The parietal cell has three types of activating receptors for acid secretion on its basolateral membrane, i.e., histamine H2, acetylcholine M3, and gastrin CCKB. Activation of acid secretion is achieved by two concomitant functional changes namely: (i) tubulovesicles fuse with the apical secretory membrane, thus recruiting functional pumps to the expanded microvillar surface, and (ii) the apical membrane acquires a permeability to KCl. The major path for parietal cell stimulation is via H2-receptor-mediated adenylate cyclase and elevation of cAMP to activate protein kinase A (PKA), which phosphorylates key effector proteins, e.g., ezrin, a membrane-cytoskeletal linker, apical Cl- or K+-channels. Ca2+ is liberated from intracellular stores by IP3, which in turn is the result of M3-, CCKB-, or possibly H2-coupled activation of phospholipase C. The resulting protein kinase C activation may have both inhibitory and excitatory roles. Elevated Ca2+ activates calmodulin-dependent kinases, e.g., calmodulin kinase II and myosin light chain kinase, that could promote vesicular motor activity. Ezrin is considered to play a main role in the vesicular transport system of the parietal cell. The regulation might be conducted through the phosphorylation of the molecule to modify its property to interact with the cytoskeletal components, membranes or membrane proteins.
Progress in the characterization of tachykinin receptors and the understanding of the physiological and pathological roles of tachykinins is highly dependent on the discovery of potent and selective antagonists with metabolic stability. We have recently described a peptidic antagonist of the tachykinin NK 1 receptor, sendide (Tyr-D-Phe-Phe-D-His-Leu-Met-NH2), that is a selective and extremely potent antagonist of NK-1 receptors, but displays no antagonistic activity on the response induced by NK-2 or NK-3-receptor agonists in the mouse spinal cord. When coadministered with substance P (SP) intrathecally (i.t.), sendide markedly inhibited the scratching, biting and licking behavior induced by SP in a dose-dependent manner. The antagonistic effect of sendide on the SP-induced behavioral response was approximately 7300 times more potent than that of CP-96, 345, a non-peptidic NK-1-receptor antagonist. The duration of the antagonistic effect of sendide was longer than that of CP-96, 345. The behavioral response elicited by other NK-1-receptor agonists, septide, physalaemin and [Sar9, Met (O2)11]-SP, was reduced significantly by a small dose of sendide. In the [3H]-SP binding assay using mouse spinal cord membranes, sendide potently displaced [3H]-SP binding, with a potency approximately 5.4×104 times greater than that of CP-96, 345. Moreover, Lt. administration of sendide was found to produce the antinociceptive effect through the blockage of NK-1 receptors in the mouse formalin and capsaicin tests. Sendide is therefore likely to become a powerful pharmacological tool for studying the functional roles of NK-1 receptors in the central nervous system.
Problems of multiple comparison were discussed without assuming technical knowledge of statistics. For the first question concerning why to use multiple comparison procedures, theoretical bases of statistical inference and multiple comparison (including type I error rate and familywise error rate) were briefly outlined. For the second question concerning how to properly use multiple comparison procedures, multiple comparison procedures were introduced, and their characteristics were compared. Families of comparisons are different among Dunnett's, Tukey's and Scheffe's tests. Assumptions of dose-response relationship are different among Dunnett's, Williams' tests and linear regression analysis. Duncan's test does not control familywise error rate at a fixed level. For the last question concerning what is remarked for multiple comparison, approaches to several problems such as abnormality and heteroscedasticity were provided. Philosophy and strategy to multiple comparison problems were discussed.
This paper considers the method of data analysis for a pharmacological experiment with multiple dose groups, in which a response variable is observed repeatedly at several time periods. The inappropriateness of conventionally used statistical methods such as the t-test, Dunnett's multiple comparison procedure and analysis of variance method is pointed out. We recommended that the dose-response relationship should be estimated as a response function of time incorporating the dose effect as parameters. We also propose to adopt a strategy that the researcher tests some hypotheses on the parameters in the response function appropriate to the objective of the experiment after estimating parameters of the response function based on the observed data. A numerical example applying the strategy to real data is presented.
The cumulative chi-squared statistic has been proposed for testing against ordered alternatives in various statistical models. As usual statistical tests of ordered column categorical data, the χ2 test, Fisher's exact test and Wilcoxon test are used. Pharmacological studies often are performed by multiple dosing. Data obtained from these studies are called ordered categorical data. The cumulative chi-squared statistic, which has been proposed by Hirotsu and Shibuya for testing against ordered alternatives in various statistical models, is little used in spite of its good applicability in the field of pharmacology. This method was too difficult for the general pharmacologist and biological scientists because it requires the use of a complex matrix and a powerful computer to carry out the analysis. However since a more simple method was proposed by Matsumoto and Yoshimura this method has been used more frequently in the biological sciences. In this paper, the one way cumulative chi-squared statistic test and two way chi-squared statistic test are compared with the chi-squared statistic test and Wilcoxon test.