Blunted Pressure Natriuresis in the Brattleboro Diabetes Insipidus Rat

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322 Blunted Pressure Natriuresis in the Brattlebr Diabetes Insipidus Rat J. Michael Gnzalez-Campy, Midri Awazu, Jey P. Granger, Jhn A. Haas, J. Carls Rmer, and Franklyn G.

1 322 Blunted Pressure Natriuresis in the Brattlebr Diabetes Insipidus Rat J. Michael Gnzalez-Campy, Midri Awazu, Jey P. Granger, Jhn A. Haas, J. Carls Rmer, and Franklyn G. Knx Antidiuretic hrmne is knwn t stimulate the renal synthesis f prstaglandins. These autacids, in turn, mdulate the pressure natriuresis phenmenn. Accrdingly, the present study was dne t test the hypthesis that, in the absence f antidiuretic hrmne and antidiuretic hrmne-dependent prstaglandin synthesis, the pressure natriuresis respnse is blunted. Experiments were perfrmed n Brattlebr diabetes insipidus rats (n=7) and Lng Evans cntrl rats (n=14). A change in perfusin pressure in the Lng Evans rats frm 89.3±1.0 t 108.7±l.l mm Hg (/?<0.05) was assciated with significant increases in the fractinal excretin f sdium (l.l±0.2 t 2.3±0.3%) and the urinary prstaglandin excretin (32.6±6.8 t 56.6± 10.0 pg/min). In cntrast, a similar change in perfusin pressure in the diabetes insipidus rat frm 88.6±1.4 t 106.2±1.5 mm Hg (p<0.05) resulted in n significant increases in either sdium r prstaglandin excretins. Treatment f a third grup f diabetes msipidus rats (n=9) with l-desamin-8-d-arginine vaspressin (1 /ig/day) restred the natriuretic respnse t increases in renal perfusin pressure. Treated diabetes insipidus and Lng Evans cntrl rats had cmparable natriuretic respnses t increases in renal perfusin pressure. Untreated diabetes msipidus rats, n the ther hand, had blunted respnses. In summary, the pressure natriuresis respnse in diabetes insipidus rats is blunted cmpared with Lng Evans cntrl rats. We cnclude that antidiuretic hrmne is necessary fr the cmplete expressin f the pressure natriuresis respnse. (Hypertensin 1989; 13: ) Increases in renal perfusin pressure result in increases in urinary sdium excretin, a phenmenn knwn as pressure natriuresis. 1 Since pressure natriuresis ccurs in the absence f changes in glmerular filtratin rate, renal plasma flw, r the filtered sdium lad, it is likely t result frm a direct inhibitin f tubular sdium transprt. 23 Pressure natriuresis may be due, at least in part, t the renal prstaglandins. Prstaglandin synthesis inhibitin blunts the effect f changes in perfusin pressure n sdium excretin. 4 Brattlebr diabetes insipidus rats lack antidiuretic hrmne. 5 These rats als have a decreased prstaglandin synthesiz- Frm the Department f Physilgy and Biphysics and the Department f Medicine, May Fundatin, Rchester, Minnesta. Supprted in part by grants HL and HL frm the Natinal Institutes f Health and by the May Fundatin. J.M.G-C. is the recipient f a Prter Physilgy Develpment Fellwship frm the American Physilgical Sciety and is a 1988 Cmmnwealth Fund Medical Fellw. Current address (M.A.) is Divisin f Pediatric Nephrlgy, Vanderbilt University, Nashville, TN Current address (J.P.G.) is Department f Physilgy, Eastern Virginia Medical Schl, Nrflk, VA Address fr crrespndence and reprints: Franklyn G. Knx, MD, PhD, Department f Physilgy and Biphysics, May Medical Schl, 200 First Street SW, Rchester, MN Received May 2, 1988; accepted Nvember 18, ing ability cmpared with the parent stck, Lng Evans rats. 67 Treating diabetes insipidus rats with antidiuretic hrmne restres prstaglandin prductin, which suggests that prstaglandin synthesis is enhanced by antidiuretic hrmne. 6 Fr the abve reasns, the diabetes insipidus rat ffers a unique mdel fr studying the pressure natriuresis phenmenn in the absence f antidiuretic hrmnedependent prstaglandin synthesis. Accrdingly, the present study was designed t test the hypthesis that the absence f antidiuretic hrmne and the resulting decreased prstaglandin synthesis lead t a blunted pressure natriuresis in the diabetes insipidus rat. Materials and Methds Experiments were perfrmed n male hmzygus Brattlebr diabetes insipidus (n=l) and Lng Evans (n=14) rats ( g bdy weight, Blue Spruce Farms, Inc., Altamnt, New Yrk). All rats were fed nrmal Purina chw that cntained 0.1 meq sdium/g f chw. All rats had free access t water. A third grup cnsisting f diabetes insipidus rats (n=9) was treated with l-desamin-8-d-arginine vaspressin (ddavp) (USB Labratries, Tarry-

Gnzalez-Campy et al Pressure Natriuresis in DI Rats 323 twn, New Yrk). Tw weeks befre the experiment, smtic minipumps were implanted intraperitneally under pentbarbital anesthesia.

