目的:本工作探讨了在不同盐摄取的条件下，脑一氧化氮合酶（brain nitric oxide synthase,bNOS）对Dahl 盐敏感（S）及Dahl盐不敏感（R）大鼠的血液动力学、血浆肾素活性（plasma renin activity,PRA）、肾小球滤过率（glumerilar filtration rate,GFR）及有效肾血浆流量（effective renal plasma flow,ERPF）等的影响。方法：7周～8周龄的S及R大鼠经股静脉导管给予低盐（0.87 mmol/d）及高盐（20.6 mmol/d）溶液输注，并经与计算机系统相联的主动脉导管记录血液动力学等的变化。所有动物在经5天的对照观察后，其中部分动物在低盐或高盐溶液中加入bNOS特异抑制剂7-nitroindazole (7-NI,1.67 mg/kg/h),继续观察5天。结果：单纯低盐及高盐输注的R大鼠，其血压无显著变化，同时给予高盐及7-NI输注的大鼠，其血压较对照期间大幅上升（120±6％）。同样，在给予高盐及高盐＋7-NI输注的S大鼠，其血压亦分别较对照期间上升了110±2％及114±3％。7-NI对S及R大鼠肾小球过滤率、有效肾血浆流量等没有明显影响。此外血浆肾素活性测定表明，低盐+7-NI输注使PRA显著降低。结论：对盐不敏感的R大鼠在抑制体内bNOS活性后，由对盐不敏感而变为对盐敏感。说明bNOS在防止高盐导致高血压的过程中起着非常重要的作用。

要点：脑组织的一氧化氮合酶经过一氧化氮合酶的特殊抑制剂7-nitroindazole处理可使Dahl盐不敏感大鼠转变为盐敏感；说明脑组织一氧化氮合酶的活性在盐敏感性高血压中的作用。

中图分类号：Q55；Q491.1；R544.1文献标识码：A

文章编号：1006-2866(1999)02-0266-06

Brain Nitric Oxide Synthase and Salt-Sensitive Hypertension

Tan Tian-ran (谭天然) and Manning,R.D,Jr

(Department of Pathophysiology,Jinan University Medical College,Guangzhou 510632,P.R.China)

ABSTRACT Aim:The goal of this study was to determine the role of brain nitric oxide synthase (bNOS) in the arterial pressure,renal hemodynamic and renal excretory changes in Dahl salt-resistant(R) and salt-sensitive(S) rats during changes in sodium intake.Methods:Fifty-three Dahl R and S rats of 7～8 weeks of age with arterial and venous catheters instrumented were subjected to low (0.87 mmol/d) or high (20.6 mmol/d) Na intake.Measurements were made during a 5 day control period followed by a 5 day period of bNOS inhibition with iv 7-nitroindazole (7NI,1.67 mg*kg^-1/h) or vehicle infusion.Mean arterial pressure increased significantly to 120±6 % control in the R-high Na and 7NI rats.Results:In R rats either high or low salt intake caused little change in mean BP,while high salt intake plus 7NI increases mean BP 120±6% compared to that in control period.High salt intaked and high salt plus 7NI increased mean BP 110±2% and 114±3% in S rats,respectively.7NI didn't change slightly(P＞0.05) in GFR,effective renal plasma flow,urinary Na excretion or urine volume.However,plasma renin activity decreased significantly in R and S rats on low Na intake +7NI.The data demonstrate that the highly salt-resistant Dahl R rat became salt-sensitive during bNOS inhibition with 7NI.However,the arterial pressure of the S rat was not affected by 7NI.Conclusion: That the nitric oxide produced by bNOS in the Dahl R rat normally helps to prevent salt-sensitive hypertension and that low functional levels of bNOS in the S rat may contribute to its salt-sensitivity.

