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(Hypertension. 1996;27:653-657.)
© 1996 American Heart Association, Inc.

Articles

Impaired Renal Vasodilation and Urinary cGMP Excretion in Dahl Salt-Sensitive Rats

Shlomoh Simchon; William Manger; Gabriele Blumberg; Jeffrey Brensilver; Stanley Cortell

From the Department of Medicine, New York University Medical Center (S.S., W.M.), the College of Physicians and Surgeons, Columbia University (S.S., S.C.), and the Division of Nephrology, St Luke's/Roosevelt Hospital (S.S., G.B., J.B., S.C.), New York, NY.

Correspondence to Dr Shlomoh Simchon, Division of Nephrology, Minturn 205, St Luke's/Roosevelt Hospital, 1111 Amsterdam Ave, New York, NY 10025.

	Abstract

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Abstract We previously have shown that Dahl salt-sensitive rats increase renal vascular resistance in response to excessive salt feeding before total peripheral resistance increases and hypertension occurs. Failure of renal vasculature to dilate, as normally occurs in Dahl salt-resistant rats fed a high salt diet, may play a role in the development of hypertension in Dahl salt-sensitive rats. We also showed that renal vasculature in salt-sensitive rats is hyperreactive to vasoconstrictors and hyporeactive to vasodilators. Atrial natriuretic peptide, by stimulating cell-bound receptors, and nitroprusside, by generating nitric oxide, cause renal vasodilation by generating cGMP. Studies were undertaken to determine whether defective renal vasodilation in Dahl salt-sensitive rats is due to impaired production of cGMP. We examined the influence of nitroprusside infusion and salt intake on renal vascular resistance and cGMP excretion in salt-sensitive and salt-resistant rats. Results demonstrate that salt feeding and nitroprusside infusion increase cGMP excretion and decrease renal vascular resistance in salt-resistant rats (P<.01), and, although this relationship was less clear in salt-sensitive rats, there was a reciprocal relationship between renal vascular resistance and cGMP excretion in all animals studied. Salt feeding and nitroprusside infusion caused less of an increase in cGMP excretion in salt-sensitive than in salt-resistant rats (P<.01). In conclusion, these studies support the concept that impairment in cGMP generation may play a primary role in the inability of the kidneys of Dahl salt-sensitive rats to vasodilate in response to increased salt intake. Such an impairment could contribute to salt retention and the development of hypertension.

Key Words: cyclic GMP • microspheres • nitric oxide • nitroprusside • vascular resistance, renal

	Introduction

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Salt-sensitive hypertension occurs in a segment of human hypertensives¹ and in a rat model developed by Dahl and coworkers.^{2 3} The latter studies showed that DS rats developed hypertension when fed a high salt diet, whereas DR rats remained normotensive despite excessive salt intake.

We have previously demonstrated an inability of the renal vasculature of DS rats to dilate in response to increased salt intake.^{4 5} Renal vascular reactivity was found to be enhanced by vasoconstrictors (norepinephrine and angiotensin II),⁶ but vasodilators (ANP and NP) failed to decrease RVR in DS rats.^{4 6} Circulating ANP, which appears to generate cGMP by stimulating receptors on vascular smooth muscle membrane, is increased in hypertensive DS rats.^{4 6} Paul et al⁷ recently demonstrated that cultured renal mesangial cells from DS rats generate less cGMP than cells from DR rats in response to ANP. NP is a potent vasodilator whose action does not depend on membrane receptors or an intact endothelium, since it increases cGMP production by directly generating NO, which stimulates soluble guanylate cyclase.⁸ To define the role of cGMP in renal vasodilation in DR and DS rats, we compared cGMP excretion with RVR in response to various levels of salt intake and to NP infusion in both strains of rats.

This study demonstrates that a reciprocal relationship exists between RVR and cGMP excretion during high salt intake and NP infusion and that the response of RVR in DS rats may reflect a deficit in cGMP production.

	Methods

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Groups and Procedures
Thirty-seven male DR and 37 DS rats (Brookhaven National Laboratory, strain obtained from Harlan Sprague-Dawley Inc, Indianapolis, Ind) were fed a "low" salt diet (0.23% NaCl) or "normal" salt diet (1% NaCl) (Purina Mills Co) after weaning. Dietary sodium content was confirmed in our laboratory.

