The distribution and characteristics of a- and ?-adrenoceptors, histamine H1 - and muscarinic cholinergic receptors has been studied in guinea-pig airways by radio-ligand binding studies, functional measurements of a mech-anical response and light microscope autoradiography. Radioligand binding studies were performed on homogenates of three different regions of the airways; the trachea, bronchi and parenchyma. The results have shown that whilst histamine H1 - and muscarinic cholinergic receptors were relatively evenly distributed throughout the airways, the density of a1 - and ?- adrenoceptors increased towards peripheral regions of the lung with the highest density in the parenchyma and lowest in the trachea. There was no evidence for the presence of a2 - adrenoceptors, but studies with selective ?- adrenocptor agents indicated that both ?1- and ?2- subtypes were present throughout the lung with the relative proportion being in the order of 15 : 85%. Isolated preparations of tracheal spirals and paren-chymal lung strips were then used to determine the response mediated by these receptor systems, in central and peripheral airways respectively. a1-, histamine H1- and muscarinic receptor agonists all produced concentration-dependant contractions of both preparations and antagonist pA2 values were almost identical to -log KI values obtained from binding studies. ?- adrenoceptor agonists however caused concentration-dependant relaxations of these preparations and the response appeared to be mediated by both ?1- and ?2- subtypes in tracheal spirals as the pA2 value for atenolol (?1-selective), varied depending on which agonist was used. In addition, the agonists noradrenaline and isoprenaline produced biphasic concentration-effect curves in the presence of the ?2- selective antagonist ICI 118,551. In contrast, only one subtype was involved in parenchymal lung strips as antagonist pA2 values were not dependant on the agonist used and the properties were consistent with those expected for a ?2- adrenoceptor. A more precise localisation of the receptors identified by binding and functional studies was then obtained by light microscope autoradiography, using frozen sections of whole lung tissue. The results support previous findings which suggested that ?- adrenoceptors, histamine H1- and muscarinic receptors were all located on airway smooth muscle, but it was not possible to study the localisation of a1- adrenoceptors by this method. ?- adrenoceptors were also found to be located on the smooth muscle of pulmonary blood vessels and there was a particularly dense labelling of alveolar tissue. Neither histamine H1- nor muscarinic receptors were identified on alveolar tissue or the smooth muscle of blood vessels. Further experiments were also per-formed whereby the labelling of ?2- adrenoceptors in the sections was prevented by incubating in the presence of the ?2- selective antagonist ICI 118,551, at a concentration that should not have affected labelling of ?1- adrenoceptors. These studies showed that whilst ?- adrenoceptors on the alveoli consisted of both the and ?1 and ?2- subtypes, those on the smooth muscle of airways and blood vessels were of the ?2- subtype only. The present findings indicate that by combining the three-types of approach it should be possible to obtain detailed information on the regulation of a particular organ or tissue by various receptor systems. In particular, it has been shown that autoradiography is a useful technique that can be used to complement binding studies performed on homogenates giving no indication of the cellular location of receptors and classical pharmacological techniques, where prior knowledge of their function is required.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:347845 |
| Date | January 1983 |
| Creators | Carswell, Heather |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/33576 |
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