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Title: Investigation into subtypes of the prostacyclin and prostaglandin E receptor present in smooth muscle
Author: Lawrence, R. A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Abstract:
This thesis describes attempts to characterise prostacyclin (IP) and prostaglandin E (EP) receptors in smooth muscle preparations using agonist potency ranking and susceptibility to receptor blockade. Platelet aggregation is inhibited by prostacyclin analogues through activation of IP-receptors present on the plasma membrane. This potentially useful anti-thrombotic action is compromised by powerful vasodilator activity. The dilator activity of cicaprost, iloprost, carbacyclin and EP157 (a novel prostaglandin endopcroxidc analogue which mimics prostacyclin in the human platelet) was measured on isolated arterial rings from man, pig, rabbit and dog: Potency decreased in the order given above and there was little evidence for significant differences between the IP receptors in the different preparations. In man the agonist potency at vascular IP sites correlates well with that of the platelet thus presenting little hope for separation of the two actions. In addition, the IP receptor present in the guinea-pig ilcum has been investigated. This receptor is of particular interest as it has been shown to mediate longitudinal muscle contraction via the release of excitatory ncu-rotransmittcrs from the myentcric plexus. Only the action of cicaprost was abolished by morphine and tetrodotoxin: PGIj, iloprost and carbacyclin were only partially inhibited and the residual contraction in each case was abolished by the EPj-reccptor antagonist, AH6809. These results suggest a high degree of selectivity for cicaprost. However, the analysis is complicated by the discovery of an IR-receptor which inhibits longitudinal muscle contraction (histaminc in the presence of AH6809). Antagonist investigations suggest that the excitatory transmitters released by IP-receptor activation are Acetylcholinc and Substrance P. Recently, the existence of three subtypes of the PGE receptor have been proposed and pharmacological/chemical efforts have centred on the characterisation of these receptors and identification of their physiological actions. A detailed study has been carried out comparing the actions of eleven PGE analogues on three tissues containing EPs-receptors. (1) Guinea-pig ileum: In the absence of enteric nerve function this tissue has previously been defined as EPi-selective. However, the present studies suggest the presence of a second receptor mediating contraction and this has some similarity to the EPs-receptor found in the guinea-pig vas deferens. In particular sulprostone and MB28767 are highly active in the presence of AH6809. (2) Chick ileum: Literature studies suggest the presence of an EPs-receptor mediating contraction. The results obtained confirm this, however detailed study has revealed differences between agonist activity in this tissue and the guinea-pig vas deferens, the most obvious being the low maximum (~ 50% of that of PGE2) of the potent EPs agonist, sulprostone. (3) Rabbit jugular vein: This tissue has recently been shown to contain PGD2 relaxant receptors, however the action of PGE2 has not yet been studied. Investigations have shown that the preparation contains a highly sensitive EPj receptor mediating relaxation (IC^o < InM). However, the PGEi analogue, butaprost, appears to be considerably less active than expected from data obtained in other preparations known to contain EPj-receptors (guinea-pig trachea and cat trachea). The rabbit jugular vein has previously been shown to contain a contractile thromboxane (TP) receptor which is highly sensitive to the thromboxane mimetic, U46619 (ECjo ~ 3nM). A number of PGE analogues have potent thromboxane-like (TP-receptor agonist) actions thus the above experiments were carried out in the presence of a TP-rcccptor antagonist. Characterisation of this receptor suggests that it has low affinity for TP-receptor antagonists in common with other rabbit tissues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.653722  DOI: Not available
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