Lithium infusion to study sodium handling in unanesthetized hypertensive rats

To investigate renal tubular handling of sodium in various types of experimental hypertension, sodium, lithium, and inulin clearances were measured simultaneously in unanesthetized rats. Fractional excretion of lithium was used as an index of proximal sodium reabsorption. Eight groups of animals, all of the Wistar-Kyoto strain, were studied. Three were hypertensive: spontaneously hypertensive rats (SHR), rats with two-kidney, one clip renal hypertension, and uninephrectomized rats with deoxycorticosterone-salt hypertension. The five normotensive control groups included animals given normal, low, or high dietary sodium loads and rats with reduced renal mass. Fractional excretion of lithium was not influenced by moderate changes of glomerular filtration rate, but was sharply enhanced by sodium loading. Increased blood pressure was associated with enhanced urinary sodium excretion in uninephrectomized deoxycorticosterone-salt hypertensive and two-kidney, one clip hypertensive rats, as a result of decreased distal tubular reabsorption ("pressure natriuresis"). In contrast, SHR showed reduced sodium excretion and decreased fractional excretion of lithium, which suggests that increased sodium reabsorption in the proximal tubule may contribute significantly to the maintenance of hypertension.     

Differential effect of salt loading on sodium and lithium excretion in Dahl salt-resistant and -sensitive rats

Fractional excretion of lithium, as a marker for proximal sodium reabsorption, was determined in normotensive Dahl S rats (susceptible to NaCl hypertension) and Dahl R rats (resistant to NaCl hypertension) before and following an acute sodium load. Baseline mean arterial pressures, inulin clearances, sodium excretion rates, and fractional lithium clearances were not different between the R and S rats. Following the salt loading and despite similar mean arterial pressures and degree of volume expansion, the glomerular filtration rate, urinary flow rates, and absolute sodium excretion rates were greater in R than S rats. The fractional excretion of lithium was also greater in R than S rats. These data demonstrate that, at equal mean arterial pressures, Dahl S rats have a reduced capacity for sodium excretion, and that this defect is present prior to the development of hypertension. Furthermore, the observation that these animals also have a lower fractional lithium excretion during volume expansion suggests that salt loading reduces proximal tubule reabsorption to a lesser extent in Dahl S than R rats. These data suggest that the subnormal sodium and water excretion observed after sodium loading in S rats may be partially due to an abnormality in proximal tubule sodium handling.     

Exaggerated natriuresis and lithium clearance in spontaneously hypertensive rats

Since hypertension is associated with changes in the handling of various cations (including sodium and lithium) across the cell membrane, the present study investigated the validity of the lithium clearance method in hypertension by comparing two measures of proximal reabsorption. Thus, fractional lithium excretion and transit time (TT)-occlusion time (OT; e-TT/T) were determined successively in the same spontaneously hypertensive rat (SHR, Okamoto strain). The rats were examined both before and after an acute saline load. The results show that the lithium clearance method can be used for the determination of proximal reabsorption in SHR. Utilizing the lithium clearance method, the changes in renal sodium handling underlying the exaggerated natriuresis were investigated in unanaesthetized catheterized rats. It was found that the exaggerated natriuresis was associated with an increased output from the proximal tubule, whereas no difference in distal sodium handling could be detected between SHR and normotensive Wistar-Kyoto rats (WKY).     

Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents

In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 age- and sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.     

Red-cell sodium-lithium countertransport and fractional excretion of lithium in normal and hypertensive humans

To examine the relations between erythrocyte sodium-lithium countertransport and renal proximal tubular sodium handling, we measured countertransport, and then subjected 30 normal and 32 hypertensive subjects, both white and black, to provocative maneuvers of volume expansion and contraction. The fractional excretions of sodium and lithium were measured simultaneously. In agreement with previous studies, we found that countertransport in erythrocytes was elevated in hypertensive patients compared with normal subjects. We also observed that whites have a higher level of countertransport than blacks. In the basal state, we found that fractional sodium excretion of hypertensive patients was no different than in normal subjects, whereas the fractional lithium excretion of hypertensive persons was increased compared with normotensive values. Volume expansion with 2 1 0.9% saline administered intravenously during a 4-hour period provoked an exaggerated natriuresis and a greater increase in fractional lithium clearance in hypertensive patients compared with the control group. With volume expansion and contraction, fractional lithium clearance and countertransport were directly correlated. Our data suggest that hypertensive persons do not have increased proximal tubular sodium reabsorption compared with normal subjects. Further, the exaggerated natriuresis of hypertension is, in part, the result of increased distal solute delivery. The fact that our hypertensive patients were older may partially explain the discrepancies between this report and previous observations.     

