Mechanisms of renal hyporesponsiveness to BNP in heart failure

Abstract

The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, is a potent natriuretic, diuretic, and vasodilatory peptide that contributes to blood pressure and volume homeostasis. These attributes make BNP an ideal drug that could aid in diuresing a fluid-overloaded patient who had poor or worsening renal function. Despite the potential benefits of BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily increase natriuresis in patients with heart failure (HF). Moreover, despite high BNP levels, natriuresis falls when HF progresses from a compensated to a decompensated state, suggesting the emergence of renal resistance to BNP. Although likely multifactorial, several mechanisms have been proposed to explain renal hyporesponsiveness in HF, including, but not limited to, decreased renal BNP availability, down-regulation of natriuretic peptide receptors, and altered BNP intracellular signal transduction pathways. Thus, a better understanding of renal hyporesponsiveness in HF is required to devise strategies to develop novel agents and technologies that directly restore renal BNP efficiency. It is hoped that development of these new therapeutic approaches will serve to limit sodium retention in patients with HF, which may ultimately delay the progression to overt HF.

Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy

“…Various mechanisms have been proposed to account for the diminished effectiveness of the NPS in the setting of CHF ( Table ) …”

B‐type natriuretic peptide and heart failure: what can we learn from clinical trials?

“…Since NPR‐C signalling may be up‐regulated in HF and may act in a manner similar to β ‐blockers actions, pharmacological agents that also target this specific signalling pathway may be beneficial. This affirmation is supported by the evidence that NPR‐C signalling may be important not only in improving coronary perfusion but also its activation may prevent against ischemia/reperfusion injury . Interestingly, the authors found that the vasorelaxant effect of NPR‐C signalling was increased in the presence of nitric oxide (NO) synthase inhibition, suggesting that they may be synergistic and complementary cardioprotective roles for NPR‐C signalling and NO‐mediated signalling in the coronary vasculature.…”

“…The inhibition of one pathway may thus be compensated for by the upregulation of the other. This may be of particular clinical significance in patients with HF who are known to have endothelial dysfunction and thus reduced or loss of NO pathway …”

“…This affirmation is supported by the evidence that NPR-C signalling may be important not only in improving coronary perfusion but also its activation may prevent against ischemia/reperfusion injury. 70,71 Interestingly, the authors found that the vasorelaxant effect of NPR-C signalling was increased in the presence of nitric oxide (NO) synthase inhibition, suggesting that they may be synergistic and complementary cardioprotective roles for NPR-C signalling and NO-mediated signalling in the coronary vasculature. The inhibition of one pathway may thus be compensated for by the upregulation of the other.…”

“…This may be of particular clinical significance in patients with HF who are known to have endothelial dysfunction and thus reduced or loss of NO pathway. [70][71][72][73][74][75][76]…”