Published online before print March 8, 2004, doi: 10.1161/01.HYP.0000123574.60586.7d
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(Hypertension. 2004;43:1133.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Renal Interstitial Guanosine Cyclic 3', 5'-Monophosphate Mediates Pressure-Natriuresis Via Protein Kinase G
From the Departments of Medicine (X.-H.J., H.E.M., H.M.S., R.M.C.) and Pathology (J.J.G., R.A.F.), University of Virginia School of Medicine, Charlottesville.
Correspondence to Dr Robert M. Carey, Box 801414, University of Virginia School of Medicine, Charlottesville, VA 22908-1414. E-mail rmc4c{at}virginia.edu
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Abstract |
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Pressure-natriuresis is the physiological protective mechanism whereby elevation of blood pressure induces a rapid increase in renal sodium (Na+) excretion. Pressure-natriuresis abnormalities are common to all forms of hypertension. We tested the hypothesis that pressure-natriuresis is mediated by renal interstitial (RI) cGMP and protein kinase G (PKG). We used anesthetized, uninephrectomized Sprague-Dawley rats and a standard pressure-natriuresis model in which bilateral adrenalectomy and renal denervation was done on rats. Renal perfusion pressure (RPP) was adjusted by manipulating clamps above and below the renal artery, and RI cGMP was quantified by microdialysis. RI cGMP increased from 3.1±0.5 to 5.5±0.4 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg. This increase in RI cGMP was eliminated by RI infusion of soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,2-
]quinoxalin-1-one (ODQ). Raising RPP from 100 to 140 mm Hg increased urinary sodium excretion from 0.2±0.1 to 0.8±0.1 µmol/min, fractional sodium excretion from 0.2±0.1% to 0.8±0.1%, and fractional lithium excretion from 20.1±3.0% to 62.7±3.7% (all P<0.05). These responses were eliminated by RI infusion of nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, ODQ, and PKG inhibitors Rp-8-pCPT-cGMP and Rp-8-Br-cGMP. Increasing RPP from 100 to 140 mm Hg decreased fractional proximal sodium reabsorption without influencing fractional distal Na+ reabsorption or glomerular filtration rate. In conclusion, pressure-natriuresis is mediated by RI cGMP and a PKG signaling pathway in target renal proximal tubule cells.
Key Words: cyclic GMP • sodium • natriuresis • blood pressure • protein kinases
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Introduction |
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Pressure-natriuresis is a major regulatory mechanism in mammalian physiology whereby an acute elevation of blood pressure induces a rapid increase in renal sodium (Na+) excretion.1 Pressure-natriuresis normally protects the organism from a long-term rise in pressure by reducing extracellular fluid volume. An understanding of the mechanism that mediates pressure-natriuresis is critical because virtually all forms of hypertension, both in experimental animals and humans, are accompanied by a defective natriuretic response to increased blood pressure. In the hypertensive state, therefore, a normal rate of Na+ excretion is achieved only at the expense of increased blood pressure.1
The underlying cause of pressure-natriuresis at high arterial pressures is unknown. While manipulation of several endocrine and/or paracrine systems can shift the pressure-natriuresis relationship to the right (less sensitive) or left (more sensitive), none of these approaches has abolished the natriuretic response to increased blood pressure.1–5
cGMP is a cyclic nucleotide mediating a variety of cell signaling processes.6 We have recently discovered that renal interstitial (RI) cGMP, formed as a result of stimulation of soluble guanylyl cyclase (sGC) activity by nitric oxide (NO), inhibits renal tubule Na+ reabsorption via protein kinase G (PKG) independently of renal hemodynamic change.7 cGMP accumulated within the RI compartment as a result of exogenous L-arginine-stimulated NO synthesis or administration of an NO donor or cGMP or 8-Br-cGMP infused interstitially induced a natriuretic response both acutely and chronically in the uninephrectomized normal rat. These observations suggested that the interstitial compartment provides a potentially important domain for cell-to-cell signaling within the kidney. These studies also raised the possibility that endogenous RI cGMP may modulate Na+ excretion and could play a critical role in pressure-natriuresis.7 In the present study, we explored the potential role of endogenous RI cGMP in the control of pressure-natriuresis.
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Methods |
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Animal Preparation
Sprague-Dawley female rats (body weight, 200±15 g, Harlan Teklad, Madison, Wis) were used. The rats were provided free access to normal sodium (0.28% sodium) diets (Bioserve Biotechnologies) and tap water for 12-hour light-dark cycles. The University of Virginia School of Medicine Animal Care Committee approved all protocols.
