UK79 300, an orally active atriopeptidase inhibitor, raises plasma atrial natriuretic peptide and is natriuretic in essential hypertension

CGS 34226 is a thiol-containing, potent dual inhibitor of endothelin converting enzyme-1 (ECE-1) and neutral endopeptidase 24.11 (NEP) with IC50 values of 11 and 5nM respectively. The purpose of the present study was to characterize the inhibitory effects of CGS 34225, an orally active prodrug of CGS 34226, on ECE-1 and NEP in vivo. The effects on ECE-1 and NEP were assessed by determining the inhibition of big endothelin-1 (big ET-1)-induced increases in mean arterial pressure (MAP) and increases in plasma atrial natriuretic peptide (ANP) concentrations respectively, in conscious rats. Thirty and 120min after the administration of vehicle, big ET-1 (0.3nmol/kg, intravenously; i.v.) produced pressor responses of approximately 800mmHg·min (area under the curve for change in MAP×time). Treatment with CGS 34225 at 1mgEq/kg, per os (p.o.), decreased the pressor effect of big ET-1 by 39 and 53% at 30 and 120min respectively (P<0.05, both times). Increasing the dose of CGS 34255 to 30mgEq/kg, p.o., resulted in greater inhibition, 84 and 92% (P<0.05) at 30 and 120min respectively. Furthermore, at this higher dose, the inhibitory effect on ECE-1 was long-lasting, averaging 86, 75 and 30% (P<0.05, all times) at 4, 8 and 24h respectively. In rats treated with vehicle, the infusion of ANP at 450ng/kg per min i.v. resulted in plasma ANP concentrations of 3.9–4.8ng/ml that remained relatively constant for 4h. Treatment with CGS 34225 at 10mgEq/kg, p.o., increased the ANP level to 7.7±1.0 and 10.6±1.8ng/ml at 1 and 4h after dosing (P<0.05, both times). These data demonstrate that CGS 34225 is a potent, orally active and long-acting inhibitor of ECE-1 and NEP in vivo. It is anticipated that compounds with this dual function may be useful in the treatment of cardiovascular diseases where the ET system plays a pathogenic role and the potentiation of ANP elicits therapeutic benefits.

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Plasma Levels of Brain Natriuretic Peptide in Healthy Subjects and Patients with Essential Hypertension: Response to Posture

Clinical Science ◽

10.1042/cs0850411 ◽

1993 ◽

Vol 85 (4) ◽

pp. 411-416 ◽

Cited By ~ 16

Author(s):

Giorgio La Villa ◽

Silvio Vena ◽

Alberto Conti ◽

Caterina Fronzaroli ◽

Aldo Brat ◽

...

Keyword(s):

Essential Hypertension ◽

Atrial Natriuretic Peptide ◽

Plasma Renin Activity ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Healthy Subjects ◽

Plasma Renin ◽

Plasma Aldosterone ◽

Plasma Atrial Natriuretic Peptide ◽

Atrial Natriuretic

1. To examine whether posture-induced changes in central volume affect brain natriuretic peptide secretion, plasma levels of human brain natriuretic peptide-32-like immunoreactivity (hBNP-32-li) were measured by radioimmunoassay in 11 healthy subjects and 20 patients with essential hypertension after 15 min supine, 15 min sitting and 15 min with the legs raised at 60°, together with plasma atrial natriuretic peptide concentration, plasma renin activity and plasma aldosterone concentration. 2. In the supine position, the plasma hBNP-32-li level was 1.57 + 0.10 fmol/ml in healthy subjects and significantly higher in hypertensive patients (2.39 +0.13 fmol/ml, P <0.001). In both groups, plasma hBNP-32-li level significantly (P <0.001) decreased when sitting (normotensive, 1.22 +0.08 fmol/ml; hypertensive, 1.85 +0.15 fmol/ml, P <0.001 versus normotensive) and increased again after leg raising (normotensive, 2.13+0.12 fmol/ml; P <0.002 versus resting; hypertensive, 2.84 + 0.16 fmol/min, P <0.001 versus resting, P <0.025 versus normotensive). 3. The plasma atrial natriuretic peptide concentration showed similar behaviour to the plasma hBNP-32-li, whereas plasma renin activity and plasma aldosterone concentration increased during sitting and decreased during leg raising in both healthy subjects and hypertensive patients, who had significantly higher plasma aldosterone levels when supine and sitting. 4. The plasma hBNP-32-li level, measured in all postural positions, was directly correlated with plasma atrial natriuretic peptide concentration (normotensive: r = 0.55, P <0.001; hypertensive: r = 0.69, P <0.001) and inversely correlated with plasma renin activity (r = −0.56, P <0.001 and r = −0.58, P <0.001). 5. We have shown that two physiological procedures, assumption of the sitting position and raising the legs to 60°, significantly affect the plasma hBNP-32-li level in healthy subjects. The response of the plasma hBNP-32-li level to postural changes is maintained in patients with essential hypertension, who have increased plasma levels of this hormone. The relevance of the observed modifications in the plasma hBNP-32-li level to the homoeostatic response to posture remains to be established.

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