RENAL RESPONSE TO URODILATIN IN HEART FAILURE

心力衰竭时尿舒张素的肾脏反应

• 批准号: 3843357
• 负责人: Z ABASSI
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3843357
• 关键词: atrial natriuretic peptide; blood pressure; congestive heart failure; dosage; glomerular filtration rate; heart disorder chemotherapy; hormone regulation /control mechanism; kidney pharmacology; laboratory rat; peptide hormone analog; protease inhibitor; saluresis; urination

Urodilatin (URO - ANP95-126), is a newly described member of the family of natriuretic peptides. It has the same structure as ANP99-126 with four additional amino acids on the amino terminal end. Likely, URO is of renal origin and secreted into urine. URO is more natriuretic than ANF at low doses. We investigated 1) The renal effects of exogenous infusion of URO and ANP99-126 before and after the induction of congestive heart failure (CHF) by creation of an aortocaval fistula (ACF) in rats, 2) The effects of pretreatment with neutral endopeptidase inhibitor (NEP-I), SQ28,063 on the renal response to URO in these rats, and 3) The effect of NEP-I and ANP clearance receptor blockade by C-ANF4-23 on the metabolism of 125I- ANP99-126 and 125I-URO. In control rats URO (0.75-12 microg/kg/h) caused dose dependent increases in urine flow (V), and absolute (UNaV) and fractional sodium excretion (FENa%). Glomerular filtration rate (GFR) rose significantly despite markedly lower mean arterial pressure (MAP). Infusion of the same doses of URO to rats with CHF induced significant increases in V, GFR, UNaV and FENa%, however the absolute levels of diuresis and natriuresis were lower in rats with CHF. When URO was infused into rats with ACF pretreated with NEP-I (40 mg/kg) the absolute urine flow and sodium excretion were not different from those obtained in control rats. Infusion of equimolar doses of ANP 99-126 into control rats resulted in diuretic and natriuretic response, which were smaller than those obtained after infusion of URO. Similarly, rats with CHF showed an attenuated renal response to ANP99-126, compared to their remarkable renal response to equimolar doses of URO. These differences between the natriuretic potency of ANP and URO, may be attributed to our findings that while ANP is removed from the circulation by NEP and ANP clearance receptors, URO is removed mainly by the latter.

尿扩张素（Urodilatin，URO-ANP 95 -126）是一个新发现的家族成员 利钠肽 它具有与ANP 99 -126相同的结构， 在氨基末端有四个额外的氨基酸。 很可能，URO是 来源于肾并分泌到尿中。URO比ANF更具利钠作用， 低剂量 我们研究了：1）外源性输注URO的肾脏效应， ANP 99 -126在诱导充血性心力衰竭前后的变化 (CHF)通过在大鼠中建立下腔静脉瘘（ACF），2） 中性内肽酶抑制剂（NEP-I），SQ 28，063预处理 3）NEP-I和NEP-II对URO大鼠肾脏反应的影响。 C-ANF 4 -23阻断ANP清除受体对~（125）I代谢的影响 ANP 99 -126和125 I-URO。 在对照大鼠中，URO（0.75-12 μ g/kg/h）引起剂量依赖性增加 尿流量（V）、绝对（UNaV）和钠排泄分数 (FENa%).肾小球滤过率（GFR）显著升高， 平均动脉压（MAP）明显降低。输注相同剂量 URO可显著增加CHF大鼠的V、GFR、UNaV 和FENa%，但利尿和尿钠排泄的绝对水平为 在CHF大鼠中更低。 当灌胃含ACF的大鼠时， 用NEP-I（40 mg/kg）预处理的绝对尿流量和钠 排泄与对照大鼠中获得的排泄没有差异。 将等摩尔剂量的ANP 99-126输注到对照大鼠中， 利尿和利钠反应，这是小于那些获得 输注URO后。 类似地，CHF大鼠表现出减弱的 对ANP 99 -126的肾反应，与其显著的肾反应相比 等摩尔剂量的URO。 利钠利尿剂和 ANP和URO的效力，可能归因于我们的研究结果，而ANP 通过NEP和ANP清除受体从循环中清除，URO 主要是由后者来消除的。