Key Words: mean Arterial Pressure;GFR;hemodynamics;urinary Sodium excretion;plasma renin activity

The arterial pressure of some human hypertensives is very sensitive to changes in sodium intake and they have been classified as "salt-sensitive," but the cause of the salt-sensitivity is not known.A recent preliminary report showed that salt-sensitive humans release less nitric oxide (NO) during NO agonist administration compared to salt-resistant essential hypertensives^［1］.In Dahl salt-sensitive (S) rats,our laboratory and others^［2,3］ showed that NO production is decreased during high sodium intake compared to Dahl salt-resistant (R) rats.L-arginine administration to Dahl S rats increased NO production and prevented salt-sensitive hypertension^［3,4］.Therefore,a decrease in NO production may be partly responsible for salt-sensitive hypertension in humans and Dahl S rats.However,the relative importance of the various isoforms of NO rats in causing salt-sensitive hypertension is not known.

Recent studies have shown that nitric oxide produced by brain nitric oxide synthase (bNOS) may play a significant role in preventing salt-sensitive hypertension in normal rats.Increases in sodium intake caused an increase in renal medullary bNOS protein in Sprague-Dawley (SD) rats^［5］.Even though the SD rat is normally salt-resistant,inhibition of bNOS in the renal medulla of these rats on a high sodium diet caused salt-sensitive hypertension^［6］.However,whether bNOS plays an important role in Dahl salt-sensitive hypertension is not known.

Preliminary results in our laboratory (R.D.Manning,Jr.,unpublished data,1998) showed that a high Na diet resulted in a much greater increase in renal medullary bNOS protein in Dahl R rats than in S rats.We hypothesize that NO produced by bNOS in the R rat helps to prevent salt-sensitive hypertension,and bNOS inhibition in the R rat will make it salt-sensitive like the S rat.Studies were conducted in Dahl R and S rats,Rapp strain during a 5-day control period and a 5-day period of bNOS inhibition with continuous iv infusion of 7-nitroindazole,sodium salt (7NI) at 1.67 mg/kg/h.Rats were subjected to either low or high Na intake,and cardiovascular and renal functional measurements were made throughout the experiment.

MATERIALS AND METHODS

1Animal preparation,experimental measurements and instrumentation: Experiments were conducted in 53 conscious 7～8 week old male,Dahl R or S rats,Rapp strain (Harlan Sprague Dawley,Indianapolis,IN).The project had the approval of the local Institutional Animal Committee.Rats were received when they were 5～6 weeks old,and surgery was done when the rats reached a weight of 200 g,and experiments were begun 1 week later when the rats had a weight of ～220 g.Aortic and vena cava catheters were implanted as we have done before^［3］,and 15 ml/day of either hypotonic or hypertonic saline was infused iv containing the following antibiotics: Mezlin,30 mg/day,(Miles,Westhaven CT) and penicillin G,5000 U/day,Rats were placed in a temperature controlled room with a 12-hour light/dark cycle.

Both catheters were exteriorized at the dorsal nape of the neck.and were connected to a dual channel infusion swivel (Instech Laboratories Inc.,Plymouth Meeting,PA).Saline solutions were infused with a Harvard apparatus syringe pump (Harvard apparatus,South Natick,MA) through a 0.22 μM filter (Cathivex,Millipore Corporation,Bedford,MA).The arterial catheter was filled with 1,000 U/ml heparin and connected to a Cobe pressure transducer (Lakewood,CO) and in turn to a pressure amplifier.Pulsatile arterial pressure signals from the amplifier were sent to a digital computer through an analog-to-digital converter and were sampled 500 Hz for 4 seconds of each minute throughout the entire 24-hour period.Heart rate and arterial pressure were determined from these data samples.

Water intake and urinary volume output were measured daily.Urine sodium concentration was determined by flame photometry and plasma renin activity by radioimmunoassay.Urinary nitrate plus nitrite excretion (UNOx) was determined using the Greiss reaction^［7］ and nitrate reductase from Escheria coli as we have done before^［3］.

GFR and ERPF were determined by measuring the radioactivity and