大鼠对心房利钠肽、内肽酶24.11抑制剂及C型心房钠尿肽受体配体的反应

Response to atrial natriuretic peptide, endopeptidase 24.11 inhibitor and C-ANP receptor ligand in the rat.

作者信息

Wilkins M R, Settle S L, Kirk J E, Taylor S A, Moore K P, Unwin R J

机构信息

Department of Clinical Pharmacology, Royal Postgraduate Medical School, London.

出版信息

Br J Pharmacol. 1992 Sep;107(1):50-7. doi: 10.1111/j.1476-5381.1992.tb14462.x.

DOI:10.1111/j.1476-5381.1992.tb14462.x

PMID:1330165

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1907610/

Abstract

The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99-126), (b) an endopeptidase-24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats. 2. Infusion of low-dose-ANP (100 ng kg-1 min-1) produced a gradual increase in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure. 3. Infusion of high-dose ANP (300 ng kg-1 min-1) produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure. 4. Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low-dose ANP infusion (100 ng kg-1 min-1) to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-1 min-1). However, unlike high-dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low-dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi.5. Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high-dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542.6. Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A-V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7. These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E-24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C-ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.

摘要

本研究比较了清醒大鼠对以下物质的肾脏和降压反应：(a) 外源性心房利钠肽（ANP）（99 - 126）、(b) 一种内肽酶 - 24.11抑制剂（坎多沙坦酯）和 (c) 一种ANP清除受体拮抗剂（SC 46542）。2. 输注低剂量ANP（100 ng·kg⁻¹·min⁻¹）使尿钠和鸟苷3':5'-环磷酸（环磷酸鸟苷）排泄逐渐增加，而肾小球滤过率（GFR）或锂清除分数（FeLi）无显著变化。血压显著下降。3. 输注高剂量ANP（300 ng·kg⁻¹·min⁻¹）使尿钠和环磷酸鸟苷排泄迅速增加3倍，同时GFR升高，但与对照组相比，对FeLi无显著影响。肾脏反应伴有血压明显下降。4. 与对照动物相比，单独使用坎多沙坦酯或SC 46542对钠排泄无显著影响。两种化合物均增强了对低剂量ANP输注（100 ng·kg⁻¹·min⁻¹）的利钠和环磷酸鸟苷反应，使其达到与高剂量ANP（300 ng·kg⁻¹·min⁻¹）相似或更高的水平。然而，与高剂量ANP不同，这些肾脏效应并未伴随GFR的显著变化，且两种化合物均未增强低剂量ANP输注的降压作用。仅坎多沙坦酯与ANP合用时，FeLi显著升高。5. 同样，坎多沙坦酯和SC 46542联合给药（无外源性ANP）使钠和环磷酸鸟苷排泄增加，与高剂量ANP相当，但GFR无显著增加，血压下降幅度明显较小。有趣的是，两种化合物联合使用时FeLi未增加，表明对钠排泄的主要贡献来自SC 46542。6. 在对ANP输注反应低下的心力衰竭大鼠动静脉瘘模型中，坎多沙坦酯和SC 46542均增加了钠和环磷酸鸟苷排泄，且血压无显著变化。7. 这些数据表明，坎多沙坦酯和SC 46542并非简单地重现ANP输注的作用，而是优先增强对ANP的利钠反应。抑制E - 24.11可能增强ANP的肾小管作用，而C型ANP受体配体的肾脏作用机制需要进一步研究。这两种操作在心力衰竭的治疗中均具有潜在价值。