2 Gnzalez-Campy et al Pressure Natriuresis in DI Rats 323 twn, New Yrk). Tw weeks befre the experiment, smtic minipumps were implanted intraperitneally under pentbarbital anesthesia. The minipumps delivered ddavp at a rate f 1 ^.g/day. n the day f the experiment, the rats were anesthetized with Inactin (Byk-Gulden, Knstanz, FRG) (100 mg/kg bdy wt i.p.) and placed n a heated table t maintain the bdy temperature at C. A trachestmy was perfrmed, and allratswere allwed t breathe spntaneusly. Catheters were placed int a jugular vein fr infusins and a cartid artery fr bld pressure mnitring and bld sampling. All rats were infused with a slutin that cntained 5% inulin and 6.25% albumin in istnic saline at a rate f 1 ml/hr fr the duratin f the experiment. The dme f the bladder was catheterized fr urine cllectin. An inflatable silastic cuff was placed arund the arta cephalad t the renal arteries. Inflatin f the cuff resulted in a decrease in renal perfusin pressure. The cuff was cnnected t an electric serv-cntrlling system that allwed fr precise cntrl f the perfusin pressure. A catheter tip was placed in the arta caudad t the renal arteries thrugh a cmmn iliac artery and served t cnfirm changes in renal perfusin pressure. A 3% bdy weight vlume expansin with isnctic albumin was given ver an hur t replace surgical lsses f fluid. Subsequently, diabetes insipidus rats were infused with a slutin f 10 mm sdium chlride in 1.4% glucse, and Lng Evans and treated diabetes insipidus rats were infused with istnic saline at rates adjusted t equal the urineflw (apprximately 6 ml/hr and 1.5 ml/hr, respectively). A minute equilibratin perid was allwed. After the equilibratin perid, a 30-minute clearance perid was begun. A 0.5 ml bld sample was taken at the midpint f the clearance perid. Plasma was remved, the packed cells were resuspended in istnic saline and infused int the rat. Renal perfusin pressure was then reduced apprximately 20 mm Hg by inflatin f the artic cuff. A 20-minute equilibratin perid at the new perfusin pressure was allwed; and then anther 30-minute clearance perid was started. In half f the animals in each grup the rder was reversed. A clearance perid was begun at a lw renal perfusin pressure and again after the perfusin pressure was allwed t return t nrmal. Since the initial mean arterial pressure in Lng Evans rats (126±3 mm Hg) was higher than in diabetes insipidus (114±2 mm Hg) and treated diabetes insipidus rats (115±3 mm Hg), renal perfusin pressure was first reduced t a cmparable level. Analyses Inulin cncentratins in plasma and urine were determined by the anthrne methd. 8 Sdium cncentratins in urine and plasma were measured with a Beckman E2A electrlyte analyzer (Beckman Instr., Inc., Fullertn, Califrnia). Plasma and urine smlalities were determined with a vapr pressure smmeter (mdel 5100, Wescr Inc., Lgan, Utah). => z z Z :. \ (D Renal Perfusin Pressure (mm Hg) LE * * TxDI» DI FIGURE 1. Line graphs shwing changes in urinary flw rate (U*V), fractinal excretin f sdium (FENa), urinary sdium excretin (UNa*V), and glmerular filtratin rate (GFR) in respnse t increases in renal perfusin pressure. LE, Lng Evans rats; TxDI, treated diabetes insipidus rats; DI, diabetes insipidus rats. *p<0.05 vs. lwer renal perfusin pressure (cntrl). **p<0.05 vs. Lng Evans rats at lwer perfusin pressure. Urinary prstaglandin cncentratins were measured by radiimmunassay as previusly described. 