[Synergistic receptor subtypes: an explanation for reserve receptors and for different intrinsic activities of full and partial agonists. Studies on the effect of substance P and its analogs on guinea pig ileum].
The contractile response of guinea-pig ileum to substance P consists of an initial rapid phasic contraction followed by a lower tonic contraction. Both contraction phases can be changed independently of each other. Substance P analogues differ in their ability to induce the phasic and tonic contraction. The structure-activity profile (calculated from ED50) for C-terminal substance P fragments and acylated analogues differ from the structure-affinity profile (calculated from the dissociation constant which was estimated by the desensitization method). These results suggest the possible existence of two substance P receptor subtypes that have different affinities for substance P analogues. Both are coupled with an increase in cytoplasmatic Ca++ and with contraction. Stimulation of SPCa-i (SPCa-influx) receptors seems to open calcium channels in the smooth muscle membrane while SPCa-r (SPCa-release) receptor stimulation seems to release membraneous Ca++. Such synergistic subreceptors could be the cause of the pharmacological phenomenon of spare receptors. If this is the case, then the intrinsic activity would reflect differences in the affinity or the selectivity of analogues for these subreceptors. Partial agonists activate only one synergistic receptor subtype or activate synergistic as well as antagonistic subtypes with similar affinities. Mixed agonist-antagonists are agonists of one, and antagonists of the other synergistic receptor subtype. Organ-selective stimulatory effects of certain analogues can be explained by the various subtypes being distributed in a different fashion between different organs. The possibility to detect the presence of different receptor subtypes from the shift of dose response curves by irreversible antagonists and from the shift of binding curves by GTP and ions is discussed.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018040:Receptors, Neurokinin-1; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011956:Receptors, Cell Surface; D018040:Receptors, Neurokinin-1; D013373:Substance P; D006632:Histamine; D000109:Acetylcholine
Synergistische Rezeptor-Subtypen: Erklärung für Reserve-Rezeptoren und für differente intrinsische Aktivitäten voller Agonisten sowie Partialagonisten. Untersuchungen zur Wirkung von Substanz P und -Analoga am Meerschweinchen-Ileum.