B-Type natriuretic peptide prevents acute hypertrophic responses in the diabetic rat heart: Importance of cyclic GMP

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 9; pp. 2389 - 2395
• Main Authors: ROSENKRANZ, Anke C, HOOD, Sally G, WOODS, Robyn L, DUSTING, Gregory J, RITCHIE, Rebecca H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-2003
• Subjects: Acute Disease; Animals; Associated diseases and complications; Atrial Natriuretic Factor - genetics; Atrial Natriuretic Factor - metabolism; Biological and medical sciences; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiomyocytes; Cells, Cultured; Chronic Disease; Cyclic GMP - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium; Gene Expression; Glucose; Heart; Heart Ventricles - metabolism; Heart Ventricles - pathology; Hypertrophy; Male; Medical sciences; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Natriuretic Peptide, Brain; Natriuretic peptides; Nitric oxide; Peptides; Phenylalanine - metabolism; Physiological aspects; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; Tritium; Australia; Heart; Endocrinopathy; Vertebrata; Mammalia; Peptides; Rat; Animal; Diabetes mellitus; Rodentia; 3',5'-GMP; Circulatory system
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.9.2389

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.