9 Statistical cmparisns were made using Student's paired r grup / test as apprpriate. Significance was accepted at p^0.05. All values are expressed as mean±sem. Results The data are summarized in Figure 1 and Table 1. A change in perfusin pressure in the Lng Evans rat frm 89.3±1 t 108.7±l mm Hg (p<0.05) is assciated with significant increases in urinary flw rate (34.4±5.8 t 61.0±8.5 /il/min), urinary sdium excretin (3.6±0.7 t 8.2±1.2 /xeq/min), fractinal excretin f sdium (1.1 ±0.2 t 2.3±0.3%), and urinary prstaglandin excretin (32.6±6.8 t 56.6±10.0 pg/

3 324 Hypertensin Vl 13, N 4, April 1989 TABLE 1. Kidney Functin at Lw and. High Renal Perfnsin Pressures LE cntrl rats (n = 14) DI rats (J7 = 7) Treated DI rats (n=9) Parameter Lw RPP High RPP Lw RPP High RPP Lw RPP High RPP RPP (mm Hg) 89.29± * * 90.65: d :1.89* Usm (msm/1) * ±39.19t ± : : d :55.72 UV (l/min) 34.42± * 92.14± : : J :7.76* GFR (mvmin/100 g bdy wt) 0.83± ± ±0.12* 0.76: : J 0.04 FE N. (%) 1.09± * 0.73± : : :! 0.43* U N,V (eq/min) 3.63± * 1.82±0.32t 3.41± : : :! 1.57* UPGE 2 (pg/ml) 841.2± * 525.6±124.0t 501.9± : :2385.4t d UPGE 2 V (pg/min) 32.57± * ± : :99.lt d * UPGE 2 V (% f cntrl) : : ! ±18.71 All values are expressed as mean±sem. LE, Lng Evans rats; DI, diabetes insipidus rats; RPP, renal perfusin pressure; Usm, urine smlality; UV, urinary flw rate; GFR, glmerular filtratin rate; FEN,, fractinal excretin f sdium; U N,V, urinary sdium excretin; UPGE 2, urinary prstaglandin E 2 cncentratin; UPGE 2 V, urinary prstaglandin E2 excretin. *p<0.05 vs. lwer perfusin pressure value. tp<0.05 vs. Lng Evans cntrl value at similar perfusin pressure. min). This change in perfusin pressure is als assciated with a significant decrease in urine smlality frm t 625.2±65.1 msm/1. In cntrast, a similar change in perfusin pressure in the Brattlebr diabetes insipidus rat frm 88.6± 1.4 t 106.2±1.5 mm Hg (p<0.05) resulted in n significant increases in the urinary flw rate, the fractinal and abslute excretins f sdium, and the urinary prstaglandin excretin. The urinary flw rate (92.1 ±15.6 vs. 34.4±5.8 ^1/min) was elevated, and the urine smlality (201.9±39.2 vs. 709±65.1 msm/ 1) and urinary sdium excretin (1.8±0.3 vs. 3.6±0.7 /ieq/min) were decreased in this grup cmpared with the Lng Evans cntrl rats at the lwer renal perfusin pressure (Figure 1, Table 1). Changes in renal perfusin pressure in the Lng Evans rats were nt assciated with significant changes in the glmerular filtratin rate, but the glmerular filtratin rate increased slightly in the diabetes insipidus rats (Figure 1, Table 1). Treatment f diabetes insipidus rats with ddavp restred the natriuretic respnse t increases in renal perfusin pressure t levels similar t thse bserved in the Lng Evans rats. Additinally, the urinary prstaglandin excretin f the treated grup was magnified cmpared with the untreated grup. There were n significant changes in the glmerular filtratin rate f the treated diabetes insipidus grup in respnse t increasing perfusin pressure. The data are summarized in Table 1 and Figures 1 and 2. The present study did nt find a significant difference in the urinary prstaglandin E2 excretry rates between anesthetized Lng Evans cntrl rats and diabetes insipidus rats (Table 1), as has been dcumented fr cnscius animals. 