate for this phosphorylation could be either a membrane protein that binds PDEA or PDEA itself. In vivo evidence, however, obtained by injecting rats intraventricularly with [gamma-32P]ATP, indicates that the PDEA does not contain radioactive phosphate in its structure. Also, PDEA could not be phosphorylated by protein kinase in vitro. The following mechanism is postulated: when the intracellular content of cAMP increases it activates a protein kinase which phosphorylates a PDEA-binding membrane protein and releases PDEA. In turn this binds to activator-deficient high Km PDE and decreases its Km to facilitate the hydrolysis of the increased concentration of cAMP.

A kinetic analysis of the cyclic nucleotide phosphodiesterase regulation by the endogenous protein activator. A study of rat brain and frog sympathetic chain.

The effect of the endogenous protein activator on the kinetic characteristics of a highly purified, activator-deficient rat brain phosphodiesterase (EC 3.1.4.-) of a highly purified, activator-deficient rat brain phosphodiesterase (EC 3.1.4-) was studied. This enzyme preparation has only a high Km for cyclic AMP and a low Km for cyclic GMP. In the presence of 20 muM Ca2+, saturating concentrations of the activator decreased the Km of this enzyme for cyclic AMP from 350 muM to about 80 muM, without changing the V. The phosphodiesterase activator did not change the Km of phosphodiesterase for cyclic GMP; however, amoderate increase of V was seen. The activator lacks species specificity; the activator isolated from the bullfrog sympathetic chain produced the same qualitative and comparable quantitative changes in the kinetic properties of the purified rat brain phosphodiesterase. Cyclic GMP is a potent competitive inhibitor of the phosphodiesterase activation by the activator (Ki=1.8 muM), using cyclic AMP as a substrate. Cyclic AMP inhibits slightly the hydrolysis of cyclic GMP by phosphodiesterase in the presence of activator (Ki=155 muM) only.

[Epithelial proliferations in organ cultures of mouse lung treated with urethane and 3,4-benzopyrene]. / Epitelni proliferati v organni kulturi ot beli drobove na mishki, tretirani s uretan i 3,4-benzpiren

The authors carried out some series of experiments under the conditions of organ cultures of lungs of mice, treated with urethane and 3,4-benzpirene. They succeeded lung culturinf up to 14-th and 21-th day. Growths of bronchial and bronciolar epithelium manifested at various degree were obtained in the lung extracts from mice, treated with urethane and 3,4-benzpirene. The most manifested proliferation was observed in extracts, treated with urethane at a dose of 10 mg/ml and 3,4-benzpirene -- 64 gamma/ml.

A neurobiological role for a protein activator of cyclic nucleotide phosphodiesterase.

This work supports the idea that PDEA is bound and stored in brain particulate fraction. The release of PDEA into cytosol where the activator-sensitive PDE is located, is the first event in the process of the regulation of cAMP metabolism and inactivation. PDEA is released by cAMP-dependent phosphorylation of the activator-binding sites. This process is Ca2+ independent and does not occur in the presence of cGMP and cGMP-dependent phosphorylation. The free, soluble PDEA activates the high Km PDE in the presence of micromolar concentrations of Ca2+. This protein decreases severalfold the Km for cAMP of the high Km activator-sensitive PDE. PDEA regulates cAMP metabolism when the concentration of cAMP is elevated by a transsynaptic activation of adenylate cyclase. The rate of synthesis and the release of PDEA might be a part of the process of receptor sub- and supersensitivity, which has been reported during denervation or as a result of chronic treatment with drugs.

[Early changes in transplants of lung organ cultures treated with several polycyclic hydrocarbons]. / Prouchvane na rannite izmeneniia v transplantati ot belodrobni organni kulturi, tretani a niakoi politsiklichni vuglevodorodi

The authors examined the early changes in transplants from lung organ cultures treated with 64/ml of 3,4-benzpirene and 4 mg/ml of 20-methylholantrene. The bronchial cycst represented the most significant changes on the control transplants. In the transplants treated with two cancerogens there were several kinds of changes increasing with the advancement of the course of the transplantation-hyperplasia of lymphocytes, hyperplasia of the bronchial epithelium, gland-like structures and bronchial cysts. Besides this there were also tumours at the end of the third month in the transplants, treated with 20-methylcholantrene--in one of the transplants there was adenom and in another-carcinoma.