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(Hypertension. 1995;26:1030-1034.)
© 1995 American Heart Association, Inc.

Articles

Nitric Oxide Synthase Isoform Activities in Kidney of Dahl Salt-Sensitive Rats

Yoshihiro Ikeda; Komei Saito; Jong-Il Kim; Mitsuhiro Yokoyama

From The First Department of Internal Medicine, Kobe (Japan) University School of Medicine.

Correspondence to Komei Saito, MD, The First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650, Japan.

	Abstract

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Abstract An abnormal L-arginine–nitric oxide axis has been suggested to be relevant to the genesis of salt-sensitive hypertension. In the present study we investigated the activities of three isoforms of nitric oxide synthase (NOS) in the kidney of Dahl salt-sensitive and salt-resistant rats. Five-week-old Dahl Iwai salt-sensitive (n=9) and salt-resistant (n=10) rats were maintained on a high salt diet (4% sodium chloride) for 4 weeks. We measured calcium-dependent and calcium-independent NOS activities in each particulate and soluble fraction of kidney by conversion of L-[³H]arginine to L-[³H]citrulline. Systolic blood pressure was elevated significantly (P<.001) in salt-sensitive but not salt-resistant rats. Calcium-dependent NOS activity in the soluble fraction was significantly lower in salt-sensitive rats than in salt-resistant rats (25.8±9.0 versus 48.2±19.2 disintegrations per microgram protein, respectively; P<.01). There were no differences in calcium-dependent NOS activity in the particulate fraction and calcium-independent NOS activity in the soluble fraction between groups. Renal norepinephrine content was lower in salt-sensitive rats than in salt-resistant rats (P<.05) and was positively correlated with calcium-dependent NOS activity in the soluble fraction (P<.01). Although no differences in endothelial and inducible-type NOS activity were observed a significant reduction in calcium-dependent NOS activity in the soluble fraction of the kidney of salt-sensitive rats suggests that the decreased neural-type NOS activity may in part be involved in the mechanism of salt-sensitive hypertension, possibly through alterations in renal sympathetic nervous activity and sodium handling.

Key Words: sodium • kidneys • norepinephrine • nitric oxide • rats, inbred strains

	Introduction

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Abnormal renal sodium handling is known to be involved in the pathogenesis of salt-sensitive hypertension in humans¹ and in some hypertensive animal models such as Dahl S rats.^{2 3 4} In Dahl S rats an abnormal relation between renal perfusion pressure and urinary sodium excretion has been reported to be present before the development of hypertension.² Recently NO was reported to increase as an adaptive response to increased dietary sodium intake, cause vasodilation, and facilitate natriuresis.⁵ An inhibition of NOS was found to blunt the pressure-natriuresis relation in normotensive animals^{6 7 8} and enhance the sensitivity to the pressor effect of increased salt intake, suggesting that an impaired NOS activity may be a factor causing salt-sensitive hypertension.⁹ In Dahl S rats a decreased urinary excretion of NO has been reported,¹⁰ and administration of L-arginine, a precursor for endothelium-derived NO,¹¹ prevents hypertension in these rats during high salt intake.^{12 13} These observations led to the hypothesis that hypertension in Dahl S rats might result from a genetic defect in the L-arginine–NO pathway. However to date it remains unclear whether an impairment of NOS activity is present and which isoform of NOS is defective in Dahl S rats.

NO is generated from the terminal guanidino nitrogen of L-arginine through the action of NOS.¹¹ Three NOS isoforms, namely the neural, endothelial, and cytokine-inducible types, have been cloned and characterized by their subcellular location and calcium requirements.¹⁴ Endothelial NOS is membrane associated, whereas both neural and cytokine-inducible forms are cytosolic proteins. The endothelial and neural isoforms are activated by calcium and calmodulin, but the inducible isoform is not calcium dependent. In this study we tried to elucidate whether an altered NOS activity is present in Dahl S rats by measuring activities of the three NOS isoforms in kidney.

