Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors

1 This study describes attempts to compare prostacyclin (IP‐) receptors in human, pig, horse, rabbit and rat platelets and in circular muscle of human, rabbit and dog mesenteric and pig gastroepiploic arteries. Three stable prostacyclin analogues, iloprost, cicaprost and 6a‐carba‐prostacyclin (6a‐ca...

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Bibliographic Details
Published in:British journal of pharmacology 1989-07, Vol.97 (3), p.657-668
Main Authors: Armstrong, Roma A., Lawrence, Ruth A., Jones, R.L., Wilson, N.H., Collier, A.
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Biological and medical sciences
Blood Platelets - metabolism
Cardiovascular Agents - metabolism
Cell Membrane - metabolism
Cell receptors
Cell structures and functions
Cyclic AMP - blood
Epoprostenol - metabolism
Fundamental and applied biological sciences. Psychology
Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors
Horses
Humans
Iloprost
In Vitro Techniques
Molecular and cellular biology
Muscle Contraction
Muscle Relaxation
Muscle, Smooth, Vascular - physiology
Platelet Aggregation
platelets
Rabbits
Rats
Receptors, Epoprostenol
Receptors, Prostaglandin - metabolism
Species Specificity
Swine
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Summary:1 This study describes attempts to compare prostacyclin (IP‐) receptors in human, pig, horse, rabbit and rat platelets and in circular muscle of human, rabbit and dog mesenteric and pig gastroepiploic arteries. Three stable prostacyclin analogues, iloprost, cicaprost and 6a‐carba‐prostacyclin (6a‐carba‐PGI2) and a prostaglandin endoperoxide analogue EP 157 (previously shown to mimic prostacyclin on human platelets) were used. 2 Our main conclusion is that prostacyclin receptors on human, pig and horse platelets are similar in nature, but distinct from those on rabbit and rat platelets. Functional studies (inhibition of aggregation) showed that iloprost and cicaprost always had similar potencies whereas 6a‐carba PGI2 was much more potent than EP 157 on rabbit and rat platelets (300 and 1000 fold on a molar basis) compared with human, pig and horse platelets (2, 7 and 7 fold respectively). Measurement of initial rates of cyclic AMP production confirmed these orders of potency. 3 Although pig platelets were quite sensitive to inhibition by EP 157 (threshold = 10 nM in some experiments), maximal inhibition of aggregation was not always achieved (20 μm). EP 157 also produced only small elevations of cyclic AMP and inhibited rises in cyclic AMP induced by iloprost. It is possible that EP 157 has a lower efficacy than iloprost at the IP‐receptor and on pig platelets it can sometimes act as a partial agonist. 4 Human, pig and horse platelet membranes bound [3H]‐iloprost at 30°C and this binding was inhibited by the four prostanoids. On human and pig membranes the order of potency was cicaprost = iloprost > 6a‐carba PGI2 > EP 157. The order of potency may be similar on horse platelet membranes, but the analysis is complicated by the presence of a second component of [3H]‐iloprost binding that is inhibited by iloprost and 6a‐carba PGI2 but not by cicaprost. This binding may be due to the presence of an EP1‐receptor, since iloprost and 6a‐carba PGI2 but not cicaprost are known to have potent EP1‐receptor agonist actions on smooth muscle preparations. IC50 values for cicaprost inhibition on human, pig and horse membranes were 110, 90 and 165 nM respectively. The need for IP‐receptor radioligands of greater specificity is apparent from these studies. 5 Minimal binding of [3H]‐iloprost to rabbit and rat platelet membranes was obtained at 30°C. Lowering the incubation temperature to 4°C and ensuring that the temperature did not rise during the filtration process increase
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.1989.tb12001.x