Wilkins M R, Settle S L, Stockmann P T, Needleman P
Department of Pharmacology, Washington University Medical School, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 1990 Aug;87(16):6465-9. doi: 10.1073/pnas.87.16.6465.
The effect of pharmacological manipulation of atriopeptin (AP) activity on sodium excretion and blood pressure was examined in the rat aortovenocaval (A-V) fistula model of cardiac failure. Introduction of an A-V shunt led to a marked and sustained elevation of plasma AP immunoreactivity and urinary cGMP levels. Further elevation of plasma AP levels by infusion of exogenous peptide induced modest increases in urinary sodium and cGMP excretion and a decrease in blood pressure but these responses were significantly attenuated compared to sham-operated animals. In contrast, low-dose infusion of M + B 22948 (a cGMP phosphodiesterase inhibitor) or thiorphan [a neutral endopeptidase (membrane metallo-endopeptidase, EC 3.4.24.11) inhibitor] induced a natriuresis in A-V fistula rats, which exceeded that seen in control animals given these compounds and matched the peak natriuresis produced in sham-operated animals by high doses of AP. In the doses used, these compounds had little effect on blood pressure. The greater renal efficacy of M + B 22948 in A-V fistula rats is consistent with postreceptor facilitation of AP activity. The effect of thiorphan on sodium excretion was accompanied by a pronounced increase in urinary cGMP and AP immunoreactivity excretion (and was attenuated by anti-AP monoclonal antibody) but could not be explained solely in terms of an increase in circulating AP levels. It is proposed that thiorphan allows filtered AP to reach renal tubule sites that are normally inaccessible to the peptide and are thus protected from down-regulation by high circulating AP levels. The implication of these observations for patients in cardiac failure is the potential for using pharmacological agents to maximize the response to endogenous AP without compromising cardiac function.
在大鼠主动脉-腔静脉（A-V）瘘管心力衰竭模型中，研究了心房肽（AP）活性的药理调控对钠排泄和血压的影响。建立A-V分流导致血浆AP免疫反应性和尿cGMP水平显著且持续升高。通过输注外源性肽使血浆AP水平进一步升高，引起尿钠和cGMP排泄适度增加以及血压降低，但与假手术动物相比，这些反应明显减弱。相反，低剂量输注M + B 22948（一种cGMP磷酸二酯酶抑制剂）或硫磷酰胺[一种中性内肽酶（膜金属内肽酶，EC 3.4.24.11）抑制剂]可诱导A-V瘘管大鼠产生利尿钠作用，这超过了给予这些化合物的对照动物的利尿钠作用，且与高剂量AP在假手术动物中产生的最大利尿钠作用相当。在所使用的剂量下，这些化合物对血压影响很小。M + B 22948在A-V瘘管大鼠中更大的肾脏效应与AP活性的受体后促进作用一致。硫磷酰胺对钠排泄的作用伴随着尿cGMP和AP免疫反应性排泄的显著增加（且被抗AP单克隆抗体减弱），但不能仅用循环AP水平的增加来解释。有人提出，硫磷酰胺可使滤过的AP到达肽通常无法到达的肾小管部位，从而免受高循环AP水平的下调作用。这些观察结果对心力衰竭患者的意义在于，有可能使用药物来最大化对内源性AP的反应而不损害心脏功能。