	Methods

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Rats and Treatment
Five-week-old male Dahl S (n=9) and Dahl R (n=10) rats (Eisai Co, Ltd, Tokyo, Japan) were maintained on a high salt (4% sodium chloride) diet and given free access to tap water. All rats were individually housed in metabolic cages for 4 weeks. Systolic blood pressure was measured every week by the tail-cuff method with an automatic blood pressure measurement system (MK-1100 Muromachi Kikai Co Ltd). Changes in body weight and pulse rate were recorded every week for 4 weeks. After 4 weeks a 24-hour urine sample was collected for measurement of sodium and creatinine and stored at -20°C until assay. After the urine sampling was completed rats were decapitated and blood samples were collected into tubes containing heparin solution (10 IU/mL) for measurement of plasma sodium, potassium, and creatinine concentrations. Plasma and urinary concentrations of sodium and creatinine were measured with an autoanalyzer.

Assay of NOS Activity and Norepinephrine Content
The kidney was removed, perfused with ice-cold saline, and homogenated in a solution of 50 mmol/L Tris-HCl at pH 7.4 containing (final concentration) 1 mmol/L EGTA, 1 mmol/L dithiothreitol, 1 µmol/L (p-aminophel)methanesulfonyl fluoride, 1 µmol/L pepstatin A, and 2 µmol/L leupeptin at 4°C. After two 5-second sonications crude homogenate of kidney was centrifuged at 100 000g for 60 minutes at 4°C. The soluble fraction was removed, 10% (vol/vol) glycerol was added, and the mixture was stored at -80°C. The particulate fraction resuspended in 50 mmol/L Tris-HCl (at pH 7.4) containing 1 mmol/L EGTA, 1 mmol/L dithiothreitol, 1 µmol/L (p-aminophel)methanesulfonyl fluoride, 1 µmol/L pepstatin A, 2 µmol/L leupeptin, 10% glycerol, and 1 mmol/L KCl was solubilized with 20 mmol/L 3[(3-cho-amidopropyl) dimethylammonio]-1-propanesulfonate. NOS activity was determined by the conversion of L-[³H]arginine to L-[³H]citrulline as described by Pollock et al¹⁵ with a slight modification. Each fraction of tissue was incubated with 80 nmol/L L-[2,3-³H]arginine for 30 minutes at 25°C in a reaction mixture of 50 mmol/L Tris-HCl at pH 7.4 containing 1 mmol/L EGTA, 1 mmol/L dithiothreitol, 1 mmol/L nicotinamide adenine dinucleotide phosphate, 300 nmol/L calmodulin, 2 mmol/L CaCl₂, 100 µmol/L tetrahydrobiopterin, 10 µmol/L flavin adenine dinucleotide, and 60 mmol/L L-valine in a final volume of 100 µL. The reaction was stopped by adding 0.5 mL stop buffer (2 mmol/L EGTA, 20 mmol/L HEPES, pH 5.5). The total volume was then applied to a 1-mL Dowex AG 50W-X8 column (Na⁺ form, Bio-Rad) preequilibrated with the stop buffer. L-[³H]citrulline was eluted twice with 0.5 mL distilled water, and the radioactivity of 1 mL of this elution was determined by liquid scintillation counter (model LS3801, Beckman Instruments). The activities of the calcium-dependent and calcium-independent NOS were determined from the differences between the L-[³H]citrulline produced from control samples in reaction mixture with and without CaCl₂ and calmodulin and samples containing 1 mmol/L N^G-nitro-L-arginine methyl ester, an inhibitor of NOS, respectively.

Renal norepinephrine content was determined by high-performance liquid chromatography. Protein concentrations were determined according to the method of Bradford¹⁶ with bovine serum albumin as a standard protein. NOS activity and renal norepinephrine content were corrected by protein concentration and expressed as disintegrations per minute per microgram protein and picograms per milligram protein, respectively.

Statistics
Values were expressed as mean±SD. Differences between the two groups were assessed with Student's unpaired t test; for NOS activity the Mann-Whitney U test was used. Correlation of the data was determined with a least-squares-fit linear regression analysis. A value of P<.05 was considered statistically significant.

