ABSTRACT
We have investigated adrenoceptor-mediated responses of muscularis mucosae from the proximal, mid and distal regions of the rat colon. Noradrenaline-induced relaxations of the muscularis mucosae in each region were unaffected by atenolol, butoxamine or propranolol, but they were attenuated by the selective beta3-adrenoceptor antagonist cyanopindolol. The beta3-adrenoceptor agonist CL216343 elicited concentration-dependent relaxation of the muscularis mucosae in all regions of the colon. Isoprenaline, a non-selective beta-adrenoceptor agonist, evoked concentration-dependent relaxations of the muscularis mucosae in all regions, but only in the proximal colon were these significantly larger than the maximum noradrenaline-induced relaxation. The alpha1-adrenoceptor agonist methoxamine caused large contractions of the proximal colonic muscularis mucosae. When proximal tissue was pretreated with phentolamine, an alpha1-adrenoceptor antagonist, maximal noradrenaline- and isoprenaline-induced relaxations did not differ significantly. Although the mid colonic muscularis mucosae was also found to possess excitatory alpha1-adrenoceptors, these were associated with small contractions and did not modify the muscle's inhibitory responses to noradrenaline. Distal colonic muscularis mucosae lacked excitatory adrenoceptors and only responded to noradrenaline with beta3-adrenoceptor-mediated relaxations. No evidence was obtained for functional alpha2-adrenoceptors on the muscularis mucosae in any region of the rat colon. These data demonstrated that noradrenaline-induced relaxation of the rat colonic muscularis mucosae was mediated via beta3-adrenoceptors throughout, but in the proximal region this was modified by concurrent excitatory alpha1-adrenoceptor activation. Based upon these observations it appeared unlikely that noradrenaline-induced relaxation of rat colonic muscularis mucosae would be functionally linked to the secretory responses of the corresponding mucosa during periods of increased sympathetic activity.
Subject(s)
Adrenergic Agonists/pharmacology , Adrenergic Antagonists/pharmacology , Colon/drug effects , Intestinal Mucosa/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Norepinephrine/metabolism , Receptors, Adrenergic/drug effects , Animals , Colon/metabolism , Dose-Response Relationship, Drug , In Vitro Techniques , Intestinal Mucosa/metabolism , Male , Muscle, Smooth/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic/metabolism , Receptors, Adrenergic, alpha-1/drug effects , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, beta-3/drug effects , Receptors, Adrenergic, beta-3/metabolismABSTRACT
It is known that the muscularis mucosae and mucosa are not pharmacologically homogeneous throughout the rat colon. The aim of this study was to simultaneously characterize all three neurokinin (NK) receptors in the muscularis mucosae and mucosa along the length of the rat colon. Strips of proximal, mid, and distal colonic muscularis mucosae were prepared for isometric recording or sheets of muscle-free mucosa were mounted in Ussing chambers for measurement of short-circuit current. In both muscularis mucosae and mucosa the greatest responses to substance P were found in the proximal region. Use of selective agonists revealed the presence of all three NK receptors in both structures, however, selective antagonism suggests that only NK2 receptors in the muscularis mucosae and NK1 receptors in the mucosa are physiologically relevant. In conclusion, substance P-induced responses in the rat colon are region-specific and not mediated by a single NK receptor subtype common to both structures.
Subject(s)
Acetylcholine/pharmacology , Colon/drug effects , Gastrointestinal Motility/drug effects , Intestinal Mucosa/drug effects , Receptors, Tachykinin/metabolism , Substance P/pharmacology , Animals , Colon/pathology , Disease Models, Animal , Female , Gastrointestinal Motility/physiology , Intestinal Mucosa/pathology , Male , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/drug effects , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-2/drug effects , Receptors, Neurokinin-2/metabolism , Receptors, Tachykinin/drug effects , Sensitivity and Specificity , Tissue Culture TechniquesABSTRACT
We have used a brief analysis of transport via cystic fibrosis (CF) transmembrane conductance regulators (CFTRs) in various organ systems to highlight the importance of basic membrane transport processes across epithelial cells for first-year medical students in physiology. Because CFTRs are involved in transport both physiologically and pathologically in various systems, we have used this clinical correlation to analyze how a defective gene leading to defective transport proteins can be directly involved in the symptoms of cholera and CF. This article is a "Staying Current" approach to transport via CFTRs including numerous helpful references with further information for a teaching faculty member. The article follows our normal presentation which begins with a discussion of the involvement of CFTR transport in the intestine and how cholera affects intestinal transport, extends to CFTR transport in various organ systems in CF, and concludes with the logic behind many of the treatments that improve CF. Student learning objectives are included to assist in assessment of student understanding of the basic concepts.
Subject(s)
Cholera/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/metabolism , Education, Medical/methods , Cell Membrane/metabolism , Cholera/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Humans , Intestinal Mucosa/metabolism , Ion Channels/metabolism , Ion Transport/physiologyABSTRACT
This study investigated the temporal relationship between inflammatory mediator production and colonic vascular architecture in rabbit and rat trinitrobenzene sulfonic acid (TNBS) models of colitis. In both species significant colonic damage and loss of mucosal integrity occurred over time. In the rabbit there was a significant increase in TxB2 levels in the muscularis propria and mucosa at 1, 6, and 48 hr after TNBS, with a significant elevation in PGE2 production in the muscularis propria at 48 hr. However, elevated mediator levels were not associated with measurable changes in vascular architecture. In contrast, significant changes in the numbers and diameters of colonic blood vessels were observed in the rat, in the absence of significant elevations in TxB2 or PGE2 levels. These data suggest that the role of lipid mediators in acute colitis is species-dependent and, although there are corresponding gross and microscopic changes in both models, these occur through disparate mechanisms.
Subject(s)
Blood Vessels/drug effects , Colitis/metabolism , Colitis/pathology , Colon/blood supply , Inflammation Mediators/metabolism , Animals , Colitis/chemically induced , Dinoprostone/metabolism , Male , Rabbits , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Thromboxane B2/metabolism , Time Factors , Trinitrobenzenesulfonic AcidABSTRACT
This study investigated adrenoreceptor-mediated responses of muscularis mucosae from the fundic and antral ends of the rabbit gastric corpus. Norepinephrine-induced fundic muscularis mucosae contractions were enhanced by propranolol and converted to relaxations by phentolamine. Methoxamine, but not clonidine, elicited large fundic contractions. Fundic muscle responded to low isoproterenol concentrations with atenolol- and butoxamine-resistant relaxations, and to high concentrations with atenolol-sensitive contractions. Norepinephrine evoked propranolol-resistant relaxations of antral muscularis mucosae that were enhanced by phentolamine. Methoxamine and clonidine elicited small antral contractions. Lower concentrations of isoproterenol caused atenolol-resistant antral relaxations that were enhanced by butoxamine; higher concentrations produced weak excitation. Fundic and antral relaxations to isoproterenol were abolished by cyanopindolol. Fundic muscularis mucosae possesses excitatory alpha1-, beta1- and inhibitory beta3-adrenoreceptors. Excitatory beta2- and inhibitory beta3-adrenoreceptors predominate in the antral region. The heterogeneous adrenoreceptor-mediated responses of the gastric muscularis mucosae suggest that adrenergic modulation of its motor activity is unlikely to be linked to acid secretion.