67 It is pssible that the anesthesia and surgical manipulatins affected the urinary prstaglandin levels. It is als pssible, as has been previusly suggested, that the excreted prstaglandins represent a variable fractin f the ttal prstaglandin synthesis. 10 Therefre, the urinary prstaglandin data are expressed as a percent f cntrl, cntrl being the urinary prstaglandin excretin at the lwer perfusin pressure. Bth the Lng Evans cntrl rats and the treated diabetes insipidus rats shwed a large increase in prstaglandin excretin with increases in perfusin pressure. Untreated diabetes insipidus rats, n the ther hand, shwed nly a slight increase in urinary prstaglandin excretin when the renal perfusin pressure was increased. These data are summarized in Figure 2. Discussin The present study demnstrates that the pressure natriuresis phenmenn is blunted in the Brattlebr diabetes insipidus rat. Since the natriuretic respnse t increases in perfusin pressure is Q H 200- ~ a. 120 H Q_ 100 ' p < 0.05 LE DI TxDI FIGURE 2. Bar graph shwing urinary prstaglandin E 2 excretin (UPgE2*V) (fr the higher renal perfusin pressure) expressed as a percent f the value btained fr the lwer renal perfusin pressure (cntrl). LE, Lng Evans rats; DI, diabetes insipidus rats; TxDI, treated diabetes insipidus rats. NS

Gnzalez-Campy et al Pressure Natriuresis in DI Rats 325 restred by ddavp, this study establishes that antidiuretic hrmne is necessary fr the cmplete expressin f a nrmal pressure natriuresis in the

4 Gnzalez-Campy et al Pressure Natriuresis in DI Rats 325 restred by ddavp, this study establishes that antidiuretic hrmne is necessary fr the cmplete expressin f a nrmal pressure natriuresis in the diabetes insipidus rat. ne mechanism fr pressure natriuresis may invlve the renal prstaglandins, since blckade f these autacids leads t a blunted natriuresis in respnse t increases in renal perfusin pressure. 4 It is knwn that antidiuretic hrmne stimulates prstaglandin synthesis in renal medullary tissue."- 13 Brattlebr rats lack antidiuretic hrmne, and their renal synthesis f prstaglandin E^ and prstaglandin F^ is knwn t be decreased. 67 Treatment with antidiuretic hrmne r the nnpressr analgue ddavp restres the synthesis f prstaglandins, 7 a respnse mstly due t interstitial cells and nt tubular elements in the kidney. 14 The present study cnfirms that treatment with ddavp increases renal prstaglandin synthesis and suggests that this synthesis is necessary fr a nrmal pressure natriuresis. Thus, the inability f the diabetes insipidus rat t increase prstaglandin synthesis may accunt fr the blunted natriuretic respnse t increasing perfusin pressure. It is pssible that prstaglandins directly inhibit the tubular reabsrptin f sdium, leading t a natriuresis The prximal tubule may be a site f actin f these autacids. This has been suggested by earlier micrpuncture studies that pint t the prximal tubule as a site reactive t increases in perfusin pressure. 17 The renal prstaglandins may als affect sdium reabsrptin at sites distal t the prximal tubule since previus studies have shwn that the medullary cllecting duct cntributes t the increased sdium reabsrptin that fllws prstaglandin synthesis inhibitin Anther mechanism whereby pressure natriuresis culd be blunted in the diabetes insipidus rat is a medullary washut. Increases in renal perfusin pressure nt nly cause a natriuresis but als decrease urine smlality and medullary slute cncentratins Medullary plasma flw in the diabetes insipidus rat is high, and the medullary salt gradient is decreased. 