	Results

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The Table shows the baseline systolic blood pressure and data at the end of the 4-week study period in each group for systolic blood pressure, pulse rate, body weight, serum electrolyte concentrations, urine volume, urinary sodium excretion, fractional excretion of sodium, creatinine clearance, and renal norepinephrine content. While initial systolic blood pressure was not different between Dahl S and R rats, Dahl S rats showed an elevation in blood pressure (P<.001) and developed salt-sensitive hypertension during the 4-week high salt period. There were no differences in pulse rate and body weight. Serum sodium concentration was higher in Dahl S than in Dahl R rats (P<.05). Serum potassium concentration, urine volume, urinary sodium excretion, fractional excretion of sodium, and creatinine clearance values were not different between the two groups. Renal norepinephrine content was lower in Dahl S than in Dahl R rats (P<.05).

View this table: [in this window] [in a new window]   Table 1. Systemic, Hemodynamic, and Laboratory Parameters for Dahl S and R Rats

Calcium-dependent and calcium-independent NOS activities in each fraction of kidney are shown in Fig 1. There was no significant difference in calcium-dependent NOS activity in the particulate fraction between Dahl S and R rats (108.1±30.4 versus 123.4±27.0 disintegrations per minute (dpm)/µg protein, respectively; P=NS; Fig 1a). We did not detect calcium-independent NOS activity in the particulate fraction. Dahl S rats exhibited significantly lower calcium-dependent NOS activity in the soluble fraction than Dahl R rats (25.8±9.0 versus 48.2±19.2 dpm/µg protein, respectively; P<.01; Fig 1b) but did not have lower calcium-independent NOS activity in this fraction (5.9±6.3 versus 5.0±3.4 dpm/µg protein, respectively; P=NS; Fig 1c). The sum of NOS activity of the three fractions in the kidney of Dahl S rats was significantly lower than that of Dahl R rats (139.8±32.2 versus 176.4±40.8 dpm/µg protein, respectively; P<.05). As Fig 2 shows calcium-dependent NOS activity in the soluble fraction correlated positively with the renal norepinephrine content (r=.63, P<.01).

View larger version (14K): [in this window] [in a new window]   Figure 1. Bar graphs showing calcium-dependent NOS activity in the particulate fraction (a) and in the soluble fraction (b) and calcium-independent NOS activity in the soluble fraction (c) of the kidney of Dahl S (solid bar) and Dahl R (open bar) rats. Values are expressed as mean±SD.

View larger version (18K): [in this window] [in a new window]   Figure 2. Scatterplot showing relation between calcium-dependent NOS activity in the soluble fraction and renal norepinephrine content in Dahl S () and Dahl R () rats.

	Discussion

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The present study demonstrates decreased calcium-dependent NOS activity in the soluble fraction, ie, neural-type NOS activity, in the kidney of Dahl S compared with Dahl R rats. Neural-type NOS recently has been shown to exist in a variety of tissues such as brain, spinal cord, sympathetic ganglion, adrenal gland, peripheral nitroxidergic nerve and macula densa.¹⁷ Terada et al¹⁸ detected the constitutive NOS in kidney, which localized in inner medullary collecting duct and thin limb, cortical collecting duct, outer medullary collecting duct, glomerulus, vasa recta, and arcuate artery. Since NO was reported to cause diuresis and natriuresis through its effects on renal tubules and vascular system¹⁹ the localization of neural-type NOS in kidney may participate in the regulation of renal hemodynamics and water and sodium handling.

Recent studies^{20 21 22 23} have indicated that NOS inhibition produces hypertension through alterations in central and peripheral sympathetic nervous activity. Sakuma et al²⁰ demonstrated an increase in sympathetic nervous activity with a concomitant elevation in blood pressure after intravenous injection of NOS inhibitors. Since this pressor effect was abolished by spinal section but not by vagotomy or sinoaortic baroreceptor denervation, NO is suggested to regulate sympathetic nervous activity in the central nervous system. Direct microinjection of NOS inhibitor into the nucleus tractus solitarius and rostal ventrolateral medulla also has been reported to cause an elevation in blood pressure and an increase in renal sympathetic nervous activity.^{21 22} Recently a nitroxidergic neural system was demonstrated in peripheral arteries. Toda and Okamoto²³ found that even after denudation of endothelium electric stimulation resulted in an arterial relaxation with the increased release of NO in vitro, suggesting that peripheral nitroxidergic nerve may cause vasodilatation. Toda and colleagues²⁴ also demonstrated that pretreatment with hexamethonium, a ganglionic blocking agent, abolished the pressor response to NOS inhibitor in vivo while pretreatment of phentolamine did not. These data suggest that hypertension caused by NOS inhibitor is attributable to an elimination of nitroxidergic neural function rather than to an impairment of basal release of NO from the endothelium. Clinically linkage analysis has revealed no relation between essential hypertension and the endothelial NOS gene in humans.²⁵ In this study we demonstrated that there was no difference in the activity of calcium-dependent NOS in particulate fraction (ie, endothelial-type NOS activity) but that neural-type NOS was decreased in the kidney of Dahl S compared with Dahl R rats. It is possible that neural-type rather than endothelial-type NOS may participate in vasodilator and depressor action through a suppression in sympathetic nervous activity and an activation of nitroxidergic vasodilator nerve.

