Individual variations of prostanoid agonist responses in rabbit aorta: evidence for the independent regulation of prostanoid receptor subtypes.
1 The frequency and selectivity of individual variations of prostanoid agonist responses in aortic strips from a population of male rabbits was studied. Three levels of responsiveness to the thromboxane mimetic U46619 occurred: responders (R), intermediate responders (IR), and non-responders (NR). R could be subdivided into R1 and R2 based on an enhanced potency of prostaglandin F2 alpha (PGF2 alpha) in R2. In the total population (n = 92), the phenotype frequency was: R, 69%; IR, 11%; and NR, 20%. In a subgroup of this population in which R1 and R2 phenotypes were determined (n = 63), the phenotype frequency was: R1, 54%; R2, 19%; IR, 6%; and NR, 21%. 2 The four rabbit aorta phenotypes, R1, R2, IR, and NR, were characterized with respect to the rank orders of prostanoid agonist potency, agonist intrinsic activities, and the effects of the thromboxane receptor antagonist SQ29548. The rank order of prostanoid agonist potency was U46619 greater than PGF2 alpha greater than PGE2 in R1 and R2, and PGF2 alpha greater than or equal to PGE2 greater than U46619 in IR and NR. For each prostanoid agonist, the intrinsic activity was highest in R (R1 congruent to R2), intermediate in IR, and lowest in NR. In R1, SQ29548 inhibited all prostanoid agonist responses equally. The contractile effects of PGF2 alpha and PGE2 were partially resistant to inhibition by SQ29548 in R2. Prostanoid agonist responses were not inhibited by SQ29548 in IR. 3 The potency of histamine was equivalent in R1, R2, IR, and NR. 4 It is concluded that there are individual variations in the functional expression of thromboxane receptor sensitivity, i.e., prostanoid agonist responses inhibited by SQ29548. Also, there are individual variations in the functional expression of the sensitivity of a non-thromboxane receptor or receptors, i.e., prostanoid agonist responses not inhibited by SQ29548. It has been proposed by others that prostanoid receptors be termed P-receptors and that the prostanoid agonist to which they are most sensitive be indicated by a preceding letter, e.g., TP- for thromboxane receptor and FP- for PGF2 alpha-selective receptor. Accordingly, we proposed a working hypothesis that suggests the four phenotypes could result from the independent regulation of the functional expression of TP- and FP-receptor subtypes with (a) R2 containing both the TP- and FP-receptor subtypes in a fully functional state; (b) R1 containing only the functional TP-receptor; (c) IR containing only the functional FP-receptor; and (d) NR containing only a low efficacy FP-receptor system. 5 The mechanisms underlying the observed individual variations are unknown but could include changes in receptor number or affinity, changes in receptor-effector coupling, changes in a second messenger system, or changes in tissue degradative or uptake processes. Further study is needed to differentiate between these possibilities.
Keith
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RA
Department of Pharmacology, Stuart Pharmaceuticals, Division of ICI Americas Inc., Wilmington, DE 19897.
Salama
A I
AI
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010641:Phenotype; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology*; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548