Pharmacology of Adenosine Receptors of the Rat Isolated Superior Cervical Ganglion

Connolly, Gerald Patrick James (1991) Pharmacology of Adenosine Receptors of the Rat Isolated Superior Cervical Ganglion. PhD thesis, University of Glasgow.

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This study has examined the effect of purines and pyrimidines on the rat superior cervical ganglion in vitro. Using an extracellular recording technique it was found adenosine and its analogues produced concentration dependent hyperpolarisations. In contrast pyrimidines such as UTP and the P2-purinoceptor agonist alpha,beta-methylene adenosine triphosphate depolarised, via a methylxanthine independent mechanism. A mechanism for the uptake and degradation of adenosine in the ganglion was evident as the effects of adenosine were enhanced in the presence of adenosine uptake inhibitors or in the presence of an adenosine deaminase inhibitor. The deaminated metabolite of adenosine, i. e. inosine was inactive. The ionic mechanism for the adenosine-induced hyperpolarisation was examined by altering the extracellular cation concentrations and the use of selective ion channel antagonists. The hyperpolarisation to adenosine was not antagonised by inorganic or dihydropyridine calcium channel antagonists, suggesting adenosine did not alter Ca2+ entry. The response to adenosine was resistant to antagonism of sodium and chloride channels and the inhibition of Na+/K+ ATPase and Na+/K+/Cl- cotransporters, but was sensitive to changes in extracellular K+ concentration. The hyperpolarisation to adenosine was enhanced in reduced external potassium solution or the presence of low concentrations of TEA suggesting adenosine may increase potassium conductance. The response to muscarinic agonists and not other agonists was selectively reduced by adenosine but not by all purines or pyrimidines. The depression of muscarine was selective for the depolarisation and not the hyperpolarisation. Both the relative order of potency of adenosine and its analogues to hyperpolarise and depress the response to muscarine were indicative of the presence of purinoceptors of the A1 subtype on the rat SCG. Studies to confirm the nature of the adenosine receptor using two selective A1-adenosine receptor antagonists. 1,3-dipropyl-8-cyclopentylxanthine and xanthine amine congener produced an apparently non-competitive inhibition. This may indicate the presence of two receptor subtypes. However, a selective A2 adenosine receptor antagonist 3,7-dimethy-1-propargyl-xanthine did not alter the inhibition of muscarinic responses or the hyperpolarisation caused by purines. The biochemical mechanism responsible for the hyperpolarisation to adenosine remains elusive. Cyclic adenosine monophosphate phosphodiesterase inhibitors Ro 20-1724 and denbufylline and an adenylate cyclase inhibitor, SQ 22,536, reduced the hyperpolarisation to purines but not the depression of the response to muscarine. However, agents known to increase cAMP levels in the ganglion did not dramatically alter the response to adenosine suggesting the responses to adenosine are not mediated by a change in cyclic nucleotide levels. The ability of phorbol esters to enhance the response to adenosine suggests that protein kinase C is involved in the interaction of adenosine with muscarine. An interaction with the arachidonic acid cascade pathway was suggested by the inhibition of the hyperpolarisation to adenosine by a selective lipoxygenase inhibitor.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Pharmacology
Date of Award: 1991
Depositing User: Enlighten Team
Unique ID: glathesis:1991-78340
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Feb 2020 12:09
Last Modified: 28 Feb 2020 12:09

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