Renal Interstitial Fluid Microdialysis
We employed a microdialysis method previously described for the rat kidney.8
Catheter Placement for Renal Interstitial Infusion
After the rats were placed under general anesthesia, an indwelling RI catheter, constructed from an 8-mm section of polyethylene tubing (PE-10, Clay Adams) connected by Bipax epoxy resin glue (Tra-Con) to a 4-cm piece of PE-60 tubing, was implanted into the kidney cortex or medulla through a small hole made by a 26-gauge needle. The catheter was anchored in place on the kidney surface as described above and was connected to a miniosmotic pump that delivered lactated Ringer’s solution or pharmacological agents into the renal interstitium at a rate of 1 µL/h. Our previous studies have shown that pharmacological agents administered directly into the renal interstitial space in this manner are widely distributed throughout the renal cortex during the infusion time.7,9–11
Glomerular Filtration Rate
Glomerular filtration rate (GFR) was determined as described12 and is reported as milliliters per minute per gram kidney weight.
Renal Blood Flow and Urine Collection
A midline celiotomy was performed. The left renal artery was exposed by careful dissection. Monitoring of renal blood flow was accomplished by inserting a renal artery flow probe on the left renal artery connected to a dual channel flow meter (Transonic Systems, Inc.). Renal cortical blood flow (RCBF) and renal medullary blood flow (RMBF) were monitored using a laser flow meter (Advance Laser Flowmeter ALF 21D).13 To monitor urine flow rate from the left (remaining) kidney, a catheter was inserted into the left ureter, and urine was collected from the kidney.
Calculation of Fractional Proximal and Distal Sodium Reabsorption
Fractional proximal reabsorption (FPR) was calculated as [(Cin–CLi)/Cin]x100, where Cin is the clearance of inulin and CLi is the clearance of lithium. Fractional distal reabsorption (FDR) was calculated as [CH2O/CH2O+CNax100], where CH2O is free water clearance and CNa is the clearance of sodium.
Pressure-Natriuresis Studies
We employed the standardized pressure-natriuresis model of Roman and Cowley.14 Seven days before the acute experiment, the right kidney was removed and the left kidney was denervated by mechanical stripping of all nerve fibers along the renal arterial sheath and coating of the artery with a 10% solution of phenol. Rats (n=24) were anesthetized intraperitoneally with Inactin 100 mg/kg and placed on a thermostatically controlled warming table to maintain body temperature at 37°C. Cannulas were placed in the right carotid and femoral arteries to enable continuous measurement of arterial pressure above and below the left renal artery. Two cannulas were placed in the right external jugular vein for intravenous infusions. A 2-mm flow probe was placed on the left renal artery, and renal blood flow was monitored using an electromagnetic flowmeter. The left ureter was cannulated for collection of urine. Two specially designed ultramicro-Blalock clamps were placed on the aorta, one above the superior mesenteric artery and one below the left renal artery, to induce increased or decreased renal perfusion pressure (RPP). The animals were acutely adrenalectomized to prevent changes in the release of adrenal steroids and catecholamines during the experiment. Plasma aldosterone, corticosteroids, norepinephrine, and vasopressin concentrations were maintained at fixed levels throughout the experiment by continuous intravenous infusion of norepinephrine (100 ng/min), aldosterone (20 ng/min), hydrocortisone (20 µg/min), and vasopressin (20 pg/min). All pharmacological agents were dissolved in 150 mmol/L sodium chloride solution containing 1% bovine serum albumin. An infusion rate of 20 µL/min was used to induce a mild saline diuresis during control periods and to maintain adequate urine flow when RPP was lowered. Inulin was added to the infusate to enable the measurement of GFR.
Pharmacological Agents
1H-[1,2,4]oxadiazolo[4,2-]quinoxalin-1-one (ODQ), a highly specific antagonist of sGC;15 Rp-8-pCPT-cGMP and Rp-8-Br-cGMP; specific PKG inhibitors, and cGMP were purchased from Biolog Life Sciences Institute. N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, was obtained from Sigma Chemical Co.
Analytical Methods
A Nova analyzer (Nova Biomedical) was used to measure urine sodium excretion (UNaV). RI cGMP levels were measured using an enzyme immunoassay kit (Cayman Chemical).
