Verlust von hochaffinen Prostacyclin-Bindungsstellen bei Patienten mit Morbus Basedow

Prostacyclin (PGI₂) mediates like TSH its cellular effects through the interaction with specific binding sites associated with the adenylate cyclase-cAMP-system. Binding of PGI₂ and the generation of cAMP induced by PGI₂ was evaluated in thyroid tissue obtained intraoperatively from euthyroid and hyperthyroid patients with diffuse normofollicular colloid struma. Transformation of the binding data according to Scatchard revealed heterogeneity of the PGI₂ binding sites in the tissue of euthyroid patients: the high-affinity binding sites were calculated to be 0.68 ± 0.18 pmol/mg protein (Ka = 16.2 ± 9.1 nM) and the low-affinity binding sites to be 5.4 ± 1.6 pmol/mg protein (Ka = 151 ± nM). In contrast, in the hyperthyroid patients the low-affinity binding sites were not demonstrable and the high-affinity sites were significantly (p <0.001) reduced (0.17 ± 0.05 pmol/mg protein, Ka = 83.5 ± 19.6 nM). The competition of the agonist for the PGI₂ sites in hyperthyroid patients was significantly (p <0.005) diminished (IC-50-values: 0.98 ± 3.1 vs 46.9 ± 12.1 μM). PGI₂ stimulated cAMP-production in a dose-dependent manner. However, the basal value was significantly lower also in the hyperthyroid patients (p <0.001). The evidence of reduced PGI₂ sites as well as reduced PGI₂-induced cAMP production in the thyroid gland of patients with Graves’ disease may indicate an important role for PGI₂ to play in the modulation of thyroid cell function.

Zusammenfassung

Prostacyclin (PGI₂) mediiert wie TSH seine zellulären Effekte über die Vermittlung von spezifischen Rezeptoren, die mit dem Adenylatzyklase- cAMP-System assoziiert sind. In der vorliegenden Studie wurden das Bindungsverhalten und die cAMP-Bildung im intraoperativ entnommenen Schilddrüsengewebe von euthyreoten und hyperthyreoten Patienten mit diffuser normofollikulärer Kolloidstruma untersucht. Die Transformierung der Bindungsdaten nach Scatchard zeigte bei den euthyreoten Patienten eine Heterogenität der PGI₂-Bindungsstellen an: die Zahl der hochaffinen Bindungsstellen betrug 0,68 ± 0,18 pmol/ mg Protein (Ka = 16,2 ±9,1 nM), die der niederaffinen 5,4 ± 1,6 pmol/mg Protein (Ka = 151 ± 43,1 nM). Im Vergleich dazu fanden sich bei hyperthyreoten Patienten keine niederaffinen PGI₂-Bindungsstellen und ein signifikanter Verlust von hochaffinen Bindungsstellen (p <0,001; 0,17 ± 0,05 pmol/mg Protein, Ka = 83,5 ± 19,6 nM). Auch die Kompetition des Agonisten um die PGI₂-Bindungsstellen war bei hyperthyreoten Patienten im Vergleich zu euthyreoten Patienten signifikant (p <0,005) erniedrigt (IC-50-Werte: 0,98 ± 3,1 vs 46,9 ± μM). PGI₂ stimulierte konzentrationsabhängig die cAMP-Bildung gegenüber dem Basalwert, welcher bei den hyperthyreoten Patienten ebenfalls signifikant niedriger war (p <0,001). Der Nachweis einer verminderten PGI₂-Rezeptorenzahl und PGI₂-induzierten cAMP-Bildung in der Schilddrüse bei Patienten mit M. Basedow könnte bedeuten, daß PGI₂ eine bedeutende Rolle in der Modulation der Schilddrüsenfunktion ausübt.

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