Impaired tissue responsiveness to B-type natriuretic peptide in heart failure: biochemical bases.

Abstract

Release of the B-type natriuretic peptide (BNP) is increased in heart failure (HF). Physiologically, BNP exerts natriuretic, diuretic, vasodilator and cardioprotective effects. A number of clinical investigations carried out with synthetic BNP for the treatment of HF have suggested that BNP-based restoration of homeostasis is inadequate. This equivocal clinical benefit of a recombinant BNP in HF raises the possibility of attenuated BNP response. The objective of this thesis is an examination of three aspects of BNP-related cardiovascular pathophysiology. The first issue tested was the effect of BNP in isolated neutrophils of control subjects via neutrophil superoxide (O₂⁻) generation. The second issue was integrity of BNP effects in acute and chronic HF patients, and the third was maintenance of BNP effect in the acute phase of Tako-tsubo cardiomyopathy (TTC), a form of “stress-induced” cardiomyopathy and another condition associated with increased BNP release. The study utilized the technique of electron paramagnetic resonance spectroscopy to quantitate the extent of O₂⁻ generation from isolated neutrophils. In control subjects, the data showed significant suppression of O₂⁻ generation in PMA- and fMLP-stimulated neutrophils. This effect was not affected by either age or gender of the study population. The effect of BNP was mimicked by a cell-permeable cGMP analog (8-pCPT-cGMP) and partially restored by a protein kinase G (PKG) inhibitor KT5823. Furthermore, BNP inhibited the fMLP-induced phosphorylation of the NAD(P)H oxidase subunit p47phox at ser345. These findings led to the conclusion that BNP suppression of O₂⁻ generation is mediated by the cGMP-PKG signaling pathway. The studies concerning HF patients had two major components: (a) examination of the BNP effect in acute HF patients and (b) determination of changes in effect with chronic treatment of such patients. Studies with acute HF patients showed a significant attenuation of BNP effects on suppressing neutrophil O₂⁻ generation compared with control subjects. However, 8-p-CPTcGMP effects were retained, which indicates that BNP effects were attenuated at the level of natriuretic peptide receptor level. Furthermore, the effect of BNP on inhibition of the fMLP-induced phosphorylation of p47phox at ser345 was lost in acute HF patients. Comparison of the acute and chronic HF patients revealed a partial restoration of BNP effects, especially in younger patients. TTC is associated with acute release of BNP into plasma as a result of inflammatory change in the heart. It was found that BNP effect was attenuated similarly in TTC patients and acute HF patients. The residual effect was not associated with either patients’ inflammatory status or catecholamine release. In summary, this study identified that (1) In control subjects without diagnosed cardiovascular disease, BNP suppressed the release of the inflammatory modulator O₂⁻ from isolated neutrophils by attenuating NAD(P)H oxidase assembly; (2) This effect of BNP was lost in patients with acute HF, but recovers partially with chronic treatment of HF. (3) In TTC patients, attenuation of BNP effect was also present. These data suggest that marked elevation of plasma concentration of BNP limits its physiological anti-inflammatory effects.