RENAL ATRIAL-NATRIURETIC-FACTOR RECEPTORS IN HAMSTER CARDIOMYOPATHY

Hamsters with cardiomyopathy (CMO), an experimental model of congestiv e heart failure, display stimulated renin-angiotensin-aldosterone and enhanced sympathetic nervous activity, all factors that lead to sodium retention, volume expansion and subsequent elevation of plasma atrial natriuretic factor (ANF) by the cardiac atria. However, sodium and wa ter retention persist in CMO, indicating hyporesponsiveness to endogen ous ANF. These studies were undertaken to fully characterize renal ANF receptor subtypes in normal hamsters and to evaluate whether alterati ons in renal ANF receptors may contribute to renal resistance to ANF i n cardiomyopathy. Transcripts of the guanylyl cyclase-A (GC-A) and gua nylyl nylyl cyclase-B (GC-B) receptors were detected by quantitative p olymerase chain reaction (PCR) in renal cortex, and outer and inner me dullas. Compared to normal controls, the cardiomyopathic hamster's GC- A mRNA was similar in cortex but significantly increased in outer and inner medulla. Levels of GC-B mRNA were not altered by the disease. On the other hand, competitive binding studies, autoradiography, and aff inity cross-linking demonstrated the absence of functional GC-B recept ors in the kidney glomeruli and inner medulla. Also, C-type natriureti c peptide (CNP), the natural ligand for the GC-B receptors, failed to stimulate glomerular production of its second messenger cGMP. In CMO, sodium and water excretion were significantly reduced despite elevated plasma ANF (50.5 +/- 11.1 vs. 309.4 +/- 32.6 pg/ml, P < 0.001). Compe titive binding studies of renal glomerular ANF receptors revealed no c hange in total receptor density, B-max (369.6 +/- 27.4 vs. 252.8 +/- 2 6.2 fmol/mg protein), nor in dissociation constant, K-d (647.4 +/- 79. 4 vs. 648.5 +/- 22.9 pM). Also, ANF-C receptor density (254.3 +/- 24.8 vs. 233.8 +/- 23.5 fmol/mg protein), nor affinity were affected by he art failure. Inner medullary receptors were exclusively of the GC-A su btype with B-max (153.2 +/- 26.4 vs. 134.5 +/- 21.2 fmol/mg protein) a nd K-d (395.7 +/- 148.0 vs. 285.8 +/- 45.0 pM) not altered by cardiomy opathy. The increase in ANF-stimulated glomerular cGMP production was similar in normal and CMO hamsters (94- vs. 75-fold). These results de monstrate that renal ANF receptors do not contribute to the attenuated renal responses to ANF in hamster cardiomyopathy.