5 Therefre, it is pssible that the preexistent medullary washut in these animals prevents further changes in water and sdium reabsrptin. As a result, pressure natriuresis becmes blunted. These bservatins may be attributed t a lack f autregulatin f medullary bld flw in respnse t changes in renal perfusin pressure. 21 Hwever, previus findings that pressure diuresis is preserved in animals with diabetes insipidus and in water diuresis d nt supprt this hypthesis In these cnditins a medullary washut wuld be expected t be already present, and changes in perfusin pressure shuld cause little r n change in diuresis and natriuresis. Nnetheless, sme f the previus studies were incmplete because they did nt measure sdium excretin 23 and cmparisns with nrmal rats were nt made Finally, a blunted pressure natriuresis in the diabetes insipidus rat may be the result f the chrnic extracellular fluid vlume cntractin attributable t the absence f antidiuretic hrmne. This chrnic change in extracellular vlume has been suggested as the cause f increased activity in antinatriuretic systems that have been dcumented in the diabetes insipidus rat This pssibility is nt supprted by the mre recent bservatins that water-replete Brattlebr rats are nt hypvlemic and that their plasma vlumes are nt different frm Lng Evans cntrl rats. 28 Nnetheless, the antinatriuretic activity f angitensin and the sympathetic nerves may antagnize the natriuretic effect f increases in perfusin pressure in these rats. In summary, increases in renal perfusin pressure in the Lng Evans rat were assciated with an increased prstaglandin synthesis and a decreased tubular sdium reabsrptin. In cntrast, similar increases in renal perfusin pressure were assciated with an inability t increase renal prstaglandin synthesis and a diminished natriuretic respnse in the Brattlebr diabetes insipidus rat. Treatment with ddavp fr 2 weeks restred the ability t increase prstaglandin synthesis and sdium excretin in respnse t increases in renal perfusin pressure. Therefre, we cnclude that antidiuretic hrmne is necessary fr the cmplete expressin f the pressure natriuresis respnse. Acknwledgments We gratefully acknwledge the technical assistance f Marcy nsgard and Sharn Sandberg, and the secretarial supprt f June M. Hanke. References 1. Guytn AC, Cleman TG, Cwley AW, Schecl KW, Manning RD, Nrman RA Jr: Arterial pressure regulatin. verriding dminance f the kidneys in lng-term regulatin and in hypertensin. Am J Med 1972^2: McDnald SJ, DeWardener HE: The relatinship between the renal arterial perfusin pressure and the increase in sdium excretin which ccurs during an infusin f saline. Nephrn 1965;2: Selkurt EE, Wmack I, Dailey WN: Mechanism f natriuresis and diuresis during elevated renal arterial pressure. Am J Physil 1965^09: Carmines PK, Bell PD, Rman RJ, Wrk J, Navar LG: Prstaglandins in the sdium excretry respnse t altered renal arterial pressure in dgs. Am J Physil 1985;248:F8-F14 5. Valtin H: Sequestratin f urea and nnurea slutes in renal tissues f rats with hereditary hypthalamic diabetes insipidus: Effect f vaspressin and dehydratin n the cuntercurrent mechanism. J Clin Invest 1966;45: Walker LA, Whrtn AR, Smigel M, France R, Frlich JC: Antidiuretic hrmne increases renal prstaglandin synthesis in viv. Am J Physil 1978;235:F18-F Dunn MJ, Greely HP, Valtin H, Kinter LB, Beeuwkes R III: Renal excretin f prstaglandins E2 and F^ in diabetes insipidus rats. Am J Physil 1978;235:E624-E FQhr J, Kaczmarczyk J, Kruttgen CD: Eine einfache clrimetrische methde zr inulinbestimmung fur nierenclearanceuntersuchungen bei stffwechselgesunden und diabetikern. Klin Wchenschr I955;33:729-73