GFR, RVR, and urinary cGMP excretion rate were measured before and during infusion of sodium nitroprusside (Nitropress, Abbott Laboratories). NP was dissolved in 5% dextrose in water (and protected from light by aluminum foil wrapping) and infused intravenously at a dose that did not change blood pressure (0.35±0.02 ng/min per gram body wt) for 15 minutes. Six groups of rats were studied. Group A: 7 DR and 7 DS rats 6 weeks of age were fed a 0.23% NaCl diet. Group B: 6 DR and 6 DS rats 10 weeks of age were fed a 0.23% NaCl diet. Group C: 7 DR and 7 DS rats 6 weeks of age were fed a 1% NaCl diet. Group D: 7 DR and 7 DS rats 10 weeks of age were fed a 1% NaCl diet. Group E: 5 DR and 5 DS rats were fed a 1% NaCl diet for 6 weeks and then fed an 8% NaCl diet for 4 days (all rats remained normotensive). Group F: 5 DR and 5 DS rats were fed a 1% NaCl diet for 6 weeks and then fed an 8% NaCl diet for 4 weeks (DS rats became hypertensive, and at 10 weeks of age results were compared with rats of similar age on 0.23% and 1% NaCl diets).

Surgical Procedure
Following anesthesia with sodium pentobarbital (35 mg/kg IP), a polyethylene catheter (PE 290, Intramedic, Becton Dickinson) was inserted through an incision into the trachea to ensure stable ventilation. A second catheter (PE 50) was inserted into the abdominal aorta via a femoral artery for blood withdrawal and recording of arterial pressure (volume removed during blood sampling was simultaneously replaced by intravenous infusion of an equal volume of donor blood). A third catheter (PE 50) was inserted into the jugular vein for intravenous infusion of NP. A fourth catheter (PE 50) was inserted into the femoral vein for intravenous infusion of ³H-inulin. For hemodynamic studies, a fifth catheter was advanced via the carotid artery into the left ventricle for injection of microspheres; the position of the catheter tip was confirmed by pressure tracing. For GFR and cGMP studies, a sixth catheter (PE 160) was placed transabdominally into the urinary bladder. Thirty minutes after inulin infusion was begun, a urine sample was collected for another 30 minutes for measurement of cGMP and ³H-inulin; at the end of that time an arterial blood sample was taken for ³H-inulin measurement. Then NP was infused for 35 minutes; 5 minutes after the infusion was begun, a urine sample was collected for 30 minutes for measurement of cGMP and inulin, and arterial blood was sampled for inulin measurement. To determine whether the systemic vasculature responded normally, NP was infused at a depressor dose of 30 pg/min after the collection of urine at the end of the experiment. All rats responded to this depressor dose of NP infusion with similar decreases in blood pressure.

Cardiovascular pressures were monitored using Statham transducers and a polygraph recorder (model 7, Grass Instrument Co). Blood samples (approximately 1 mL) were centrifuged, and plasma was removed, frozen, and stored until inulin measurement. Urine was frozen and stored until cGMP and inulin levels had been measured. Rats were handled in accordance with National Institutes of Health and New York University Medical Center's guidelines for animal care.

