Augmentation of the natriuretic activity of exogenous and endogenous atriopeptin in rats by inhibition of guanosine 3',5'-cyclic monophosphate degradation.

Abstract

To investigate the relationship between AP, cyclic GMP, and sodium excretion, we studied the effect of a cyclic GMP phosphodiesterase inhibitor (M + B22948) on the natriuretic response to (a) an infusion of AP (103-126) and (b) acute volume expansion in rats. The phosphodiesterase inhibitor markedly potentiated the effect of low-dose AP infusions on urinary sodium and cyclic GMP excretion without potentiating the fall in blood pressure. Acute volume expansion (1% body wt) led to small but significant (P < 0.01) rises in plasma AP and urinary cyclic GMP levels. Pretreatment with the phosphodiesterase inhibitor enhanced the natriuretic and cyclic GMP response to volume loading, an effect that was attenuated by administration of a monoclonal antibody directed against AP. These data indicate that cyclic GMP mediates the natriuretic activity of AP and AP and cyclic GMP play active roles in the natriuresis of acute volume expansion. Moreover, pharmacological manipulation of cyclic GMP levels may prove a useful therapeutic strategy for facilitating the natriuretic but not the hypotensive effects of

Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome.

“…The volume expansion natriuresis was somewhat more robust from normal kidneys infused with zaprinast, a response also observed by Wilkins and associates (34). However, a much more striking effect was seen in nephrotic kidneys.…”

“…IBMX is a nonspecific inhibitor of PDEs, yet we saw no difference in nephrotics with respect to AVP-dependent cAMP stimulation. This finding suggests the possibility that differential metabolism of cyclic A c6.0 i20 nucleotides in normal vs. nephrotic cells might be confined to a specific cGMP PDE (35), an hypothesis supported by the results with zaprinast, a compound with selectivity for this PDE isoform (34). Direct measurement of this enzyme activity in normal and nephrotic glomeruli and IMCD cells will be an important test of this hypothesis.…”

“…We then sought to determine if enhanced degradation of the cellular cGMP produced by a normal interaction between ANP and the receptor-cyclase complex could account for the impaired cGMP levels we observed in nephrotic tissues. We used IBMX, a general inhibitor ofcyclic nucleotide PDEs, and zaprinast, an agent more specific for cGMP PDE (34), for this purpose. IBMX increased basal, nonstimulated levels ofcGMP in both glomeruli and IMCD cells.…”

Synthesis and secretion of an atriopeptin-like protein in rat kidney cell culture.

“…This assay was performed as follows. A monoclonal antibody (MRW9C6 1) raised in mouse against AP24 (14) was initially bound to 96-well plastic plates (6106L10, Thomas Scientific, Swedesboro, NJ) by overnight incubation (100 ug/ml). Nonspecific binding to the wells was minimized by preincubation of wells with 1% gelatin.…”

Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

“…For several of the responses to ANP, including increased glomerular filtration, natriuresis, and direct vasorelaxation (1,(4)(5)(6), there is evidence that cGMP is the intracellular second messenger of hormone action. Two ANP receptors have been cloned and expressed to date.…”