Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure.

Abstract

1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.

Effects of Exogenous and Endogenous Natriuretic Peptides on Forearm Vascular Function in Chronic Heart Failure

“…Many studies have detailed the central hemodynamic, arterial, renal, and adrenal effects of exogenous [1][2][3][4][5][6][7][8] and endogenous 9 NPs in animal models of HF 1 and in human HF, 2-9 but little is known about the effects of NPs on the capacitance vasculature in this condition. In the present study, we assessed the effects of all 4 currently known human NPs on the forearm vasculature in matched groups of optimally treated cHF patients.…”

“…Systemic infusion of NP 8,27 (or elevation of endogenous NP by inhibiting their breakdown) 9 has been shown to increase stroke volume (SV) 27 and cardiac index 8 in patients with HF, despite a decrease in CVP, 8,9 a finding apparently in conflict with the Frank-Starling mechanism. This is almost certainly caused by a decrease in the volume of the right ventricle and a decrease in pericardial pressure, which increases effective LV distending pressure despite a decrease in LVEDP (ie, diastolic ventricular interaction).…”

“…[1][2][3][4][5][6][7] Despite minimal effects on plasma volume and resistance vessel tone, infusion of NPs in patients with HF has consistently been shown to reduce central venous pressure (CVP). 8,9 This raises the possibility that the venodilator effects of NPs may be preserved in HF.…”

Renal effects of concurrent E‐24.11 and ACE inhibition in the aorto‐venocaval fistula rat

“…These properties suggest that E-24.11 inhibitors may be useful for the treatment of cardiac failure. Given alone, however, the effects of these compounds in patients with heart failure are modest and variable (Northridge et al, 1989;Munzel et al, 1992;Good et al, 1995). The initial response to E-24.11 inhibitors is a 2 to 7 fold increase in urinary sodium excretion; chronic dosing leads to a small, sustained reduction in right and left atrial pressure but little or no reduction in systemic blood pressure (Northridge et al, 1989;Munzel et al, 1992).…”

Omapatrilat: Neurohormonal and Pharmacodynamic Profile When Administered with Furosemide

“…15 Currently, however, no strong clinical evidence supports a role for selective NEP inhibitors alone in the treatment of heart failure. Positive hemodynamic effects have usually been limited to a modest decrease in right atrial and pulmonary capillary wedge pressure, [16][17][18] sometimes with a transient increase in cardiac index, 18 but with no improvement in arterial pressure, heart rate, or total peripheral resistance. [16][17][18] In animal studies, however, when selective NEP inhibitors were administered with ACE inhibitors, there were additional hemodynamic and renal benefits compared with those achieved with either alone.…”