Statistical Analysis
Results are presented as mean±1SE. Data were analyzed by paired Student t test. ANOVA was used for multiple comparisons, and P<0.05 was considered statistically significant.
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Results |
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To explore whether acute increases in RPP could increase renal interstitial fluid cGMP, we employed a standard pressure-natriuresis model.14 We demonstrated that renal cortical and medullary interstitial cGMP levels increased in a highly significant manner when RPP was raised from 100 to 140 mm Hg (Figure 1). Cortical RI cGMP increased from 3.1±0.5 to 5.5±0.4 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg. This response was blocked by RI infusion of ODQ. When RPP was decreased from 100 to 80 mm Hg, RI cGMP was not significantly altered. Medullary RI cGMP also increased from 2.45±0.27 to 3.99±0.85 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg; this response also was blocked by RI infusion of ODQ. Lowering RPP from 100 to 80 mm Hg did not influence medullary RI cGMP.
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To determine whether the pressure-induced increase in RI cGMP is responsible for the natriuresis, we performed two sets of experiments in nephrectomized, adrenalectomized rats. First, we demonstrated that RPP was directly related to urinary Na+ excretion in the presence of a vehicle (control) infusion directly into the renal cortical interstitium (Figure 2A). Then we demonstrated that the increase in Na+ excretion from 0.2±0.1 to 0.8±0.1 µmol/min (P<0.05), when RPP was increased from 100 to 140 mm Hg, was blocked completely with renal interstitial infusion of sGC inhibitor ODQ15 (Figure 2A). ODQ also prevented an increase in cGMP in response to increased RPP above 100 mm Hg without influencing cGMP at normal or low RPP (Figure 1). We further demonstrated that inhibition of PKG, a second messenger of cGMP, with Rp-8-pCPT-cGMP within the cortical interstitial space eliminated the natriuretic response to increased RPP (Figure 2). We also observed that the natriuretic response to increased RPP was blocked by RI administration of NO synthesis (NOS) inhibitor L-NAME.
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To determine the pharmacological specificity of Rp-8-pCPT-cGMP as an inhibitor of PKG, we used Rp-8-Br-cGMP, another PKG antagonist (Figure 3). Rp-8-Br-cGMP completely abrogated the natriuretic response to increased RPP and did not influence RI cGMP.
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Total renal blood flow (RBF),RCBF, and RMBF were increased slightly by high RPP, whereas they were decreased more significantly by low RPP. Rp-8-pCPT-cGMP did not influence RBF, RCBF, or RMBF at low RPP, but blocked increases in RBF, RCBF, and RMBF at high RPP (Figure 4A). Fractional excretion of Na+ (FENa) was increased at high RPP (from 0.2±0.1% to 0.8±0.1% at 100 and 140 mm Hg, respectively [P<0.01]), and this response was blocked by RI infusion of L-NAME, ODQ, or Rp-8-pCPT-cGMP (Figure 2B). GFR was unaltered by an increase in RPP above normal or by RI infusion of L-NAME, ODQ, or Rp-8-pCPT-cGMP (Figure 2D). However, GFR was significantly reduced at low perfusion pressure.
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We addressed the tubule segment targeted for the action of cGMP to mediate pressure-natriuresis. Fractional excretion of lithium (FELi), a marker of proximal tubule Na+ reabsorption, increased significantly (from 20.1±3.0% at 100 mm Hg to 62.7±3.7% at 140 mm Hg RPP ([P<0.01]) at high perfusion pressure (Figure 2C). This effect was blocked individually by L-NAME, ODQ, and Rp-8-pCPT-cGMP (Figure 2C). Consistent with these observations, fractional proximal Na+ reabsorption (FPRNa) decreased at high RPP; this response also was blocked by L-NAME, ODQ, or Rp-8-pCPT-cGMP (Figure 2E). In contrast, fractional distal Na+ reabsorption (FDRNa) was unchanged by increased RPP, and L-NAME, ODQ, and Rp-8-pCPT-cGMP had no significant effect on FDRNa (Figure 2F).
To determine whether the RI level of cGMP is related to the degree of natriuresis, we infused exogenous cGMP directly into the RI space and constructed a cumulative concentration-response curve of RI cGMP on renal Na+ excretion in anesthetized rats (n=6) (Figure 5). Increases in RI cGMP were associated with stepwise cumulative increments in UNaV over a range of RI cGMP administration (0 to 72 µg/kg per minute). The increase in UNaV, resulting from an increase in RI cGMP from 3 to 5.5 fmol/min, was 0.6 µmol/min whether cGMP was infused exogenously (Figure 5) or increased as a result of the rise in RPP from 100 to 140 mm Hg (Figure 2A).
