B-type natriuretic peptide prevents acute hypertrophic responses in the diabetic rat heart: importance of cyclic GMP.
Stimulation of cardiomyocyte guanosine 3',5'-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by high-glucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [(3)H]phenylalanine incorporation and atrial natriuretic peptide and beta-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.
Rosenkranz
Anke C
AC
Howard Florey Institute, University of Melbourne, Victoria, Australia.
Hood
Sally G
SG
Woods
Robyn L
RL
Dusting
Gregory J
GJ
Ritchie
Rebecca H
RH
D000208:Acute Disease; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D002478:Cells, Cultured; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020097:Natriuretic Peptide, Brain; D010649:Phenylalanine / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D012333:RNA, Messenger; D014316:Tritium; D020097:Natriuretic Peptide, Brain; D010649:Phenylalanine; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP