STIMULATION OF RAT MESANGIAL CELL THROMBOXANE A(2) RECEPTORS INHIBITSPARTICULATE BUT NOT SOLUBLE GUANYLYL CYCLASE

Thromboxane A(2) (TxA(2)) participates in the pathogenesis of clinical and experimental glomerular disease. We performed radioligand binding and functional studies of TxA(2) receptors in rat mesangial cells. Co mpetitive inhibition of specific binding of the TxA(2) analogue [I-125 ]BOP by unlabeled antagonists in intact cells or membranes was observe d, with a rank order potency of SQ-29548 (half-maximal inhibitory conc entration = 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 exp osed to atrial natriuretic peptide (ANP) but not the nitric oxide dono r nitroprusside. Membranes from cells exposed to I-BOP for 10 min exhi bited a 38% decrease in ANP-responsive guanylyl cyclase activity. U-46 619 blocked the inhibitory effect of ANP on serum-stimulated [H-3]thym idine incorporation but not that of nitroprusside. In summary, we desc ribe a novel effect mediated by a mesangial cell TxA(2) receptor, i.e. , inhibition of ANP signaling.