Determining the parameters of concentration-response relationship for histamine on the isolated portion of guinea pig stomach and guinea pig right atrium.

In our previous experiments measuring acid secretion in the isolated mouse stomach we found higher EC50 values (agonist concentration, evoking half maximal effect) for histamine than in the experiments on the isolated guinea pig right atrium (contraction frequency). The difference could be due to nonequilibrium conditions in the isolated mouse stomach preparation or to species differences. In order to check this possibility and to test the consistency of concentration-response relationship (CRR) parameter determination on an isolated secretory organ, we compared EC50 for histamine and pA2 for famotidine on the two isolated preparations from the same species, guinea pigs. Both, EC50 and pA2 values were significantly different when measuring gastric acid secretion (9.7 microM and 6.07) from the parameters, found in the isolated right atrium measuring frequency of contractions (1.6 microM and 7.06). From these results it can be concluded that the isolated portion of guinea pig stomach is suitable for CRR determination; but the parameters obtained are in the range of higher concentrations than the real ones because of kinetic particularities of the preparation.

Stereoselective and endothelium-independent action of nicardipine on the isolated porcine coronary artery.

The qualitative and quantitative effects of the (+)-S and (-)-R enantiomers and of the racemic mixture of the Ca2+ channel antagonist, nicardipine, were compared on the isolated porcine coronary artery with intact and removed endothelium. All three forms of nicardipine inhibited the contractions induced by KCl (5-90 mM) in both vessel preparations. The potency (IC50) of the (+)-S and (-)-R enantiomers and of the racemic mixture was 6.6, 31.8 and 10.9 nM in the vessel with endothelium and 6.4, 41.9 and 9.8 nM in the vessel without endothelium. The parameters of the concentration-response curves for each form of nicardipine at a submaximal KCl (60 mM) concentration and the potency ratios between the two enantiomers ((+)-S/(-)-R) were not statistically significantly different (P>0.05) in the two vessel preparations. In conclusion, qualitatively, all three forms of nicardipine showed only Ca2+ channel antagonistic effects in both vessel preparations. Quantitatively, the inhibition of contraction was stereoselective, the (+)-S enantiomer being the most potent, and was endothelium-independent.

The dynamics of serum thyroglobulin elimination from the body after thyroid surgery.

Thyroglobulin (Tg) is a glycoprotein produced exclusively by the thyroid. It can be found in the serum of healthy people as well as of those with various thyroid disorders. Elimination of Tg from the body occurs through the liver. The data on Tg serum half-life in the literature are scarce, and the reported values vary from 6-96 h. The aim of our study was to determine the Tg half-life after surgical removal of the thyroid gland. Knowing the exact half-life of Tg would enable rational timing of sampling serum for determination of Tg after thyroid surgery or chemotherapy and/or irradiation for evaluation of treatment in patients with differentiated thyroid cancer (DTC). In 11 patients (10 females and one male, aged 27-85 years) serum samples were taken 24, 48, 72 and 168 h after a near-total or total thyroidectomy. Serum Tg levels were determined and Tg half-life calculated by the use of a one-compartment kinetic model. Mean Tg half-life was 65.2 h (SEM = 4.3), and Tg levels decrease below 5-10 ng/ml approximately only 25 days after thyroidectomy (7-10 x t1/2). Therefore, earlier determination of Tg cannot be used either for reliable detection of distant metastases or for evaluation of the effect of chemotherapy and/or irradiation.

Mast cell histamine in gastric secretion--a study on the isolated portion of a guinea pig stomach.

The effects of an H3-agonist, R-alpha-methylhistamine (0.1 and 1 microM), on gastric acid secretion and on mast cell histamine release was studied on the isolated portion of guinea pig stomach. Secretion, induced by calcium ionophore, A23187 (1 microM), and by vagal stimulation was determined by continuous pH measurement, mast cell degranulation was examined histologically. Secretory effects were not significantly changed by H3-agonist. Mast cell degranulation, elicited by vagal stimulation, was not influenced by R-alpha-methylhistamine, but the degranulating effect of A23187 was clearly augmented by the H3-agonist. The results support the view that H3-receptors could influence the release of mast cell histamine in the guinea pig stomach.