As for the role of NOS in kidney there is evidence²⁶ that the development of N^G-nitro-L-arginine methyl ester–induced hypertension is attenuated in renal-denervated compared with sham-operated rats, suggesting that the integrity of sympathetic nervous system is a factor in causing hypertension resulting from NOS inhibition. In this study we demonstrated the decreased renal norepinephrine content in Dahl S compared with Dahl R rats. Previous studies reported that increased sympathetic nervous activity in the heart and kidney of Dahl S rats is associated with an increased norepinephrine turnover rate,²⁷ which is accompanied by a reduced tissue norepinephrine content, reflecting higher norepinephrine utilization in the respective organs.^{27 28 29} The decreased renal norepinephrine content in our Dahl S rats is consistent with these findings, indicating the increased renal sympathetic nervous activity in these rats. In addition there was a positive relation between renal norepinephrine content and neural-type NOS activity in the combined group of Dahl S and R rats. Recently NO application was reported to increase intraaxonal catecholamine levels of adrenergic nerve fibers, suggesting that NO inhibits norepinephrine release from nerve endings.³⁰ Thus the decreased neural-type NOS activity in kidney of Dahl S rats might be relevant to the genesis of salt-sensitive hypertension through increased renal sympathetic nervous activity.

NO also has been reported to decrease sodium reabsorption directly in several nephron segments.³¹ Greater sodium transport has been demonstrated in inner medullary collecting-duct cells from Dahl S rats compared with those from Dahl R rats in which neural-type NOS was detected abundantly.¹⁸ Therefore decreased neural-type NOS activity may directly cause decreases in sodium and water excretion. In addition since blockade of distal nephron sodium transport by NOS inhibition has been reported to attenuate pressure natriuresis³² the decreased neural-type NOS activity in the kidney of Dahl S rats might impair an adequate natriuresis during high sodium loading. That is, the kidney from Dahl S rat can excrete only one half as much sodium as that from Dahl R rats when the two strains are compared at an equal level of inflow pressure. In fact Patel et al³³ reported that L-arginine administration enhances the pressure-natriuretic response in Dahl S rats by preventing blood pressure elevation.

Inducible-type NOS is present in renal tubules of several segments in the basal state and can be induced by cytokine treatment in mesangial cells, medullary interstitial cells, and papillary surface epithelium.³⁴ Chen and Sanders¹³ demonstrated that inducible NOS in the arterial wall is the candidate gene in salt-sensitive hypertension in the Dahl/Rapp rats, since dexamethasone supplementation abolishes the antihypertensive effect of L-arginine. Recently molecular genetic linkage analysis revealed that the locus for the inducible-type NOS cosegragates with blood pressure in the Dahl S rat.³⁵ However we found no difference in the inducible-type NOS in kidney between the two groups. The reason remained unclear, but the difference in the strain of our Dahl Iwai and their Dahl/Rapp rats is one possible explanation. Another possible reason is that we examined enzyme activity in vitro; NO production by inducible- or endothelial-type NOS might be decreased in vivo owing to abnormal substrate synthesis or availability.³⁶ The possibilities of decreased renal synthesis of arginine from citrulline and decreased arginine uptake into renal sites of NOS cannot be ruled out in the present study.