Hemodynamic Measurements
CO (in mL/min) and RBF (in mL/min per 100 grams of kidney) were determined by a microsphere method (previously validated in our laboratory by comparison with electromagnetic flowmeter and ¹³³Xe washout technique^{9 10 11 12} ), with 15.0±1.0 µm diameter microspheres (New England Nuclear Corp) injected into the left ventricle. Two measurements were made using latex microspheres labeled with radionuclides ⁵⁷Co and ⁴⁶Sc. An injection of microspheres labeled with ⁵⁷Co was given before infusion of NP for control blood flow measurements. A second injection of microspheres labeled with ⁴⁶Sc was given after NP infusion. The use of microspheres labeled with two different radionuclides permits determination of blood flow at two different time periods in the same animal. Reference blood samples were withdrawn from the abdominal aorta at a rate of 0.8 mL/min for 2 minutes (total of 1.6 mL blood; withdrawal of the blood was started 10 to 15 seconds before injection of microspheres and blood was simultaneously replaced by infusing donor blood). After the experiment, rats were euthanatized by injecting a saturated KCl solution into the left ventricle. Kidneys were immediately removed and tissue activities of ⁵⁷Co and ⁴⁶Sc were determined with a gamma counter (model 5130, Auto-Gamma System, Packard Instrument Co) connected to a multichannel analyzer (Tracor Northern Co). Resistance to flow was calculated as the ratio of mean arterial blood pressure to regional blood flow. RVR was calculated as the ratio of mean arterial blood pressure (in mm Hg) to RBF (in mL/s per 100 gram kidney wt), whereas nonrenal vascular resistance was calculated as the ratio of mean arterial pressure to CO minus total RBF (in mL/s). TPR was calculated as the ratio of mean arterial blood pressure (in mm Hg) to CO (in mL/s).

Glomerular Filtration Rate
GFR was determined from ³H-inulin clearance.¹³ A solution containing 2.0 mCi/mL per kilogram of ³H-inulin (New England Nuclear Corp) was infused (0.072 mL/min IV) for 90 minutes. After plasma samples were thawed, radioactivity was counted in a beta counting system (Beckman LS-230, Liquid Scintillation System, Beckman Instruments, Inc) to determine ³H activity, with PCS scintillation liquid (Amersham/Searle Corp) as a counting medium. Urine samples were thawed and counted after appropriate dilution. GFR was calculated as the ratio of urinary excretion rate of ³H-inulin to its plasma concentration.

Urinary cGMP Determination
cGMP concentrations in aliquots of urine (0.2 µL) were determined by radioimmunoassay after acetylation with a commercially available assay kit (¹²⁵I-cGMP kit, New England Nuclear Corp). Acetylation agent was 0.05 mL acetic anhydride plus 0.1 mL triethylamine.¹⁴ The cGMP standard was diluted to yield 2000 pmol/mL to 100 pmol/mL of cGMP. In a preliminary study we found that cGMP excretion remained constant during a 3-hour vehicle (dextrose) infusion in either DS or DR rats. Furthermore, during our experimental studies, no increase occurred in arterial or renal venous plasma cGMP concentration. cGMP excretion rate (in picomoles per minute per 100 gram) is calculated as UcGMPxV (per 100 gram of kidney), where UcGMP is urinary concentration of cGMP (in picomoles per milliliter) and V is urinary flow (in milliliters per minute).

Statistical Analysis
Results are presented as mean±SD; significance of changes was evaluated by ANOVA, followed by a Student-Newman-Keuls test for multiple comparisons (significance is considered to be P<.05).

	Results

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Table 1 shows the systemic hemodynamics in DR and DS rats at 6 or 10 weeks of age. Blood volume of the rats did not change as could be seen from stable hematocrits before and after NP infusion. This NP infusion dose did not cause any significant change in mean arterial blood pressure but caused a decrease in TPR (P<.01) compensated for by an increase in CO (P<.01) in all rats. That response was similar in DS and DR rats fed 0.23%, 1%, or 8% NaCl diets. DS rats fed a high salt diet (8% NaCl) for 4 days were normotensive, but they had an increase in CO accompanied by a decrease in TPR. When DS rats were fed an 8% NaCl diet for 4 weeks, they had an increase in mean arterial blood pressure caused by an increase in CO. TPR did not change. No statistical differences were observed in systemic hemodynamics between 6-week-old rats and 10-week-old rats fed either a 0.23% or 1% NaCl diet.

