Diabetes predisposes myocardium to left ventricular hypertrophy. A key antihypertrophic mechanism is cyclic GMP. This mechanism mediates the endothelium-independent actions of B-type natriuretic peptide (BNP). Cyclic GMP also appears to contribute to the antihypertrophic effects of angiotensin-converting enzyme (ACE) inhibitors.

Diabetes also compromises endothelium-dependent pathways. Notably, the disease predisposes to dysfunction of endothelial nitric oxide. This compromise can have important consequences, since nitric oxide protects myocardium from ischemic injury.

Dr. Ritchie and colleagues have evaluated how diabetes in the rat heart impacts the acute antihypertrophic actions of BNP. They compared this to the actions of bradykinin, an ACE inhibitor (ramiprilat) and a neutral endopeptidase (NEP) inhibitor (candoxatrilat). They hypothesized that they would observe preservation of the antihypertrophic actions of BNP, but not of the ACE inhibitor.

Investigators isolated hearts from diabetic rats and age-matched controls. They perfused these hearts for 90 minutes with BNP, bradykinin, ramiprilat, candoxatrilat or vehicle. After the first 30 minutes, they added angiotensin II, then allowed for incorporation of a radiochemical ([3H] phenylalanine) for 60 minutes.

They then used an assay of phenylalanine incorporation to determine level of protein synthesis. They also used radioimmunoassays to measure atrial natriuretic peptide (ANP) and beta-myosin heavy chain mRNA expression.

Protein Synthesis

Results show that BNP blocked protein synthesis in these diabetic rat hearts. In non-diabetic hearts (controls), angiotensin II increased left ventricular phenylalanine incorporation by 170% versus vehicle alone. Bradykinin, ramiprilat, BNP and candoxatrilat all prevented this stimulation. In diabetic hearts, phenylalanine incorporation was 143% higher compared with the controls. Angiotensin II further stimulated phenylalanine incorporation 137% compared with diabetic vehicle. Importantly, BNP abolished this hypertrophic response (p < 0.001 versus angiotensin II alone). None of the other treatments (bradykinin, ramiprilat, or candoxatrilat) abolished response.

mRNA Expression

In addition, BNP also blocked ANP and beta-myosin heavy chain mRNA expression. In control hearts, all agents prevented an angiotensin II-stimulated increase in ANP mRNA expression. In diabetic hearts, ANP expression at baseline was approximately 3 times higher than in control hearts. Adding angiotensin II led to a further increase in ANP mRNA. Investigators found BNP reduced the ANP mRNA to near baseline levels (p < 0.05; p = 0.16 when adjusted for multiple comparisons). None of the other agents modulated the ANP mRNA increase to any significant degree.

Administering BNP also appeared to reduce expression of beta-myosin heavy chain mRNA expression, although this finding did not reach statistical significance.

Cyclic GMP

In control hearts, all agents stimulated cyclic GMP to some degree. However, in diabetic rat hearts, only BNP exhibited significant stimulatory effects.

Dr. Ritchie and colleagues have shown that BNP prevents angiotensin II-related hypertrophic responses, while bradykinin, an ACE inhibitor and NEP inhibitor do not. In addition, BNP increased cGMP in diabetic hearts, unlike any other treatment in this investigation. Their findings support the hypothesis that administering natriuretic peptide may be an effective way to prevent cardiac hypertrophy in diabetes.