Previous studies have reported that under low salt intake the responses of blood pressure and glomerular filtration rate to inhibition of NOS in Dahl S rats were similar to those in Dahl R rats,¹² suggesting that there is no difference in the L-arginine–NO pathway between the two when given a low salt intake. Since we did not examine the NOS activity of Dahl S rats on a low salt diet in this study it remains unclear whether the reduced activity of the neural-type NOS is a consequence of the hypertension or the genetic differences between the rats. However, the present results suggest that impairment of the adaptational increase of NO production plays a crucial role in salt sensitivity.^{5 9} In this study while we revealed the difference of the neural-type NOS activity in kidney during high salt intake we did not compare its activity from other tissues such as brain or adrenal gland. Further study is needed to know whether the change in NOS activity occurred only in kidney or in ubiquitous tissues.

In summary we demonstrated the decreased activity of neural-type NOS and renal norepinephrine content in the kidney of Dahl S compared with Dahl R rats. The decreased activity of this isoform may enhance the renal sympathetic nervous activity and can affect the pressure natriuretic response to high sodium intake, which in part may contribute to the development of salt dependent hypertension in Dahl S rats.

	Selected Abbreviations and Acronyms

 

Dahl R = Dahl Iwai salt-resistant Dahl S = Dahl Iwai salt-sensitive dpm = disintegrations per minute NO = nitric oxide NOS = nitric oxide synthase

Received June 18, 1995; first decision September 12, 1995; accepted October 2, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Bianchi G, Cusi D, Gatti M, Lupi GP, Ferrari P, Barlassina C, Piotti GB, Bracchi G, Colombo G, Gori D, Velis O, Mazzei D. A renal abnormality as a possible cause of essential hypertension. Lancet. 1979;1:173-177. [Medline] [Order article via Infotrieve]

2. Tobian L, Lange J, Azar S, Iwai J, Koop D, Coffee K, Johnson MA. Reduction of natriuretic capacity and renin release in isolated blood perfused kidneys of Dahl hypertensive-prone rats. Circ Res. 1978;43(suppl I):I-92-I-98.

3. Roman RJ. Abnormal renal hemodynamics and pressure-natriuresis relationship in Dahl salt-sensitive rats. Am J Physiol. 1986;251:F57-F65.

4. Kirchner KA. Greater loop chloride uptake contributes to the blunted pressure natriuresis in Dahl salt-sensitive rats. J Am Soc Nephrol. 1990;1:180-186. [Abstract]

5. Shultz PJ, Tolins JP. Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide. J Clin Invest. 1993;91:642-650.

6. Majid DSA, Williams A, Navar LG. Inhibition of nitric oxide synthesis attenuates the pressure induced natriuretic responses in anesthetized dogs. Am J Physiol. 1993;264:F79-F87. [Abstract/Free Full Text]

7. Salmon MG, Lahera V, Miranda-Guardiola F, Romero JC. Blockade of pressure natriuresis induced by inhibition of renal synthesis of nitric oxide in dogs. Am J Physiol. 1992;262:F718-F722. [Abstract/Free Full Text]

8. Baylis C, Harton P, Engels K. Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol. 1990;1:875-881. [Abstract]

9. Tolins JP, Shultz PJ. Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt. Kidney Int. 1994;46:230-236. [Medline] [Order article via Infotrieve]

10. Hayakawa H, Hirata Y, Suzuki E, Sugimoto T, Matsuoka H, Kikuchi K, Nagano T, Hirobe M, Sugimoto T. Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats. Am J Physiol. 1993;264:H1535-H1541. [Abstract/Free Full Text]

11. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664-666. [Medline] [Order article via Infotrieve]

12. Chen PY, Sanders PW. L-Arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J Clin Invest. 1991;88:1559-1567.

13. Chen PY, Sanders PW. Role of nitric oxide synthesis in salt-sensitive hypertension in Dahl/Rapp rats. Hypertension. 1993;22:812-818. [Abstract/Free Full Text]

14. Forstermann U, Schmidt HHHHW, Pollock JS. Isoforms of nitric oxide synthase. Biochem Pharmacol. 1992;42:1849-1857.

15. Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HHHHW, Nakane M, Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991;88:10480-10484. [Abstract/Free Full Text]

16. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254. [Medline] [Order article via Infotrieve]

17. Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isoform characterization, purification, molecular cloning, and function. Hypertension. 1994;23:1121-1131. [Abstract/Free Full Text]

18. Terada Y, Tomita K, Nonoguchi H, Marumo F. Polymerase chain reaction localization of constitutive nitric oxide synthase and soluble guanylate cyclase messenger RNAs in microdissected rat nephron segments. J Clin Invest. 1992;90:659-665.

