Alteration of lung atrial natriuretic peptide receptors in genetic
cardiomyopathy.
Mukaddam-Daher, Suhayla, Johanne Tremblay, Nobuaki Fujio, Caroline
Koch, Marek Jankowski, Edmond W. Quillen, Jr., Jolanta Gutkowska.
Laboratory of Cardiovascular Biochemistry and Laboratory of Cell
Biology, Centre de Recherche, H[acute]otel-Dieu de Montr[acute]eal,
Montreal (Quebec) H2W 1T8; and Department of Obstetrics and
Gynecology, Royal Victoria Hospital, McGill University, Montreal
(Quebec) H3A 1A1
APStracts 3:0032L, 1996.
These studies were designed to characterize the atrial natriuretic
peptide (ANF) receptor subtypes (guanylyl cyclase NPR-A and NPR-B,
and NPR-C) in lungs of normal hamsters and to evaluate alterations in
receptor kinetics in genetic cardiomyopathy, a model of human
congestive heart failure. Lung membranes were obtained from normal
and 200-230 day old cardiomyopathic hamsters. Cross-linking and
competition binding receptor assays using 125I-hANF showed that lung
membranes exhibit natriuretic peptides receptors, mainly guanylyl
cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl
cyclase by ANF and CNP confirmed the presence of NPR-A and NPR-B. The
maximum binding capacity of total ANF binding sites (Bmax, 442 +/- 68
vs. 271 +/- 57 fmol/mg protein, p<0.05) was reduced, but
dissociation constant (Kd, 0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was
not altered in cardiomyopathic animals. Similar reductions were
observed in the binding sites for BNP (438 +/- 83 vs 236 + 53 fmol/mg
protein) and CNP (321 +/- 80 vs 165 +/- 56 fmol/mg protein,
p<0.05) which may reflect a decline in NPR-A and NPR-B and/or
NPR-C. Acid wash improved binding of 125I-rANF to lung membranes of
both normal and CMO hamsters, but the tendency towards reduced
binding in CMO hamsters did not reach statistical significance
implying that down-regulation may not have been due only to prior
occupancy of the receptors. Transcripts of NPR-A, NPR-B and NPR-C
receptors in hamster lungs were detected by quantitative polymerase
chain reaction (PCR). Compared to normal controls, the
cardiomyopathic hamster lung NPR-A mRNA was reduced by 50% but NPR-B
mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs
showed less activation of guanylyl cyclase by ANF. These studies
demonstrate that lung natriuretic peptides receptors are down
-regulated in hamster cardiomyopathy.
Received 29 September 1995; accepted in final form 7 February
1996.
APS Manuscript Number L291-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 March 96