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Discussion |
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Pressure-natriuresis is a major homeostatic control mechanism designed to protect against a long-term rise in arterial blood pressure. The cause of pressure-natriuresis is unknown; pressure-natriuresis has been demonstrated to occur in the absence of renal sympathetic nerves and a variety of hormonal inputs to the kidney. Our recent results showing that RI cGMP engenders natriuresis7 suggested that cGMP compartmentalized within the kidney is a candidate mediator of pressure-natriuresis.
The major finding of the present study is that RI cGMP mediates pressure-natriuresis via PKG. First, we demonstrated that RI cGMP increased in response to high RPP. Unexpectedly, cGMP was not altered by low RPP. These results suggested that cGMP might be involved selectively in natriuretic response to increased RPP. Second, we documented that the increase in cGMP and Na+ excretion at high RPP was stopped by blockade of sGC in the interstitial compartment. We also demonstrated that pressure-natriuresis was abolished by RI pharmacological inhibition of NO synthase or PKG. These results indicate that an NO-sGC-cGMP pathway involving the interstitial compartment is required for pressure-natriuresis and that cGMP action to promote natriuresis at high RPP is mediated by PKG. Third, we demonstrated that pressure-natriuresis at high RPP occurs in the absence of a change in glomerular filtration, whereas at low RPP low GFR is involved in the antinatriuretic response. Thus, pressure-natriuresis at high RPP is largely due to an inhibition of renal tubule Na+ reabsorption, while at low RPP the antinatriuretic response is related to hemodynamic mechanisms. Fourth, pressure-natriuresis at high RPP was accompanied by a slight but significant increase in RBF, RCBF, and RMBF. Thus, while the major action of RI cGMP in response to increased RPP seems to be a result of a direct effect to inhibit tubule cell Na+ transport, decreased filtration fraction could also play a role by changing Starling forces in the peritubular capillaries. Fifth, we demonstrated that pressure-induced natriuresis was accompanied by an increase in the FELi, a decrease in FPRNa, and no change in FDRNa. These results implicate a proximal tubule target whereby RI cGMP decreases Na+ reabsorption in response to high pressure. Altogether, the results strongly support a primary action of cGMP via PKG at the renal tubule as a major physiological mechanism of the natriuresis induced by high blood pressure. The results are consistent with those of others who demonstrated a proximal tubule site of RPP-induced inhibition of Na+ reabsorption.16,17
In the present study, increasing RPP was associated with increased cGMP levels in both the cortex and medulla. We identified the target cells for inhibition of sodium reabsorption caused by increased RPP via FELi as proximal tubule cells. However, a limitation of the present study is that we were unable to determine the role of medullary NO and cGMP, which is an appropriate subject of future study.
The present studies were conducted in renal denervated rats, and some studies have shown that renal denervation may alter the response to NOS blockers.18,19 However, our data showing that NOS blockade inhibits pressure-natriuresis are consistent with studies20,21 indicating that L-NAME abolishes pressure-natriuresis independently of the renal nerves.
Studies reported during the past decade have indicated that an increase in intrarenal NO activity during increased RPP may be responsible for pressure-natriuresis.22–25 Increased urinary excretion of NO metabolites have been documented with increased RPP.21,22 Also, systemic administration of NOS inhibitors has attenuated the natriuresis caused by a rapid increase in pressure.16,22,24,25 The present study provides a working model whereby natriuresis in response to increased RPP occurs (Figure 6). Increased RPP releases intrarenal NO, stimulating sGC to form cGMP, which is released into the renal interstitial compartment. RI cGMP acts at the proximal nephron to decrease Na+ reabsorption via PKG.
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The present study raises the issue of the relative roles of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the NO-mediated effects shown here. Both eNOS and nNOS are expressed in the kidney. The predominant site of expression of eNOS is vascular endothelium; the predominant site of nNOS expression is the macula densa.26 However, the relative abundance of these two isoforms is not known, and whether the increase in shear stress with elevated RPP is sufficient to generate enough NO to initiate natriuresis has not been studied previously. In particular, studies of pressure-natriuresis in eNOS-null mice have not yet been conducted.27 The contribution of the various NOS isoforms to pressure-natriuresis is an appropriate subject for future studies.