19. Lahera V, Salmon MG, Miranda-Guardiola F, Moncada S, Romero JC. Effects of N^G-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol. 1991;261:F1033-F1037. [Abstract/Free Full Text]

20. Sakuma I, Togashi H, Yoshida M, Saito H, Tamura M, Kobayashi T, Yasuda H, Gross SS, Levi R. N^G-methyl-L-arginine, an inhibitor of L-arginine–derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo: a role for nitric oxide in the central regulation of sympathetic tone? Circ Res. 1992;70:607-611. [Abstract/Free Full Text]

21. Shapoval LN, Sagach VF, Pobegalio LS. Nitric oxide influences ventrolateral medullary mechanism of vasomotor control in the cat. Neurosci Lett. 1991;132:47-50. [Medline] [Order article via Infotrieve]

22. Harada S, Tokunaga S, Momohara M, Masaki H, Tagawa T, Imaizumi T, Takeshita A. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res. 1993;72:511-516.[Abstract/Free Full Text]

23. Toda N, Okamoto T. Possible role of nitric oxide in transmitting information from vasodilator nerve to cerebroarterial muscle. Biochem Biophys Res Commun. 1990;170:308-313. [Medline] [Order article via Infotrieve]

24. Toda N, Kitamura Y, Okamoto T. Neural mechanism of hypertension by nitric oxide synthase inhibitor in dogs. Hypertension. 1993;21:3-8. [Abstract/Free Full Text]

25. Bonnardeaux A, Nadaud S, Charru A, Jeunemaitre X, Corvol P, Soubrier F. Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension. Circulation. 1995;91:96-102. [Abstract/Free Full Text]

26. Matsuoka H, Nishida H, Nomura G, Van Vliet BN, Toshima H. Hypertension induced by nitric oxide synthesis inhibition is renal nerve dependent. Hypertension.. 1994;23:971-975. [Abstract/Free Full Text]

27. Peuler JD, Patel KP, Morgan DA, Whiteis CA, Lund DD, Pardini BJ, Schmidt PG. Altered peripheral noradrenergic activity in intact and sinoaortic denervated Dahl rats. Can J Physiol Pharmacol. 1989;67:442-449. [Medline] [Order article via Infotrieve]

28. Dawson R, Oparil S. Genetic and salt-related alterations in monoamine neurotransmitters in Dahl salt-sensitive and salt-resistant rats. Phamacology. 1986;33:322-333.

29. Racz K, Kuchel O, Buu NT. Abnormal adrenal cathecholamine synthesis in salt-sensitive Dahl rats. Hypertension. 1987;9:76-80. [Abstract/Free Full Text]

30. Addicks K, Bloch W, Feelish M. Nitric oxide modulates sympathetic neurotransmission at the prejunctional level. Micro Res Tech. 1994;29:161-168.

31. Husted RF, Stokes JB. Differences in Na transport by innermedullary collecting duct cells from Dahl rats. J Am Soc Nephrol. 1991;2:478. Abstract.

32. Dewan SA, Majid L, Navar G. Blockade of distal nephron sodium transport attenuates pressure natriuresis in dogs. Hypertension. 1994;23:1040-1045. [Abstract/Free Full Text]

33. Patel A, Layne S, Watts D, Kirchner KA. L-arginine administration normalizes pressure natriuresis in hypertensive Dahl rats. Hypertension. 1993;22:863-869. [Abstract/Free Full Text]

34. Ahn KY, Markus GM, Kirsten MM, Bruce CK. In situ hybridization localization of mRNA encoding inducible nitric oxide synthase in rat kidney. Am J Physiol. 1994;267:F748-F757. [Abstract/Free Full Text]

35. Deng AY, Rapp JP. Locus for the inducible, but not a constitutive, nitric oxide synthase cosegragates with blood pressure in the Dahl salt-sensitive rat. J Clin Invest. 1995;95:2170-2177.

36. Luscher TF, Haefeli WE. L-arginine in the clinical arena: tool or remedy? Circulation. 1993;87:1746-1748.[Free Full Text]

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