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8), Tyr(NH(2))(9)]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonist-treated rats GFR was modestly reduced (P<0.05), and there were large falls in both absolute and fractional sodium excretion (P<0.01 in each case) and absolute and fractional water excretion (P<0.05 in each case), indicating effects on both filtered load and fractional tubular reabsorption. The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule. We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.     

Increased Proximal Tubular Sodium Reabsorption in Hypertensive Patients with Type 2 Diabetes

Hyperinsulinaemia and sodium retention have been studied in 22 Type 2 diabetic patients (10 normotensive, 12 hypertensive) and 10 normal control subjects matched for age, sex, and body mass index. Exchangeable sodium was similar in the three groups. Plasma renin activity and plasma angiotensin II were lower in both groups of diabetic patients than in the normal control subjects (p<0.01). Plasma atrial natriuretic peptide was increased in the hypertensive patients (7.3 ± 1.1 vs normotensive 4.7 ± 1.1 pmol I^?1 and control 4.0 ± 0.2 pmol I^?1, p<0.01). Fractional lithium clearance, a measure of sodium clearance from the proximal tubule, was decreased (18.5 ± 1.4, p<0.01) and fractional excretion of sodium in the distal tubule was increased (6.66 ± 0.66, p<0.01) in untreated hypertensive diabetic patients compared with both normotensive diabetic patients (25.3 ± 1.6 and 3.96 ± 0.52 respectively) and normal control subjects (25.2 ± 2.9 and 3.31 ± 0.38, respectively). Fasting serum insulin was higher in hypertensive than in normotensive diabetic patients (18.5 ± 3.0 vs 10.7 ± 1.1 mU I^?1, p<0.01) and higher in both groups than in normal control subjects (5.6 ± 0.1 mU I^?1, both p<0.01). Creatinine clearance was higher in both groups of diabetic patients than in normal control subjects (p<0.05). Thus there appears to be increased proximal renal tubular sodium reabsorption in these hypertensive Type 2 diabetic patients, matched by a reduction in distal sodium reabsorption so that net sodium excretion was maintained. This was associated with fasting hyperinsulinaemia.     

Effects of acute volume loading on kidney function in patients with essential hypertension, as estimated by the lithium clearance method

This study investigated the mechanism underlying the exaggerated natriuresis seen in patients with essential hypertension. The study used the lithium clearance method, which permits accurate determination of both proximal and distal sodium reabsorption in man. One litre of isotonic sodium chloride, intravenously (i.v.), produced a significant increase in sodium excretion in patients with essential hypertension, both during and after the infusion. This increase in sodium excretion was accompanied by a significant increase in the clearance of lithium, indicating an increased output of isotonic fluid from the proximal tubules. The calculated distal reabsorption of sodium increased during the natriuresis. In the normotensive controls, sodium excretion increased only after the infusion of 1 l isotonic saline. This was accompanied by a modest increase in absolute distal sodium reabsorption. However, when the amount of saline was increased to 2 l, similar changes to those seen in hypertensives given 1 l of saline occurred in normotensive subjects. Furthermore, chronic antihypertensive treatment abolished the phenomenon of exaggerated natriuresis. It is concluded that the exaggerated natriuresis represents the normal response to sodium loading being reset to a lower level. This resetting may be a secondary consequence of the high blood pressure, since lowering the pressure abolishes the phenomenon.     

A lithium clearance study of sodium reabsorption at the proximal tubule in liver cirrhosis with ascites

Since the reabsorption of lithium occurs almost exclusively in the proximal tubule and is associated with that of sodium, the fractional excretion of lithium (FELit) ws examined in 18 patients with cirrhosis in order to examine the reabsorption rate of sodium at the proximal tubule. As expected, the fractional excretion of sodium (FENa) was significantly lower in cirrhotic patients with ascites (0.43 +/- 0.10%, mean +/- SEM) than in cirrhotic patients without ascites (0.75 +/- 0.14%, P less than 0.05) and healthy controls (0.82 +/- 0.17%, P less than 0.05). By contrast, there was no significant difference in FELit among cirrhotic patients with ascites (16.7 +/- 2.0%), cirrhotic patients without ascites (15.4 +/- 2.0%) and controls (17.4 +/- 1.5%). It is unlikely, therefore, that in cirrhotic patients with ascites, the impaired sodium excretion is solely caused by the abnormal sodium reabsorption capacity of the proximal tubule.     

Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia

To investigate the nephron site of the enhanced tubular calcium reabsorption in familial hypocalciuric hypercalcaemia (FHH), the renal plasma clearance of lithium and calcium and the glomerular filtration rate were determined simultaneously after an overnight fast in nine FHH patients and ten healthy controls. As the renal plasma clearance of lithium equals the rate of the proximal tubular fluid delivered into the thin descending loop of Henle's loop, the reabsorption of calcium in the proximal and distal tubule, respectively, could be calculated. We found that the FHH patients had a significantly higher fractional calcium reabsorption in the proximal tubule (77.6 +/- 4.7 (%) vs 73.3 +/- 3.1, P less than 0.05). The same held true for the absolute proximal calcium reabsorption (1.49 +/- 0.12 (mmol/l) vs 1.07 +/- 0.05, P less than 0.001). There was a significant linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption (r = 0.70, P less than 0.05). The distal tubular calcium reabsorption did not differ in the two groups. Our results therefore suggest that the enhanced tubular calcium reabsorption in FHH takes place exclusively in the proximal renal tubule.     

Proximal sodium reabsorption: An independent determinant of blood pressure response to salt

The purpose of this study was to evaluate the contribution of renal sodium handling by the proximal tubule as an independent determinant of blood pressure responsiveness to salt in hypertension. We measured blood pressure (BP), renal hemodynamics, and segmental renal sodium handling (with lithium used as a marker of proximal sodium reabsorption) in 38 hypertensive patients and 27 normotensive subjects (15 young and 12 age-matched) on a high and low sodium diet. In control subjects, changing the diet from a low to a high sodium content resulted in no change in BP and increases in glomerular filtration rate (P<0.05), renal plasma flow (P<0.05), and fractional excretion of lithium (FE(Li), P<0.01). In hypertensive patients, comparable variations of sodium intake induced an increase in BP with no change in renal hemodynamics and proximal sodium reabsorption. When analyzed by tertiles of their BP response to salt, salt-insensitive hypertensive patients of the first tertile disclosed a pattern of adaptation of proximal sodium reabsorption comparable to that of control subjects, whereas the most salt-sensitive patients of the third tertile had an inverse pattern with a high FE(Li) on low salt and a lower FE(Li) on high salt, suggesting an inappropriate modulation of proximal sodium reabsorption. The BP response to salt correlated positively with age (r=0.34, P=0.036) and negatively with the changes in FE(Li) (r=-0.37, P=0.029). In a multivariate analysis, the changes in FE(Li) were significantly and independently associated with the salt-induced changes in BP. These results suggest that proximal sodium reabsorption is an independent determinant of the BP response to salt in hypertension.     

The effect of atrial natriuretic factor on blood pressure, heart rate, and renal functions in conscious, spontaneously hypertensive rats

Atrial natriuretic factors, polypeptides released by atrial myocytes, may play a role in the control of blood pressure and the regulation of renal salt and water excretion. Our studies were designed to assess the role of a synthetic peptide, atriopeptin II, on blood pressure and heart rate, renal hemodynamics, and salt and water excretion in conscious, spontaneously hypertensive rats and in normotensive Wistar-Kyoto rats. Changes in mean arterial pressure and heart rate were recorded following intravenous bolus injections (0.1, 1.0, 10, 100 micrograms/kg) of atriopeptin II in 5 spontaneously hypertensive and 5 Wistar-Kyoto rats. In a second group of rats the peptide was infused for 90 minutes in two different doses: low dose, 1 microgram/kg + 2 micrograms/kg/hr; and high dose, 10 micrograms/kg + 20 micrograms/kg/hr. Bolus injections of atriopeptin II resulted in dose-dependent decreases in mean arterial pressure in the hypertensive, but not in the normotensive, rats; heart rates remained unchanged. Blood pressure decreased gradually during the sustained infusion of both doses of atriopeptin II, with the spontaneously hypertensive strain showing increased sensitivity compared to the Wistar-Kyoto strain. Heart rate decreased in both strains during infusion of the high dose; the decrease was significant only in the hypertensive rats. The low dose of atriopeptin II increased the clearance of free water in both strains of rats; sodium excretion was increased only in the hypertensive rats. The high-dose atriopeptin II was associated with transient natriuresis, unaltered glomerular filtration rate, and decreased effective renal blood flow in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased inositol monophosphate production in cardiovascular tissues of DOCA-salt hypertensive rats

