Gy. Mózsik

Some feed-back mechanisms by drugs in the interrelationship between the active transport system and adenyl cyclase system localized in the cell membrane

Abstract The Na + -K + -dependent (transport) ATP-ase was prepared from rat heart and gastric tissues, human gastric mucosa and the effects of adrenaline, atropine, acetylcholine, neostigmine and NaF were tested on it. The experiments presented have shown that adrenaline and atropine in a wide range of concentrations of NaF cause a highly significant inhibition of Na + -K + -dependent ATP-ase from four types of tissues; acetylcholine and neostigmine were without effect. Interrelationships between the active transport ATP-ase system and adenyl cyclase system are discussed. From the effects of drugs on both systems under in vitro conditions it is concluded that (i) the transport ATP-ase system is 100- to 1000-times more sensitive to drugs than the adenyl cyclase system, (ii) the stimulation by drugs of adenyl cyclase is associated with blocking of Na + -K + -dependent ATP-ase activity, (iii) activity of Na + -K + -dependent ATP-ase present in the incubation system causes inhibition of adenyl cyclase activity, (iv) the products of adenyl cyclase activity (cyclic adenosine 3′,5′-monophosphate and adenosine 5′-monophosphate) directly inhibit the Na + -K + -dependent ATP-ase activity, (v) the active transport ATP-ase system and adenyl cyclase system are separate.

Direct inhibitory effect of adenosine monophosphates on Na+-K+-dependent ATPase prepared form human gastric mucosa

Abstract Preparations of Na + -K + -dependent ATPase were obtained from human gastric mucosa and the effects of adenosine monosphosphates (cyclic 2′,3′-adrenosine monophosphate, cyclic 3′,5t-adenosine monophosphate and 5′-adenosine monophosphate) on its activity were measured. Direct inhibitory effects of adenosine monophosphates on transport ATPase activity were found. The adenyl cyclase and transport ATPase systems are discussed.

Inhibition of Mg2+Na+K+-dependent ATPase system from human gastric mucosa by prostaglandins E1 and E2

Abstract The Mg 2+ -dependent and Na + ue5f8K + -dependent (Na + ue5f8K + -activated or transport) ATPase (EC 3.6.1.3.) were prepared from human fundic gastric mucosa and the effects of prostaglandins E 1 and E 2 on their activity studied. Significant inhibitions of Mg 2+ -dependent, total (Mg 2+ -dependent and Na + ue5f8K + -dependent) and Na + ue5f8K + -dependent ATPase activities were caused by prostaglandins E 1 and E 2 , in concentrations of 10 −9 to 10 −6 M. A possible role of Mg 2+ ue5f8Na + ue5f8K + -dependent ATPase system is discussed in the inhibition of gastric secretion by type E prostaglandins.

Development of 'pharmacological denervation phenomenon' in patients treated with atropine

Abstract The parotid secretion of patients subjected to chronic atropine treatment was examined before, during 2–4 weeks, and after the course of treatment. The basal and reflex secretions (to 0.5 and 5.0% citric acid applied locally) were measured as well as the secretions in response to acetylcholine, norepinephrine and histamine. During the course of treatment there was a decrease in the inhibitory effect of atropine on the parotid secretion, which was not caused by a change in its absorption, metabolism or excretion. During the atropine treatment there was an increase in the basal and submaximal reflex secretions and in the secretion produced by norepinephrine; a smaller increase was observed in response to acetylcholine. 3–5 days after the end of atropine treatment, the basal, submaximal reflex and norepinephrine-induced secretions returned to pretreatment level; the acetylcholine-induced secretion was also reduced but to a lesser degree. From these data the authors conclude that a pharmacological denervation phenomenon develops in human beings. This indicates that there is an alteration in the balance of the mediator-effector system which is reversible, for in 3–5 days after the atropine treatment the pharmacological denervation phenomenon disappears and the original state is re-established.

Development of drug cross-tolerance in patients treated chronically with atropine.