The effect of different calcium antagonists on histamine- and carbachol-induced acid secretion in the isolated mouse stomach.

Earlier experiments suggested that the action of muscarinic agonists in gastric acid secretion might be partly mediated by endogenous histamine release. This possibility could be tested by use of various calcium antagonists provided that they show different activity on histamine- and carbachol-induced secretion. In the present work, three calcium antagonists, verapamil, nifedipine and sodium nitroprusside were used on the isolated mouse stomach where acid secretion induced by histamine and by carbachol was measured. Verapamil (100 microM) did not affect either histamine- or carbachol-induced acid secretion. Nifedipine (100 microM) reduced histamine-induced acid secretion, whereas the effect of carbachol remained unchanged. Sodium nitroprusside (10-100 microM) reduced both histamine- and carbachol-induced acid secretion. The differences in action of calcium antagonists in histamine- and carbachol-induced acid secretion could exclude the possibility that the effect of carbachol is partly mediated by histamine release from mast cells present in the mouse stomach.

The effect of compound 48/80 and of electrical field stimulation on mast cells in the isolated mouse stomach.

It has been shown that compound 48/80 evokes acid secretion in the isolated mouse stomach by releasing histamine from mast cells. The aim of the present work was to study the distribution and type of mast cells in the isolated mouse stomach and to examine the effect of compound 48/80 and of electrical field stimulation (EFS) on these cells. Histological examination of the stomachs showed only the presence of connective tissue mast cells (CTMC) in all parts of the stomach except in the glandular mucosa where mucosal mast cells (MMC) predominated (MMC -71%, CTMC -29%). Compound 48/80 and EFS did not affect MMC, whereas CTMC showed marked degranulation in all parts of the stomach including the glandular mucosa. It can be concluded that CTMC, present in the gastric mucosa and being sensitive also to EFS, may be involved in the regulation of gastric secretion in the mouse.

Histamine and calcium secretion in the submandibular gland of the cat evoked by two types of stimulation.

The aim of this work was to compare the pools of histamine and calcium in the submandibular gland of the cat during two kinds of stimulation of the gland. Submandibular glands of the cat were stimulated electrically (chorda tympani nerve) and by close arterial infusion of pilocarpine. Each stimulation was adjusted in such a way as to obtain a near maximal secretory response. Concentrations of histamine and calcium were measured in nonstimulated and stimulated glands, in saliva, secreted during stimulation and in the venous outflow from the gland before and during the stimulation. The experiments showed that: pilocarpine stimulation lowered the histamine concentration in the gland more than electrical stimulation of the chorda tympani nerve. Calcium stores in the gland were depleted to the same extent by each type of stimulation. the concentration of histamine and calcium in the saliva produced by close arterial pilocarpine infusion was significantly higher than in the saliva secreted during nerve stimulation. histamine and calcium concentrations were higher in the venous outflow from stimulated glands than before stimulation. The results indicate a close relationship between histamine and calcium in salivary secretion, although the origins of the two substances are different.

The effect of compound 48/80, substance P and pentagastrin on the isolated guinea pig atrium.

It has been shown that histamine is present in guinea pig hearts. In the present work, the effect of some substances, known to liberate mast cell histamine, on the isolated guinea pig atria was studied. Compound 48/80 (100 micrograms/ml), pentagastrin (10(-6) M) and substance P (10(-5) M) were added 2-3 times to the isolated organs and the frequency of contractions was measured. At the end of experiments, the atria were examined histologically for mast cell degranulation. Compound 48/80 and pentagastrin increased the frequency of contractions of isolated atria. Substance P provoked a dose-dependent decrease of contraction frequency; this effect was diminished by atropine (10(-5) M). All three substances provoked pronounced degranulation of mast cells present in the atrium, the effect of substance P being significantly greater than the effects of the other two substances. It can be concluded that mast cells, present in guinea pig atrium, are sensitive to the histamine liberators used; histamine is released in quantities high enough to produce an effect.

