Comparison of Candoxatril and Atrial Natriuretic Factor in Healthy Men

Abstract

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.

Therapeutic benefits of increasing natriuretic peptide levels

“…However, neutral endoThe high response rate may relate to the fact that omapatpeptidase inhibition has demonstrated only a limited ability rilat may be effective independently of the renin levels. to lower systemic blood pressure [89], which may be Thus in patients with salt-sensitive low renin hypertension, related to vasoconstrictive properties of selective neutral as often observed in black individuals, ACE inhibitors endopeptidase inhibition [90]. In addition to the vasoconusually are not as effective as in patients with normal or strictive potential of natriuretic peptides [39], other mechahigh renin levels [104].…”

“…Increased levels of seems to be one of the most efficacious antihypertensive circulating ET-1 could be demonstrated after administradrugs yet known. tion of candoxatril, a selective neutral endopeptidase There are effects of omapatrilat beyond pure blood inhibitor [89]. Similarly, locally applied candoxatrilat pressure lowering.…”

The Mechanism of Action of LCZ696

“…39,40 However, candoxatril has no effect on, or increases, systolic BP (SBP) in normotensives, an effect prevented by enalapril, and does not reduce BP in hypertensive subjects, probably because its vasodilatory effect may be offset by an increased activity of the RAAS and sympathetic nervous system and/or by downregulation of NP receptors. 41,42 In addition, since neprilysin acts on numerous physiological targets, the effect of candoxatril was broader than anticipated. 41 Neprilysin inhibition results in activation of the RAAS, therefore, in order to be clinically beneficial, neprilysin inhibition requires concomitant inhibition of the RAAS.…”

“…41,42 In addition, since neprilysin acts on numerous physiological targets, the effect of candoxatril was broader than anticipated. 41 Neprilysin inhibition results in activation of the RAAS, therefore, in order to be clinically beneficial, neprilysin inhibition requires concomitant inhibition of the RAAS. 43 Vasopeptidase inhibitors are dual inhibitors of ACE and neprilysin and, therefore, emerged as a new therapeutic option in HF and hypertension, but their pharmacological profile is complex.…”

Candoxatril improves exercise capacity in patients with chronic heart failure receiving angiotensin converting enzyme inhibition

“…Candoxatril is an orally active inhibitor of EC 3.4.24.11 and is well tolerated in man [10][11][12][13][14] . It causes an elevation in plasma atrial natriuretic peptide concentrations [4,12,15] and thereby induces a natriuresis [12,15,16] , a diuresis [12,15] , and a reduction in plasma renin activity and aldosterone concentrations [4,12] .…”