The purpose of the present study was to investigate alpha 1-adrenergic receptors in the heart as well as the activity and the sensitivity of the phosphoinositide pathway on tissue slices of atria, ventricles, and femoral artery of hypertensive rats treated for 4 weeks with deoxycorticosterone acetate (DOCA) and 1% saline. DOCA-salt hypertensive rats were characterized by an increased sympathoadrenal tone, as suggested by increased norepinephrine and epinephrine plasma levels. The basal activity of the phosphoinositide pathway, estimated by measuring the accumulation of inositol monophosphate in the presence of an excess of lithium, was found to be greater in atria than in ventricles and femoral artery in both normotensive and DOCA-salt hypertensive rats, but it was twofold greater in atria and ventricles of DOCA-salt hypertensive rats compared with normotensive rats. Following stimulation by norepinephrine, the production of inositol monophosphate was greater in atria and femoral artery than in ventricles in both groups. However, in DOCA-salt hypertensive rats, the production of inositol monophosphate was markedly enhanced, being about twofold greater in atria and femoral artery and about three times greater in ventricles than in tissues of normotensive rats. These differences between DOCA-salt hypertensive and normotensive animals do not appear to be associated with a difference in alpha 1-adrenergic receptor number or affinity since cardiac alpha 1-adrenergic receptor number was unchanged in hypertensive rats and the binding affinity to the receptor was significantly decreased in hypertensive rats compared with normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of superficial proximal convoluted tubule to decreased and increased renal perfusion pressure. In vivo microperfusion study in rats

Although urinary sodium excretion is positively influenced by acute changes in renal perfusion pressure, micropuncture studies show highly conflicting results concerning the response of superficial proximal tubule sodium reabsorption to changes in renal perfusion pressure. In the present study, the changes of superficial proximal reabsorption to decreased and increased renal perfusion pressure were determined in rats by an in vivo microperfusion method. In vivo microperfusion was selected as the method to determine the proximal sodium reabsorption because this method made it possible to deliver a constant fluid and electrolyte load to the proximal tubule without the influence of possible changes of glomerular filtration rate. Renal perfusion pressure was decreased from normal pressure by inflating a suprarenal aortic cuff and was increased from the normal level by the occlusion of celiac and mesenteric arteries and the infrarenal aorta. Although fractional excretion of sodium (FENa) in the urine was decreased from 1.24 +/- 0.23% to 0.45 +/- 0.11% (n = 7, p less than 0.01) when renal perfusion pressure was decreased from 125 +/- 6 to 99 +/- 3 mm Hg, absolute tubular reabsorption by the superficial proximal convoluted tubules was not increased (from 4.4 +/- 0.5 to 4.2 +/- 0.3 nl/min/mm, n = 22). When the renal perfusion pressure was elevated from 126 +/- 4 to 149 +/- 4 mm Hg, tubular reabsorption by the superficial proximal tubules was decreased from 4.1 +/- 0.3 to 2.5 +/- 0.3 nl/min/mm (n = 36, p less than 0.01) with an accompanying increase in FENa (from 1.28 +/- 0.24% to 2.29 +/- 0.37%, n = 9, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal distal tubular handling of sodium in central fluid volume homoeostasis in preascitic cirrhosis.

