1,721,007 research outputs found
Role of K+ in the histamine H3 receptor- and adenosine A1 receptor-mediated effects in the guinea-pig isolated duodenum.
No full textRole of K+ in the histamine H3 receptor- and adenosine A1 receptor-mediated effects on the isolated guinea pig duodenum
No full textRole of histamine H(3) receptors in the control of gastrointestinal motility. An overview.
No full textOver the last few years, the biochemical and functional characterization of H3 receptors has been a matter for extensive investigation, culminating in the cloning of the human, guinea pig and rat receptor protein from brain tissues. This discovery contributed to determine the distribution of receptors in the body and to define the molecular mechanisms which follow activation. The major breakthrough in the histamine H3 receptor field came with the synthesis of selective and potent agonists and antagonists, which unravelled the function of this receptor subtype in the different tissues. As expected from the ubiquitous location of histamine in the body, histamine H3 receptors have also been identified in virtually every tissue, although they are quantitatively less abundant than H1 and H2 receptors. Concerning the gastrointestinal tract, this new receptor subtype seems to have multiple cellular locations, which include neurons, enteric ganglia, paracrine and immune cells and, in some tissues, also smooth muscle cells. Therefore it might be regarded as a general regulatory system of different digestive functions, including motility. The effects mediated by histamine H3-receptors mainly reflect the presynaptic inhibition of the release of either excitatory or inhibitory neurotransmitters from the myenteric plexus. The molecular mechanism of presynaptic inhibition seems to involve a restriction of calcium entry into the nerve endings, but other mechanisms (reduction of cAMP), possibly associated to different H3 receptor subtypes, may be involved. Despite the widespread distribution and the well defined inhibitory effects evoked in the majority of in vitro models of intestinal motility, no clear cut evidence of its involvement in the control of peristalsis could be provided. In vivo models of gastrointestinal transit, indeed, did not reveal a defined effect of histamine H3 receptor ligands, even though the possibility of a central inhibition was pointed out in several studies. Therefore, it is not clear at the present what is the physiological meaning of the histamine H3 receptor in the control of gastrointestinal motility and whether it could represent a potential target for novel therapeutic interventions in deranged motility, taking into account that human gastrointestinal tissues are apparently devoid of this receptor
Assessment of gastrointestinal propulsive activity using three different models of peristalsis in vivo in the mouse
No full textThe protocols described in this unit are designed to assess the acute effects of drugs on the
propulsive activity of the gastrointestinal muscles in the conscious mouse. These protocols
are currently applied to investigate the pharmacological activity of novel compounds
undergoing preclinical development and to obtain predictive data needed to advance drugs
into clinical trials. Moreover, these methods could be useful in evaluating the functional
toxicity by environmental or alimentary pollutants, like xenobiotics and naturally occurring
toxins endowed with noxious activity in the control of physiologic peristalsis. The
three models detailed—the measurement of gastric emptying, ileal transit, and colonic
propulsion—are substantially non-invasive and do not require analgesic pretreatments
or the induction of general anesthesia. In contrast to an in vitro approach, these in vivo
studies provide a unified understanding of drug effects on gut functionality, in particular
when the central nervous system, the extrinsic nerves, or the (neuro)endocrine system
is targeted by the test drugs
Assessment of gastrointestinal motility using three different assays in vitro
No full textThe protocols detailed in this unit are designed to assess the motor activity of different gastric and intestinal muscle preparations in vitro and the effects of drugs that modulate gastrointestinal motility. The preparations described are characterized by different contractile behaviors, consisting of spontaneous (duodenum), neurogenic (ileum), and drug-stimulated (fundus, ileum) motility; these reproduce motility patterns occurring in the gut wall in vivo. These protocols document the variety of factors that can influence the responses of isolated tissues and describe how such tissues can be used for testing substances that affect gut movements. These preparations allow evaluation of direct interactions with the processes that control contractile machinery, as well as indirect effects resulting from the modification of neurotransmitter release from myenteric neurons. These models can be exploited to assay novel compounds undergoing preclinical development or to evaluate the functional toxicity exerted by environmental or alimentary pollutants, like xenobiotics and naturally occurring toxins, as well as the mechanisms underlying these effects
Assessment of intestinal peristalsis in vitro.
No full textThe protocol detailed in this unit is designed to assess intestinal peristaltic motility in the isolated small intestine in vitro and to measure the effects of drugs able to interfere with gut propulsive activity. The procedure is based on Trendelenburg's classic technique, described at the beginning of the 20th century in the isolated guinea pig ileum and, later on, extended to other intestinal preparations from the same animal and other animal species. This unit illustrates the basic procedures for setting up the intestinal preparation, recording peristalsis under near‐physiologic conditions, and testing the pharmaco‐toxicological effects of drugs and pollutants on the contractile behavior of the gut wall. The protocol allows evaluating the action of drugs affecting sensory and/or motor neurons of the enteric nervous system and how these neurons control the development of the motor program of the gut wall. This model can be exploited to investigate novel compounds undergoing preclinical development and both inhibitors and stimulants of gastrointestinal peristaltic activity, as well as environmental or alimentary pollutants, like xenobiotics and naturally‐occurring toxins, endowed with noxious activity with regard to digestive functions. Curr. Protoc. Toxicol. 54:21.11.1‐21.11.14. © 2012 by John Wiley & Sons, Inc
Synthesis of 1,2-benzisothiazolyloxypropanolamine derivatives and investigation of their activity at β-adrenoceptors
No full textThe synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1–7) or 7- (compounds 8–14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at β-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the β-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the β3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express β1-, β2- and β3-adrenoceptors, respectively. When compared with the reference, non-specific, β-adrenoceptor agonist isoprenaline, the products tested did not show any consistent β-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 μmol/l), ICI 118,551 (1 μmol/l) or bupranolol (1–10 μmol/l), thus excluding that the spasmolytic effect involves any β-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting β-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with β-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at β3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at β1- (cardiac) adrenoceptors. At the maximum concentrations tested (1–100 μmol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes
Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypropanolamine derivatives in isolated rat tissues
No full textIn an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the beta1- and beta3-adrenoceptor-mediated responses, respectively. None of these products showed any beta-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta1-recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring
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