5 326 Hypertensin Vl 13, N 4, April Schryver S, Sanders E, Beierwaltes WH, Rmer JC: Crtical distributin f prstaglandin and renin in islated dg glmeruli. Kidney Int 1984^5: Sejersted M, Vikse A, Eide I, Kiil F: Renal venus and urine PGE 2 utput during intrarenal arachidnic acid infusins in dgs. Ada Physil Scand 1984;121: Kalisker A, Dyer DC: In vitr release f prstaglandin frm the renal medulla. Eur J Pharmacl 1972;19: Fejes-Tth G, Naray-Fejes-Tth A, Frlich JC: Acute effects f antidiuretic hrmne n urinary prstaglandin excretin. J Pharmacl Exp Ther 1983,227: Nadler J, Zipser RD, Cleman R, Hrtn R: Stimulatin f renal prstaglandins by pressr hrmnes in man: Cmparisn f prstaglandin E^ and prstacyclin (6-ket prstaglandin F, a ). J Clin Endcrinl Metab 1983 ;56: Jacksn BA: Renal prstaglandin E2 synthesis in the Brattlebr hmzygus diabetes insipidus rat. Prstaglandins Leuktrienes Med 1986;22: Stkes JB, Kkk JP: Inhibitin f sdium transprt by prstaglandin E2 acrss the islated, perfused rabbit cllecting tubule. J Clin Invest 1977^9: Stkes JB: Effect f prstaglandin E2 n chlride transprt acrss the rabbit thick ascending limb f Henle. Selective inhibitin f the medullary prtin. J Clin Invest 1979; 64: Haas JA, Granger JP, Knx FG: Effect f renal perfusin pressure n sdium reabsrptin frm prximal tubules f superficial and deep nephrns. Am J Physil 1986; 250(Pt 2):F425-F Wilsn DR, Hnrath U, Snnenberg H: Prstaglandin synthesis inhibitin during vlume expansin: Cllecting duct functin. Kidney Int 1982^22: Higashihara E, Stkes JB, Kkk JP, Campbell WB, DuBse TD Jn Crtical and papillary micrpuncture examinatin f chlride transprt in segments f the rat kidney during inhibitin f prstaglandin prductin. Pssible rle fr prstaglandins in the chlruresis f acute vlume expansin. J Clin Invest 1979;64: Thurau K, Deetjen P: Die diurese bei arteriellen drucksteigenrungen. PftQgers Arch 1962^74: Rman RJ, Smits C, Kaldunski M: Renal prstaglandins may influence the pressure-natriuresis respnse by altering medullary bld flw (abstract). Fed Prc 1986;45: Navar LG: Distal nephrn diluting segment respnses t altered arterial pressure and slute lading. Am J Physil 1972^22: Navar LG, Uther JB, Baer PG: Pressure diuresis in dgs with diabetes insipidus. Nephrn 1971;8: Aperia AC, Brberger CG, Sderlund S: Relatinship between renal artery perfusin pressure and tubular sdium reabsrptin. Am J Physil : Bank N: The renal regulatin f sdium transprt. Bull NY AcadMed 1970;46: Wten G, Hansn T, Lamprecht F: Elevated serum dparaine-/3-hydrxylase activity in rats with inherited diabetes insipidus. J Neural Transm 1975;36: Kinter LB, Schrier D, Flamenbaum W, Beeuwkes R: The renin angitensin system in cnscius Brattlebr strain rats. Renal Physil 1982;5: Gardiner SM, Bennett T: Interactin between neural mechanisms, the renin-angitensin system, and vaspressin in the maintenance f bld pressure during water deprivatin: Studies in Lng Evans and Brattlebr rats. Clin Sci 1985; 68: KEY WRDS prstaglandins antidiuretic hrmne kidney natriuresis sdium excretin

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