Other studies have demonstrated increased urinary excretion of urodilatin (atrial natriuretic peptide 95 to 126) during increased RPP and also that guanylin or uroguanylin are natriuretic peptides through stimulation of particulate guanylyl cyclase.28–30 Our studies specifically show that soluble, not particulate, guanylyl cyclase activity is requisite to the pressure-natriuretic response.
The source of RI cGMP was not addressed in this study, but there is substantial evidence that the proximal tubule contains sGC that can be regulated by NO.31,32 Therefore, it is highly likely that the increase in renal interstitial hydrostatic pressure that is requisite to pressure-natriuresis33 signals release of cGMP from the proximal tubule, which in turn is the target for inhibition of sodium reabsorption. However, it is also possible that cGMP may be formed via sGC in cortical interstitial cells.34 Irrespective of the cellular origin of cGMP, our studies suggest that compartmentalization of extracellular cGMP in the renal interstitium is potentially important physiologically as it is in the gastrointerstitial tract.35
The cell signaling mechanisms distal to PKG, whereby cGMP engenders an inhibition of tubule sodium reabsorption in response to increased RPP, are unknown. Our studies show that RI cGMP action to inhibit Na+ reabsorption is mediated through PKG. Mammalian PKG exists as two major forms: PKG I, a soluble enzyme consisting of and ß isoforms derived from the alternative splicing of 1 gene, and PKG II, a myristoylated membrane-associated enzyme derived from a second gene.36 Both PKG I and PKG II are expressed in the kidney.37,38 In the kidney, PKG I has been reported in vascular smooth muscle cells, mesangial cells, and interstitial cells, whereas PKG II has been associated with late proximal tubule, thick ascending limb, and juxtaglomerular cells.37,38 PKG I is known to decrease intracellular Ca++, while PKG II stimulates chloride secretion via the cystic fibrosis transmembrane conductance regulator channel in the intestinal mucosa.39 In vitro studies have demonstrated that cGMP inhibits renal tubule Na+-K+-ATPase and the Na+-H+ sodium exchanger, providing potential mechanisms for cGMP-induced changes in Na+ transport and natriuresis in vivo.31,32,40,41 In the present study, PKG I and PKG II could not be distinguished pharmacologically, because Rp-8-pCPT-cGMP and Rp-8-Br-cGMP can inhibit both kinases.39
Perspectives
The present studies demonstrate that pressure-natriuresis is mediated by an intrarenal mechanism whereby an increase in RPP releases NO, resulting in an extrusion of cGMP into the RI space. RI cGMP acts at the proximal tubule to inhibit Na+ reabsorption and induce natriuresis via PKG. Taken together with our recent studies42 in proximal tubule cells, the data strongly suggest that extracellular RI cGMP is a major critical mediator of pressure-natriuresis. As a result of these findings, it will be important to test whether abnormalities in the RI cGMP-PKG pathway are responsible for abrogation of pressure-natriuresis in various experimental animal models of hypertension.
Received November 13, 2003; first decision December 1, 2003; accepted February 11, 2004.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Guyton AC, Coleman TG, Young DB, Lohmeier TE, DeClue JW. Salt balance and long-term blood pressure control. Annu Rev Med. 1980; 31: 15–27.[CrossRef][Medline] [Order article via Infotrieve]
2. Gross V, Lippoldt A, Schneider W, Luft FC. Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR (mRen-2) 27 rats. Hypertension. 1995; 26: 471–479.
3. Gross JM, Dwyer JE, Knox FG. Natriuretic response to increased pressure is preserved with COX-2 inhibitors. Hypertension. 1999; 34: 1163–1167.
4. Tornel J, Madred MI, Garcia-Salom M, Wirth KJ, Fenoy FJ. Role of kinins in the control of renal papillary blood flow, pressure natriuresis, and arterial pressure. Circ Res. 2000; 86: 589–595.
5. Cowley Jr AW. Long-term control of arterial blood pressure. Physiol Rev. 1992; 72: 231–300.
6. Murad F. Cyclic GMP. synthesis, metabolism, and function. Adv Pharmacol. 1994; 26: 1–5.[Medline] [Order article via Infotrieve]
7. Jin X-H, Siragy HM, Carey RM. Renal interstitial cGMP mediates natriuresis by a direct tubule mechanism. Hypertension. 2001; 38: 309–316.
8. Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest. 1997; 100: 264–269.[Medline] [Order article via Infotrieve]
9. Wang Z-Q, Felder RA, Carey RM. Selective inhibition of the renal subtype D1A receptor induces antinatriuresis in conscious rats. Hypertension. 1999; 33: 504–510.
10. Carey RM, Wang Z-Q, Siragy HM, Felder RA. Renal dopamine production and release in the rat: a microdialysis study. Adv Pharmacol. 1998; 42: 873–876.[Medline] [Order article via Infotrieve]
11. Moore AF, Heiderstadt NT, Huang E, Howell NL, Wang Z-Q, Siragy HM, Carey RM. In vivo targeting of the renal angiotensin type-2 (AT2) receptor with antisense oligonucleotides increases blood pressure in conscious rats. Hypertension. 2001; 37: 1285–1291.
12. Muchant DG, Thornhill BA, Bellmonte DC, Felder RA, Baertschi A, Chevalier RL. Chronic sodium loading augments natriuretic response to acute volume expansion in the preweaned rat. Am J Physiol Reg Physiol. 1995; 269: R15–R22.
13. Lu S, Mattson DL, Roman RJ, Becker CG, Cowley AW Jr. Assessment of changes in intrarenal blood flow in conscious rats using laser-Doppler flowmetry. Am J Physiol Renal Physiol. 1993; 264: F956–F962.
14. Roman RJ, Cowley Jr AW. Characterization of new model for the study of pressure-natriuresis in the rat. Am J Physiol Renal Physiol. 1985; 248: F190–F198.
15. Olson LJ, Knych ET Jr., Herzig TC, Drewett JG. Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation. Hypertension. 1997; 29: 254–261.
16. McDonough AA, Leong PKK, Yang LE. Mechanisms of pressure-natriuresis: how blood pressure regulates renal sodium transport. Ann NY Acad Sci. 2003; 986: 669–677.[Medline] [Order article via Infotrieve]
17. Liang M, Knox FG. Production and functional roles of nitric oxide in the proximal tubule. Am J Physiol Regul Integr Comp Physiol. 2000; 278: R1117–R1124.
18. Wu XC, Harris PJ, Johns EJ. Nitric oxide and renal nerve-mediated proximal tubular reabsorption in normotensive and hypertensive rats. Am J Physiol Renal Physiol. 1999; 277: F560–F566.
19. Vallon V, Peterson OW, Gabbai FB, Blantz RC, Thomson SC. Interactive control of renal function by alpha 2-adrenergic system and nitric oxide: role of angiotensin II. J Cardiovasc Pharmacol. 1995; 26: 916–922.[Medline] [Order article via Infotrieve]
20. Reinhart GA, Lohmeier TE, Mizelle HL. Temporal influences of the renal nerves on renal excretory function during chronic inhibition of nitric oxide synthesis. Hypertension. 1997; 29: 199–204.
21. Madrid MI, Salom MG, Tornel J, Lopez E, Fenoy FJ. Interactions between nitric oxide and renal nerves on pressure-diuresis and natriuresis. J Am Soc Nephrol. 1998; 9: 1588–1595.[Abstract]
22. Salom 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 Renal Physiol. 1992; 262: F718–F722.
23. Fenoy FJ, Ferrer P, Carbonell L, Garcia-Salom MG. Role of nitric oxide on papillary blood flow and pressure natriuresis. Hypertension. 1995; 25: 408–414.
24. Majid DSA, Omoro SA, Chin SY, Navar LG. Intrarenal nitric oxide activity and pressure natriuresis in anesthetized dogs. Hypertension. 1998; 32: 266–272.
25. Majid DSA, Said KE, Omoro SA. Responses to acute changes in arterial pressure on renal medullary nitric oxide activity in dogs. Hypertension. 1999; 34: 832–836.
26. Kone BC, Baylis C. Biosynthesis and homeostatic roles of nitric oxide in the normal kidney. Am J Physiol Renal Physiol. 1997; 272: F561–F578.
27. Ortiz PA, Garvin JL. Cardiovascular and renal control in NOS-deficient mouse modes. Am J Physiol Regul Integr Comp Physiol. 2002; 284: R628–R638.
28. Kirchhoff K, Bub A, Marxen P, Forssmann WG. Urodilatin inhibits sodium reabsorption in the isolated perfused kidney. Exp Nephrol. 1994; 2: 351–357.[Medline] [Order article via Infotrieve]
29. Heringlake M, Wagner K, Schymacher J, Pagel H. Urinary excretion of urodilatin is increased during pressure natriuresis in the isolated perfused rat kidney. Am J Physiol Renal Physiol. 1998; 277: F347–F351.