Abstract Studies were carried out on the quantitative inhibitory effect of a quaternary parasympatholytic compound (Gastrixone: 8-methyl-tropinium-bromide-xanthene-9-carboxilate) upon the basal and reflex parotid secretion in patients treated chronically with atropine before, during (2–4 weeks) treatment and 3–6 days after cessation of treatment. A significant decrease in the inhibitory effect of Gastrixone was observed during the course of treatment. This was shown to be a reversible process since the original effect returned 3–6 days after the end of atropine treatment. No alterations in absorption, metabolism and excretion of Gastrixone were found during the atropine treatment. These results suggest the development of drug cross-tolerance to Gastrixone during the course of atropine treatment. The hypothesis is put forward, based on experiments on cholinesterase activity, that the site of the drug cross-tolerance phenomenon is at the receptor level, the alteration of cholinergic receptor structure being induced by prolonged atropine treatment.

Interrelationships between the Gastric Secretory Responses, Prostaglandin E2 Inhibition and Serum Level of Immunoreactive Gastrin in Pylorus-Ligated and Antrectomized Rats

The effects of prostaglandin E2 (PGE2) have been studied on the gastric secretion and the serum level of immunoreactive gastrin in pylorus-ligated and antrectomized rats. It has been observed that: (1) a significant inhibition of gastric secretion (volume and acid output) was caused by PGE2, applied in doses of 75, 150 and 300 microgram/kg body weight, subcutaneously, in both pylorus-occluded and antrectomized rats: PGE2 inhibition of gastric secretion was more pronounced in rats with antrectomy; (2) no significant changes were found in the serum gastrin levels of both pylorus-ligated and antrectomized rats, and (3) no significant changes in serum levels of immunoreactive gastrin were produced by different doses of PGE2, in comparison with their marked inhibitory effects on gastric H+ secretion. It was concluded that there is no essential role of the immunoreactive gastrin, originated from the antral part of the stomach, neither in development of gastric hypersecretion nor in PGE2-produced inhibition on gastric secretion of the pylorus-occluded rats.

Some effects of prolonged treatment with atropine on the stomach wall of the rat: (a biochemical-pharmacological approach of the effects of vagal exclusion — vagotomy and atropine treatment — on cellular-molecular level)

Abstract A biochemical-pharmacological analysis of the stomach wall was made in rats chronically treated with atropine. The acid-soluble inorganic and organic phosphates, phospholipid phosphates, ribonucleic acid and deoxyribonucleic acid were measured from the membranous (rumenal) and glandular (pyloric) parts of the stomach wall. It was observed that 1) the glandular part and the membranous part of the stomach wall did not react similarly to prolonged (25 days) atropine treatment; 2) “short term” (reversible) and “long term” (irreversible) biochemical process were present in the glandular part of the stomach wall ten days after cessation of prolonged (25 days) atropine treatment. A biochemical-cellular-morphological theory was made to explain the difference between a “chemical” and a “surgical” vagotomy and for the development of drug tolerance on the stomach wall at the cellular-molecular level.

Base alterations of nucleic acids in stomach wall after prolonged atropine treatment

Abstract The base composition and quantitative alterations in purine and pyrimidine of ribonucleic (RNA) and deoxyribonucleic acid (DNA) have been studied in the glandular (pyloric) and membranous (rumenal parts of the rat stomach after prolonged atropine treatment. Prolonged atropine treatment produced alterations in both composition and total quantities of purine and pyrimidine bases of RNA in the membranous and glandular parts of the rat stomach, while the purine and pyrimidine bases of DNA were altered only quantitatively. Alterations in base composition and quantities of purine and pyrimidine bases of RNA were only reversible in the membranous part of the stomach in 10 days after cessation of treatment.

Inhibition of Na+-K+-Dependent ATP-ase from Mucosa of Human Small Intestine by Butyl-Biguanide

The membrane ATP-ase was prepared from mucosa of human small intestine with differential centrifugation and treated with 2 M NaJ. The effect of butyl-biguanide, which inhibits the active transport (absorption) of glucose from the small intestine in man and also in animals, has been studied in relation to Mg++-dependent, total (Na+-K+-dependent and Mg++-dependent) and Na+-K+-dependent ATP-ase activities exclusively. A significant inhibition of total and Na+-K+-dependent ATP-ase was caused by butyl-biguanide, while no significant stimulation of Mg++-dependent ATP-ase activity was obtained. The possible role of Na+-K+-dependent ATP-ase activity in the glucose absorption from small intestine, on the one hand, and the inhibition by butyl-biguanide of glucose absorption, on the other hand, have been discussed.