B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

Abstract

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 highglucose-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 ␤-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.

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

“…As expected from neprilysin inhibition, 34 levels of both urinary cyclic GMP and plasma BNP were higher during treatment with LCZ696 than with enalapril; the increases in cyclic GMP reflect the fact that the peptides whose levels are enhanced by neprilysin inhibition act through enhancement of cyclic GMP. [35][36][37] In contrast, in comparison with enalapril, patients receiving LCZ696 had consistently lower levels of NTproBNP (reflecting reduced cardiac wall stress) and troponin (reflecting reduced cardiac injury) throughout the trial. The contrasting effects of LCZ696 on the 2 types of natriuretic peptides represents an important finding, because the levels of the 2 peptides characteristically parallel each other during the course of heart failure.…”

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

“…Several recent reports suggest that activation of the B2-kinin receptors (B2R) could reduce the proliferative effect of several growth factors in cultured cell lines (15,45,50) and in mesangial cells (1,18). B2-kinin receptor is involved in the antihypertrophic effect of BK documented in cultured cardiomyocytes (30,52,53,55) but also in vivo, mainly in the heart (24,25,40,56). Moreover, the antihypertrophic effect of BK in vivo on the renal vasculature in mice has been also reported (67).…”

Nonheart failure-associated elevation of amino terminal pro-brain natriuretic peptide in the setting of sepsis

“…The deleterious effects manifest as a decrease in blood pressure and SVR, concomitant with poorer tissue oxygenation (31). Additionally, BNP exerts a cardiac antihypertrophic action independent of the endothelial NO production in diabetic rats (32). In septic shock, Gram-negative organisms mediate myocardial depression by a mechanism that involves NO release (33).…”