Siragy H M, Lamb N E, Rose C E, Peach M J, Carey R M
Department of Internal Medicine and Pharmacology, University of Virginia School of Medicine, Charlottesville 22908.
Am J Physiol. 1988 Oct;255(4 Pt 2):F749-54. doi: 10.1152/ajprenal.1988.255.4.F749.
ACRIP is a competitive inhibitor of renin in which an analogue of statine, (3R,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of porcine renin substrate. ACRIP inhibits the enzymatic activity of renin, thus blocking the initiation of the angiotensin cascade. We studied the intrarenal action of ACRIP in small quantities without measurable systemic effects on renal function. In the first experiment, ACRIP was administered intrarenally at 0.02, 0.2, and 2 micrograms.kg-1.min-1 to uninephrectomized conscious dogs (n = 6) in metabolic balance at sodium intake of 10 meq/day. ACRIP, in doses of 0.02 and 0.2 micrograms.kg-1.min-1, markedly increased urine sodium excretion (UNaV) from 5.8 +/- 1.4 to 15.1 +/- 5.1 and 19.9 +/- 3.2 mu eq/min, respectively. Urinary flow rate (UV) underwent a similar increase and glomerular filtration rate (GFR) increased from 25.7 +/- 2.5 to 35.6 +/- 2.5 at 0.02 micrograms.kg-1.min-1 of ACRIP. Renal plasma flow (RPF), plasma renin activity (PRA), and plasma aldosterone concentration (PAC) were not affected. At 2 micrograms.kg-1.min-1, ACRIP traversed the kidney in quantities large enough to produce a reduction in systemic PRA and mean arterial pressure and caused natriuresis, diuresis, and increased GFR. In a second experiment, ACRIP was administered intrarenally at 0.2 micrograms.kg-1.min-1 in a separate group (n = 4) under identical conditions. ACRIP-induced increases in UV and UNaV were completely blocked by concurrent intrarenal administration of angiotensin II. The results indicate that intrarenal angiotensin II acts as a physiological regulator of renal sodium and fluid homeostasis.
ACRIP是肾素的竞争性抑制剂，其中一种statine类似物，即(3R,4S)-4-氨基-3-羟基-6-甲基庚酸，被整合到猪肾素底物类似物中。ACRIP抑制肾素的酶活性，从而阻断血管紧张素级联反应的启动。我们研究了小剂量ACRIP的肾内作用，其对肾功能无明显的全身影响。在第一个实验中，将ACRIP以0.02、0.2和2微克·千克⁻¹·分钟⁻¹的剂量肾内注射给处于代谢平衡状态、钠摄入量为10毫当量/天的单侧肾切除清醒犬（n = 6）。剂量为0.02和0.2微克·千克⁻¹·分钟⁻¹的ACRIP分别使尿钠排泄量（UNaV）从5.8±1.4显著增加到15.1±5.1和19.9±3.2微当量/分钟。尿流率（UV）也有类似增加，在ACRIP剂量为0.02微克·千克⁻¹·分钟⁻¹时，肾小球滤过率（GFR）从25.7±2.5增加到35.6±2.5。肾血浆流量（RPF）、血浆肾素活性（PRA）和血浆醛固酮浓度（PAC）均未受影响。在2微克·千克⁻¹·分钟⁻¹时，ACRIP经肾的量足以使全身PRA和平均动脉压降低，并引起利钠、利尿和GFR增加。在第二个实验中，在相同条件下将ACRIP以0.2微克·千克⁻¹·分钟⁻¹的剂量肾内注射给另一组（n = 4）。同时肾内注射血管紧张素II可完全阻断ACRIP诱导的UV和UNaV增加。结果表明，肾内血管紧张素II是肾钠和液体稳态的生理调节因子。