30. Forte LR, London RM, Freeman RH, Forte LR. Guanylin peptides: renal actions mediated by cyclic GMP. Am J Physiol. 2000; 278: F180–F191.
31. Guzman NJ, Fang MZ, Tang SS, Ingelfinger JR, Garg LC. Autocrine inhibition of Na+/K+-ATPase by nitric oxide in mouse proximal tubule epithelial cells. J Clin Invest. 1995; 95: 2083–2088.[Medline] [Order article via Infotrieve]
32. Roczniak A, Burns KD. Nitric oxide stimulates guanylate cyclase and regulates sodium transport in rabbit proximal tubule. Am J Physiol. 1996; 270: F106–F115.[Medline] [Order article via Infotrieve]
33. Khraibi AA, Knox FG. Effect of renal decapsulation on renal interstitial hydrostatic pressure and natriuresis. Am J Physiol Reg Physiol. 1989; 257: R44–R48.
34. Theilig F, Bostanjoglo M, Pavenstadt H, Grupp C, Holland G, Slosarek I, Gressner AM, Russwurm M, Koesling D, Bachman S. Cellular distribution and function of soluble guanylyl cyclase in rat kidney and liver. J Am Soc Nephrol. 2001; 12: 2209–2220.
35. Jin X-H, Siragy HM, Guerrant RL, Carey RM. Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum. J Clin Invest. 1999; 103: 167–174.[Medline] [Order article via Infotrieve]
36. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev. 2000; 52: 375–414.
37. Tamura N, Itoh H, Ogawa Y, Nakagawa O, Harada M, Chun T-H, Suga S, Yoshimasa T, Nakao K. cDNA cloning and gene expression of human type 1 cGMP-dependent protein kinase. Hypertension. 1996; 27: 552–557.
38. Gambarian S, Hausler C, Markert T, Pohler D, Jarchau T, Walter U, Haase W, Kurtz A, Lohmann S. Expression of type II cGMP-dependent protein kinase in rat kidney is regulated by dehydrational correlated with renin gene expression. J Clin Invest. 1996; 98: 662–670.[Medline] [Order article via Infotrieve]
39. Lohmann SM, Vandrager AB, Smolenski A, Walter U, Dejong HR. Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci. 1997; 22: 307–312.[CrossRef][Medline] [Order article via Infotrieve]
40. Liang M, Knox FG. Nitric oxide reduces the molecular activity of Na+-K+-ATPase in opossum kidney cells. Kidney Int. 1999; 56: 627–634.[CrossRef][Medline] [Order article via Infotrieve]
41. Liang M, Knox FG. Production and functional roles of nitric oxide in the proximal tubule. Am J Physiol Regul Integr Comp Physiol. 2000; 278: R1117–R1124.
42. Sasaki S, Siragy HM, Gildea JJ, Felder RA, Carey RM. Production and role of extracellular guanosine cyclic 3', 5'-monophosphate in sodium uptake in human proximal tubule cells. Hypertension. 2004; 43: 286–291.
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F. Ahmed, B. A. Kemp, N. L. Howell, H. M. Siragy, and R. M. Carey Extracellular Renal Guanosine Cyclic 3'5'-Monophosphate Modulates Nitric Oxide and Pressure-Induced Natriuresis Hypertension, November 1, 2007; 50(5): 958 - 963. [Abstract] [Full Text] [PDF]
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 A. Nishiyama, K. E. Jackson, D. S. A. Majid, M. Rahman, and L. G. Navar Renal interstitial fluid ATP responses to arterial pressure and tubuloglomerular feedback activation during calcium channel blockade Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H772 - H777. [Abstract] [Full Text] [PDF]
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M. Herrera and J. L. Garvin Recent Advances in the Regulation of Nitric Oxide in the Kidney Hypertension, June 1, 2005; 45(6): 1062 - 1067. [Abstract] [Full Text] [PDF]
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H. M. Siragy, C. Xue, P. Abadir, and R. M. Carey Angiotensin Subtype-2 Receptors Inhibit Renin Biosynthesis and Angiotensin II Formation Hypertension, January 1, 2005; 45(1): 133 - 137. [Abstract] [Full Text] [PDF]
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