View this table: [in this window] [in a new window]   Table 1. Systemic Hemodynamics in DR and DS Rats at 6 or 10 Weeks of Age and Effects of NP Infusion

Table 2 reveals that 6- or 10-week-old DR rats responded to NP infusion with approximately a twofold increase in GFR (P<.01) on 0.23% and 1% NaCl diets. In DS rats fed a 0.23% NaCl diet, NP infusion resulted in only an approximate 1.5-fold increase (P<.01) in GFR; and, when they were fed a 1% NaCl diet, NP infusion resulted in no augmentation of GFR. The results in Table 2 and Fig 1 demonstrate that an increase in dietary salt in DR rats was associated with a rise in cGMP excretion from 15±2 to 255±25 pmol/min per 100 gram and in RBF from 521±12 to 1103±41 mL/min per 100 gram, which was associated with a decrease in RVR from 11±0.6 to 5±0.08 mm Hg/mL per second per 100 gram (P<.01). In contrast, salt feeding failed to progressively increase cGMP excretion or to decrease RVR in DS rats. In addition, NP infusion in DS rats caused a significant decrease of RVR only in rats on a 0.23% diet (Table 2 and Fig 2); in 6-week-old DS rats on a 1% NaCl diet, there was actually an unexplained increase in RVR that was associated with a decrease in cGMP. In contrast, NP infusion in DR rats invariably caused RVR to decrease significantly (P<.01) from preinfusion levels. NP caused a pronounced increase in cGMP excretion (P<.01) in all DR rats, whereas the increase in cGMP in DS rats in response to NP infusion was markedly impaired (P<.01). When data from DR and DS rats are combined, there is a significant negative correlation between cGMP production and RVR (y=-0.45x+10.8; r=-.71); however, a relatively small increase in cGMP resulted in maximal renal vasodilation (Fig 3).

View this table: [in this window] [in a new window]   Table 2. Renal Hemodynamics and cGMP in DR and DS Rats at 6 or 10 Weeks of Age and Effects of NP Infusion

View larger version (43K): [in this window] [in a new window]   Figure 1. Effect of NaCl intake on RVR (top) and cGMP excretion (bottom) in DS (back row) and DR (front row) rats. Data are the control values reported in Table 2. Rats fed 0.23% and 1% NaCl diets after weaning were studied. A group of rats fed a 1% NaCl diet was changed to an 8% NaCl diet and studied after 4 days (normotensive rats) or after an additional 4 weeks (hypertensive DS rats). Vertical lines indicate SDs. *P<.01 from animals on a 0.23% NaCl diet; §P<.01 DS compared with DR rats.

View larger version (47K): [in this window] [in a new window]   Figure 2. Effect of NP infusion on RVR (top) and cGMP excretion (bottom) in DS (back row) and DR (front row) rats. Data are the infusion values reported in Table 2. Rats fed 0.23% and 1% NaCl diets from weaning were studied. A group of rats fed a 1% NaCl diet was changed to an 8% NaCl diet and studied after 4 days (normotensive rats) or after an additional 4 weeks (hypertensive DS rats). Vertical lines indicate SDs. *P<.01 from animals on a 0.23% NaCl diet; §P<.01 DS compared with DR rats.

View larger version (18K): [in this window] [in a new window]   Figure 3. RVR as a function of cGMP excretion in DR () and DS (x) rats on various NaCl diets and also after NP infusions.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Previous studies suggested that salt-induced hypertension that develops in DS rats may be related to an inability of their renal vasculature to dilate in response to salt feeding.^{4 5} These earlier studies showed that compared with DR rats, DS rats have little or no reduction in RVR in response to a high salt diet before an increased TPR and hypertension develop. The renal vasculature of DS rats was hyperresponsive to the vasoconstrictors norepinephrine and angiotensin II.⁶ In contrast, intravenous administration of ANP or NP, vasodilators whose action depends on the production of cGMP, failed to reduce RVR in DS rats.⁶ The current study was designed to assess the role of cGMP production in the ability of kidneys of DR rats to vasodilate and to determine whether a deficient generation of cGMP may exist in DS rats.

ANP is thought to cause renal vasodilation by activating a non–heme-containing transmembrane protein with a single subunit, so-called particulate guanylate cyclase. ANP binds to specific receptors on the endothelial cell membranes and causes an increase in cGMP production. In contrast, NP is thought to act, after conversion to a NO radical, by directly activating a soluble heme-containing enzyme consisting of two subunits, so-called soluble guanylate cyclase, thereby increasing cGMP production in the cytoplasm.⁸ A defect in the ability of DS rats to increase cGMP production was suggested from our observations that ANP and NP were ineffective renal vasodilators in DS rats and from the study of Paul et al,⁷ which reported that renal mesangial cells from DS rats grown in tissue culture generate less cGMP than DR rats when ANP is added to the medium.

