肾组织环磷酸鸟苷通过直接的肾小管作用引起泌钠作用(英文)

Renal interstitial guanosine cyclic 3′,5′-monophosphate mediates natriuresis by a direct tubule mechanism

目的 检测NO(一氧化氮 )和cGMP(环磷酸鸟苷 )可引起肾脏泌钠作用的假设。方法 cGMP及其类似物 ,NO合成酶底物通过微透析泵输入肾组织间隙以及肾动脉。通过慢性及急性动物实验 ,观察肾脏泌钠作用及血流动力学变化。结果 肾组织间隙给予cGMP及其 8 Br cGMP 1μg/h ,使 2 4h尿钠排出从对照组 (0 .6± 0 .1)mmol/2 4h增加到 (1 2± 0 10 )mmol/2 4h及 (2 .15± 0 .42 )mmol/2 4h (P <0 .0 0 1)。蛋白激酶G抑制剂Rp 8 pCPT cGMP能够拮抗二者的利钠作用 ,L 精氨酸 (L Arg) (NO合成酶底物 ) 4 0mg·kg 1·min 1可引起尿钠排出增加 (急性动物实验 ) ,从对照组 (1 6± 0 1) μmol/30min到(4 1± 0 1) μmol/30min(P <0 0 0 1) ,这一效应能被可溶性鸟苷酸环化酶的抑制剂ODQ阻断。NO供体SNAP可增加肾脏利钠作用从 (1.6 5± 0 .11) μmol到 (2 .93± 0 .0 8) μmol/30min(P <0 .0 0 1) ,这一效应同样被ODQ阻断。肾动脉输入cGMP(3μg/min) ,可引起尿钠排出增加 ,肾血流量及肾小球滤过率增加。肾组织cGMP增加肾脏泌钠作用 ,但不影响肾血流量及肾小球滤过率。结论 肾脏NO诱导利钠作用通过可溶性的鸟苷酸环化酶的激活以及cGMP产生。cGMP通过蛋白激酶G抑制肾小管钠的重吸收 ,与血流动力学改变无关。

The objective was to test the hypothesis that renal interstitial (RI)guanosine cyclic 3′,5′-monophosphate(cGMP)is natriuretic in vivo . Delivery of cGMP and 8 Br cGMP at 24 μg/d directly into the renal interstitial (RI)space of conscious rats ( n =8,each group)on normal sodium intake increased urine sodium excretion (U Na V) from (0.56±0.15) and (0.7±0.17) mmol/24 h on day 3 and day 4,respectively,to (1.17±0.14)and (1.61±0.11) mmol/24 h ( P <0.01)for cGMP and (2 15±0 42)and (2 16±0 1) mmol/24 h( P <0.001) for 8 Br cGMP,respectively.Protein kinase G (PKG) inhibitor Rp 8 pCPT cGMP blocked cGMP and 8 Br cGMP induced urinary sodium excretion to control levels.Acute RI infusion of L Arginine (L Arg) (40 mg·kg 1 ·min 1 ),but not D Arg,caused an increase in U Na V from(1.65±0.11) to(4.07±0.1) μmol/30 min ( P <0.01). This increase was blocked by RIN nltro L Arg methyl ester(L NAME; 100 ng·kg 1 ·min 1 ), by the phosphodiesterase (PDE Ⅱ) activator 5, 6DMcBIMP (0.01 mol/L ,by PDE Ⅱ (0.03 U·kg 1 ·min 1 )itself or by soluble guanylyl cyclase (sGC)inhibitor ODQ(0.12 mg·kg 1 ·min 1 ).The PDE Ⅱ activator also blocked L Arg stimulated cGMP levels.NO donor SNAP (S nitroso N acetylpenicillamine;0.12 μmol·mg 1 ·min 1 )increased U Na V,from (1 65±0 11)to (2 93±0 08) μmol/30 min( P <0 01)and this response was blocked completely by ODQ.Renal arterial (RA) but not RI administration of heat stable enterotoxin of Escherichia coli (STa) induced natriuresis.RA infusion of cGMP (3 μg/min) increased U Na V,renal blood flow(RBF) and glomerular filtration rate (GFR).Renal cortical interstitial cGMP infusion increased U Na V with no effect on total RBF,renal cortical blood flow (RCBF) of GFR.Similarly,the natriuretic actions of renal interstitial L Arg or SNAP were not accompanied by any change in RBF or GFR.Medullary cGMP infusion had no effect on U Na V,total RBF of medullary blood flow.Texas red labeled cGMP infused via the RI space was distributed exclusively to cortical renal tubular cells.The results demonstrate that RI cGMP inhibits renal tubule sodium absorption via PKG independently of hemodynamic changes.These observations indicate that the cortical interstitial compartment provides a potentially important domain for cell to cell signalling within the kidney.