Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP.
Atrial natriuretic peptide (ANP) prevents hypertrophy of neonatal cardiomyocytes. However, whether this effect is retained in the adult phenotype or if other members of the natriuretic peptide family exhibit similar antihypertrophic properties, has not been elucidated.


OBJECTIVE
Our objective was to examine whether the natriuretic peptides protect against adult cardiomyocyte hypertrophy in vitro.


METHODS
Adult rat cardiomyocytes were incubated with angiotensin II (Ang II)+/-ANP, B-type (BNP) or C-type (CNP) natriuretic peptides for determination of [3H]phenylalanine incorporation, c-fos mRNA expression and cyclic GMP. The effects of 8-bromo-cyclic GMP (cyclic GMP analogue), HS-142-1 (particulate guanylyl cyclase inhibitor) and KT5823 (cyclic GMP-dependent protein kinase inhibitor) were also investigated.


RESULTS
Ang II-stimulated increases in markers of hypertrophy, [3H]phenylalanine incorporation (to 136+/-3% of control, n=9) and c-fos mRNA expression (4.3+/-1.4-fold, n=5), were completely prevented by each of ANP, BNP or CNP. This protective action was accompanied by increased cardiomyocyte cyclic GMP. Inhibitory actions on [3H]phenylalanine incorporation were mimicked by 8-bromo-cyclic GMP, and were abolished by HS-142-1. KT5823 blocked the response to BNP and CNP, but not to ANP.


CONCLUSIONS
ANP prevents hypertrophy of adult rat cardiomyocytes. This protective action is shared by BNP and CNP and involves activation of particulate guanylyl cyclase receptors. Antihypertrophic effects of BNP and CNP are mediated through cyclic GMP-dependent protein kinase, but ANP can activate additional pathways independent of cyclic GMP to prevent adult cardiomyocte hypertrophy. These novel findings are of interest particularly since BNP appears to exert antifibrotic rather than antihypertrophic actions in vivo, while CNP is thought to act at least in part via the endothelium.
Rosenkranz
Anke C
AC
Howard Florey Institute, c/- The University of Melbourne, Parkville, VIC 3010, Australia.
Woods
Robyn L
RL
Dusting
Gregory J
GJ
Ritchie
Rebecca H
RH
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D004347:Drug Interactions; D006162:Guanylate Cyclase / Q000502:physiology; D008297:Male; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology; D000099242:Atrial Natriuretic Factor Receptor B
D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D006162:Guanylate Cyclase; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B; C016276:8-bromocyclic GMP; C091715:atrial natriuretic factor receptor A