The effect of compound 48/80 on the carbachol-evoked acid secretion of the isolated mouse stomach.

The aim of the present work was to determine in the isolated mouse stomach whether the depletion of mast cell histamine by compound 48/80 influences the acid secretion, evoked by carbachol. Each effect of carbachol was compared to the effect of histamine (10(-6) M), applied after each carbachol application. After carbachol and histamine, compound 48/80 was applied twice or three times successively; the second and the third application were not able to evoke any secretion. After 48/80, the applications of carbachol and histamine were repeated and their effects compared to those before the applications of compound 48/80. Three concentrations of the compound were used: 20, 100 and 500 micrograms/ml. The lowest concentration of the histamine liberator did not significantly change the response to carbachol, The highest one reduced it but the effect of histamine was reduced, too. Compound 48/80 in concentration 100 micrograms/ml significantly augmented the secretory effect of carbachol. The possible explanation for this effect is that histamine, liberated from mast cells, is taken up by some other cells in the tissue from where it is liberated by carbachol stimulation.

The role of tissue mast cells in exocrine secretion: studies in the submandibular gland of the cat.

Histamine was found to be stored in the submandibular gland of the cat mainly in the mast cells. The amine is released from mast cells by compound 48/80 and pilocarpine. This was demonstrated in the in vivo and in vitro experiments and by histological examination. During the physiological stimulation of the gland, via the electrical stimulation of the chorda tympani nerve, significant changes of histamine content were not found. This could be explained by the increased synthesis of histamine during physiological stimulation. The physiological role of histamine in salivary secretion was demonstrated. The similarity between the roles of histamine, mast cells and chromaffine-like cells in salivary and gastric secretion is discussed.

The inhibition of salivary secretion by histamine H2-antagonists--a study on the cat submandibular gland.

The aim of the present work was to establish whether the secretory process can be influenced by histamine H2-receptor antagonists, burimamide and metiamide. These drugs were applied intravenously and the secretion was evoked by the electrical stimulation of the chorda tympani nerve or by carbachol (i.v.). In addition to the measurements of the flow of saliva, the blood flow through the gland was measured in some experiments. Both H2-antagonists significantly reduced the rate of salivary secretion induced by the chorda tympani stimulation. The experiments with burimamide did not permit the calculation of dose-response relationship. From the experiments with metiamide the ED50 was 4.6 mumols/kg and Emax was 30% reduction of secretion. The secretory response to carbachol was not diminished by burimamide. In addition to the effect of metiamide on salivation, the reduction of the blood flow through the gland was observed: the effect on the blood flow was significantly smaller, and slower in onset, than the effect on salivation. These results support the hypothesis that H2-receptors are involved in the process of salivary secretion. Histamine effects on glandular elements seem to be more significant than its effect on the blood vessels.

Analysis of the dose-response relationship of histamine and N tau-methylhistamine.

The dose-response relationship of histamine (Hi) and N tau-methylhistamine (MeHi) was analysed in isolated ileum and the right auricle of the guinea pig, in isolated mouse stomach and in the blood flow through the submandibular gland of the cat. It was shown that the intrinsic activity of MeHi is slightly less than that of Hi. MeHi is equally active on either type of Hi receptor; the differences found in the isolated mouse stomach and in the blood flow through the salivary gland can be explained by non-equilibrium conditions. The dissociation constant of MeHi (3.5 X 10(-4) M) is nearly the same in the isolated ileum and the right auricle of the guinea pig and in isolated mouse stomach.