Shultz and Tolins¹⁵ postulated that an increase in dietary salt intake causes an increase in NO synthesis, an endothelium-derived relaxing factor. Lüscher et al¹⁶ also postulated that an increase in dietary salt intake results in endothelium-dependent relaxation. On the basis of a demonstration that hypertension develops in rats when NOS is inhibited, Tolins et al,¹⁷ concluded that this defect in NOS may be a pathogenic factor in the development of salt-sensitive hypertension. Chen and Sanders,¹⁸ and more recently Deng and Rapp,¹⁹ have postulated that hypertension develops in DS rats because of a decrease in the production of NO. The study of Deng and Rapp¹⁹ suggests that there are specific alleles for NOS that are lacking when DS rats are bred with normotensive rats. This study indicates by molecular genetic linkage analysis the locus for the inducible NOS cosegregates with blood pressure in the DS rat. This genetic analysis clearly implicates the enzyme responsible for NOS in the phenotypic expression of the disease in these rats. Chen and Sanders¹⁸ showed that hypertension could be prevented in DS rats on an 8% NaCl diet if they were treated with L-arginine, the substrate for NOS associated with an increase in urinary cGMP excretion. Early studies^{20 21} showed that DS rats can be protected from the development of hypertension if they are treated with a variety of antihypertensive medications whose modes of action occur by a variety of pathways, including calcium channel blocking agents²⁰ and diuretics.²¹ Since these studies did not focus on the role of cGMP in hypertension and our previous studies showed that NP infusion dilates the renal vessels of DR rats but not of DS rats,⁶ we investigated the role of renal cGMP production in renal vasodilation by direct stimulation of cGMP with NP infusion. The present study demonstrates that failure of NP to reduce RVR is accompanied by failure to increase cGMP production.

cGMP production plays a central role in the dilation of renal vasculature, because there is a significant negative correlation between cGMP production and RVR (r=-.71) in DR and DS rats; even a small increase in cGMP production is associated with a major impact on RVR (Fig 3). The increase in urinary cGMP, although primarily derived from glomerular mesanglial or epithelial cells,²² is closely correlated with RVR and appears to reflect renal vascular generation of cGMP. As previously shown, when a nonhypotensive dose of NP was given to DS and DR rats, the expected decrease in RVR occurred in DR rats but not DS rats.⁶ In addition, there was a strikingly smaller increase in cGMP excretion in DS than DR rats (P<.01) on excessive salt and in response to NP infusion. Although the DS rats on a 1% NaCl diet excreted less cGMP than DR rats on the same diet, it is unclear why DS rats on the 1% NaCl diet excreted more cGMP and had a greater decrease in RVR than they did on an 8% NaCl diet.

These results suggest that there is a defect in the ability of DS rats to generate cGMP either in response to chronic administration of a high salt diet or in response to the acute administration of NP. It appears that hypertension in DS rats on a high salt diet may be related to their inability to generate cGMP, which impairs renal vasodilation and salt excretion. Whether impaired cGMP excretion results from a deficiency of cGMP production and/or NO production (or conceivably is due to an inhibitor of NO production) remains to be determined.

	Selected Abbreviations and Acronyms

 

ANP = atrial natriuretic peptide CO = cardiac output DR = Dahl salt-resistant DS = Dahl salt-sensitive GFR = glomerular filtration rate NO = nitric oxide NOS = nitric oxide synthase NP = nitroprusside RBF = renal blood flow RVR = renal vascular resistance TPR = total peripheral resistance

	Acknowledgments

 
This study was supported in part by the National Hypertension Association and by Morningside Nephrology Associates. We acknowledge the excellent technical assistance of Ruth Johnston and Mildred Hulse. We appreciate the consultation of Dr Francis Haddy.

	References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simchon, S. Articles by Cortell, S. Search for Related Content PubMed PubMed Citation Articles by Simchon, S. Articles by Cortell, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Dietary Sodium High Blood Pressure