Diabetes predisposes to left ventricular hypertrophy (LVH) and endothelial NO dysfunction. Cyclic GMP (cGMP) is a key antihypertrophic mechanism, mediating endothelium-dependent and -independent antihypertrophic actions of bradykinin (BK) and B-type natriuretic peptide (BNP) respectively. Further, BK/cGMP contribute to the acute antihypertrophic effects of ACE inhibitors. We tested the hypothesis that the antihypertrophic actions of BNP are preserved in hearts from diabetic rats. Hearts isolated from male Sprague Dawley rats (8 weeks streptozotocin-diabetes) or age matched shams were perfused for 90 mins at constant pressure with vehicle, BK, BNP, ramiprilat (Ram) or the neutral endopeptidase (NEP) inhibitor candoxatrilat (Cdx). Angiotensin (Ang) II was added after the first 30 mins. Hearts then incorporated [3H]phenylalanine for 60 mins. Phenylalanine incorporation and mRNA expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (B-MHC) were determined in left ventricular homogenates as markers of LVH. As shown in the Table, Ang II significantly increased all markers of LVH in sham hearts; these increases were inhibited by BK, BNP, Ram and Cdx. BK, BNP and candoxatrilat also stimulated cGMP. In diabetic hearts, basal phenylalanine incorporation and ANP and B-MHC mRNA were elevated (to 143+/-10%, 2.9+/-0.6 fold and 2.9+/-0.4 fold of sham controls respectively, all p<0.05). Ang II further increased phenylalanine incorporation and ANP mRNA in these diabetic hearts. Only BNP both prevented Ang II-stimulated hypertrophic responses, and increased cGMP in diabetic hearts. In conclusion, acute antihypertrophic and cGMP-stimulatory actions of BNP are preserved in diabetic rat hearts, unlike those of bradykinin or inhibitors of ACE or NEP. This supports the proposal that exogenous natriuretic peptide administration is an effective strategy to prevent cardiac growth in diabetes, where endothelium-dependent pathways are compromised.