Kinins mediate the inhibition of atrial natriuretic peptide diuretic effect induced by pepsanurin

Pepsanurin is a peptidic fraction resulting from pepsin digestion of plasma globulins, that inhibits ANP renal excretory actions. We studied whether kinin-like peptides mediate the anti-ANP effect by testing if pepsanurin: 1) was blocked by the kinin B12 receptor antagonist HOE-140, 2) was produced from kininogen, and 3) was mimicked by bradykinin. Anti-ANP activity was assessed in anesthetized female rats by comparing the excretory response to two ANP boluses (0.5 mug iv) given before and after ip injection of test samples. Pepsanurin from human or rat plasma (1-5 mL/Kg), and bradykinin (5-20 mug/Kg), dose-relatedly inhibited ANP-induced water, sodium, potassium and cyclic GMP urinary excretion, without affecting arterial blood pressure. The same effect was exerted by pepsin hydrolysates of purified kininogen, whereas hydrolysates of kininogen-free plasma had no effect. HOE-140 (5 mug, iv) did not alter baseline, or ANP-induced excretion, but blocked the anti-ANP effects of pepsanurin. Histamine (15 mug/Kg) plus seroalbumin hydrolysates did not affect ANP response, despite inducing larger peritoneal fluid accumulation as compared with pepsanurin or bradykinin. We concluded that kinins cleaved from kininogen mediate the anti-ANP effects of pepsanurin by activation of kinin B2 receptors, independently of changes in systemic arterial pressure or peritoneal fluid sequestration.

El proceso digestivo y la regulación de la función excretora renal: pepsanuria y procininas inhibidoras de la acción diurética del péptido natriurético auricular / Digestive process and regulation of renal excretory function: pepsanurin and prokinin inhibitors of diuretic action of atrial natriuretic peptide

In order to clarify the blunting effect of peptides released by pepsin from blood plasma on ANP diuretic action, 2 prokinins designated PU-16 were tested. Both of them were able to inhibit in nanomolar doses the diuretic-saluretic action of 0.5 ug i.v. bolus of ANP given to anesthetized rats either by intravenous route or introduced in the duodenal lumen. PU-16 in doses of 0.5 ug and 1 ug were able to reduce in 72 and 96.5 per cent respectively the natriuresis induced bu 0.5 ug intravenous bolus of ANP. The data support the hypothesis that prokinins liberated in the digestive tract, could be physiological factors involved in hydrosaline homeostasis, moderating the ANP mediated increase of water, Na and K excretion during digestion

Human neuroblastoma cells express a novel metallo-endopeptidase activity able to inactivate atrial natriuretic factor: inhibition during retinoic acid-induced differentiation

A new metallo-endopeptidase which hydrolyzes atrium natriuretic factor (ANF) has been isolated from human neuroblastoma NB-OK-1 cells. In the present study we show that this metallo-endopeptidase is also present in several other human neuroblastoma cell lines, which include CHP 100, SH-SY5Y, SK-N-BE(2), BE(2)-C and BE(2)M-17. Additionally, we show that this endopeptidase activity is reduced to about 20 per cent of the control during retinoic acid (RA)-induced neuronal differentiation in the RA-sensitive SK-N-BE(2) cells, but not in the RA-resistant BE(2)-M17 cells. This suggests that the inhibition is related to neuronal differentiation and not to a direct effect of 5 microM RA on the enzyme activity. This new enzyme is clearly distinct from neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-converting enzyme (ACE,EC 3.4.15.1), since specific inhibitors for these endopeptidases (10 microM phosphoramidon and 1 mM captopril, respectively) had no effect on their activity. However, this enzyme was inhibited 100 per cent by 10 mM o-phenanthroline showing an inhibitory spectrum similar to that of another novel metallo-endopeptidase recently isolated in our laboratory from Xenopus laevis skin secretion. Although the physiological function of this new enzyme in human neuroblastoma cells is not known at the present time, we suggest that it may participate in inactivation of neuropeptides such as atrium natriuretic factor (ANF), substance P, somatostatin-14 and bradykinin in vivo

Pepsanurina en la insuficiencia cardíaca congestiva / Pepsanurin in congestive heart failure

We have identified a plasmatic substance, "pepsanurin" (PU) obtained by pepsin hydrolysis which inhibits the renal effects of the atrial natriuretic factor (ANF). To investigate whether patients with congestive heart failure (CHF) have increased plasma levels of PU we prepared PU from 10 patients with CHF class IV (NYHA), 9 patients with CHF class II or III and 16 healthy controls. Anesthetized rats were used to test the effects of ANF, 0.5 ug/100 g body weight i.v., before and following the intraperitoneal injection of 0.5 ml of PU. The inhibition of the diuretic and natriuretic effects of ANF was 40.9 ñ 11.9% and 49.8 ñ 12% respectively for control subjects. Corresponding figures for clas CHF patients were 62.3 ñ 3.1% and 73.8 ñ 3.5% (p < 0.02) and for class II-III patients 39.2 ñ 7.0% and 53.1 ñ 8.2% (NS). Accordingly, an increased capacity to generate PU may underlie the decreased sensitivity to ANF in patients with advanced CHF

Atrial natriuretic factors (ANF) and antidiuretic agents

Se demuesta que, en ratas anestesiadas y perfundidas con solución isotónica de glucosa, la administracíon i.v. previa de lisil-vasopresina, en dosis de 0.1 a 10 m, no inhibe la respuesta diurética y salurética del FNA (2.5 ug); en cambio, la dosis de 50 mU, que produce una elevación transitoria, pero acentuada de la presión arterial, intensifica el efecto del FNA. La pepsanurina obtenida de la hidrólisis de globulinas de 20 ml de plasma humano, administrada i.p., 40 a 60 m antes de la administración i.v. de FNA, produce una significativa inhibición de la respuesta diurética natriurética