Stimulation of rat mesangial cell thromboxane A2 receptors inhibits particulate but not soluble guanylyl cyclase.
Thromboxane A2 (TxA2) participates in the pathogenesis of clinical and experimental glomerular disease. We performed radioligand binding and functional studies of TxA2 receptors in rat mesangial cells. Competitive inhibition of specific binding of the TxA2 analogue [125I]BOP by unlabeled antagonists in intact cells or membranes was observed, with a rank order potency of SQ-29548 (half-maximal inhibitory concentration = 3.4 nM > L-657925 (21 nM) > GR-32191 (200 nM) > L-657926 (1,300 nM). The potency of agonists was I-BOP (0.43 nM) > ONO-11113 (6.7 nM) > U-46619 (80 nM). U-46619 and unlabeled I-BOP inhibited the rate of net guanosine 3',5'-cyclic monophosphate accumulation in cells exposed to atrial natriuretic peptide (ANP) but not the nitric oxide donor nitroprusside. Membranes from cells exposed to I-BOP for 10 min exhibited a 38% decrease in ANP-responsive guanylyl cyclase activity. U-46619 blocked the inhibitory effect of ANP on serum-stimulated [3H]thymidine incorporation but not that of nitroprusside. In summary, we describe a novel effect mediated by a mesangial cell TxA2 receptor, i.e., inhibition of ANP signaling.
Paul
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RV
Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina, USA.
Saxenhofer
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H
Wackym
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Halushka
P V
PV
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001667:Binding, Competitive; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012995:Solubility; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D009599:Nitroprusside; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D006152:Cyclic GMP