BACKGROUND/AIMS: Patients with preascitic liver cirrhosis have an increased central plasma volume, and, for any given plasma aldosterone concentration, they excrete less sodium than healthy controls. A detailed study of the distribution of sodium reabsorption along the segments of the renal tubule, especially the distal one, is still lacking in preascitic cirrhosis. METHODS: Twelve patients with Child-Pugh class A cirrhosis and nine control subjects (both groups on a normosodic diet) were submitted to the following investigations: (a) plasma levels of active renin and aldosterone; (b) four hour renal clearance of lithium (an index of fluid delivery to the loop of Henle), creatinine, sodium, and potassium; (c) dopaminergic activity, as measured by incremental aldosterone response to intravenous metoclopramide. RESULTS: Metoclopramide induced higher incremental aldosterone responses, indicating increased dopaminergic activity in patients than controls, which is evidence of an increased central plasma volume (+30 min: 160.2 (68.8) v 83.6 (35.2) pg/ml, p<0.01; +60 min: 140.5 (80.3) v 36. 8 (36.1) pg/ml, p<0.01). Patients had increased distal fractional sodium reabsorption compared with controls (26.9 (6.7)% v 12.5 (3. 4)% of the filtered sodium load, p<0.05). In the patient group there was an inverse correlation between: (a) absolute distal sodium reabsorption and active renin (r -0.59, p<0.05); (b) fractional distal sodium reabsorption and sodium excretion (r -0.66, p<0.03). CONCLUSIONS: These data suggest that in preascitic cirrhosis the distal fractional tubular reabsorption of sodium is increased and critical in regulating both central fluid volume and sodium excretion.     

Adducin polymorphism affects renal proximal tubule reabsorption in hypertension

Abnormalities in renal sodium reabsorption may be involved in the development and maintenance of experimental and clinical hypertension. Adducin polymorphism is thought to regulate ion transport in the renal tubule. It has recently been shown that there is a significant linkage of alpha-adducin locus to essential hypertension and that the 460Trp allele is associated with hypertension. Patients with this allele display larger blood pressure changes with body sodium variation. The aim of this study was to test whether alpha-adducin polymorphism is involved in abnormalities of renal function. Because proximal tubular reabsorption has been shown to be tightly coupled to renal perfusion pressure, this segmental tubular function was investigated in 54 (29 Gly/Gly and 25 Gly/Trp) untreated hypertensive patients in basal conditions with the use of endogenous lithium concentration and uric acid. Fractional excretions of lithium and uric acid were significantly decreased in the Gly/Trp hypertensive patients compared with the Gly/Gly hypertensives. The contribution of alpha-adducin to fractional excretion of lithium was investigated by multiple regression analysis. Adducin genotype was significantly (R2=0.11, F=6.5; P<0.01) and directly related to fraction excretion of lithium; gender, age, urinary Na+, urinary uric acid, mean blood pressure, and plasma renin activity were not related. In conclusion, the adducin gene can be considered to be a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport Na+ and hence contributes to the level of blood pressure.     

Renal lithium reabsorption in man: physiologic and pharmacologic determinants.

In order to evaluate the premise that renal lithium reabsorption may reflect proximal tubular sodium reabsorption, the fractional excretion of lithium (FELi) was measured, during a variety of experimental maneuvers known to affect renal cation reabsorption, in normal volunteers who had been pre-loaded with lithium. Furosemide increased FELi, as well as sodium, calcium, and magnesium excretion, during the first hour following diuretic administration. Subsequently, sodium, calcium, and magnesium excretion continued to remain elevated after furosemide, despite progressive volume depletion, but FELi values usually declined at least to pretreatment levels. Oral glucose ingestion increased lithium, calcium, and magnesium excretion while sodium and potassium excretion decreased concomitantly. Increases in FELi during volume expansion with saline were correlated with changes in fractional flow (V/GFR) in natriuretic subjects. Parathyroid extract (PTE) increased both FELi and fractional phosphate excretion (FEphos). FELi and FEphos were correlated significantly in the studies with furosemide and PTE, but not after saline volume expansion. In persons who previously had undergone unilateral nephrectomy, FELi was not increased over values in normal subjects. These results indicate that changes in lithium reabsorption may be dissociated from the reabsorption of other cations. They are consistent with the hypothesis that FELi may reflect proximal tubular sodium rejection, but do not exclude other more distal sites of lithium reabsorption.     

Renal interstitial guanosine cyclic 3', 5'-monophosphate mediates pressure-natriuresis via protein kinase G

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-alpha]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 micromol/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.     

Altered responsiveness of proximal tubule fluid reabsorption of peritubular angiotensin II in spontaneously hypertensive rats

Stimulation of proximal tubular fluid reabsorption by peritubular angiotensin II (Ang II) was examined by split-drop micropuncture in 5- and 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). In WKY, the maximum stimulation occurred at 10(-11) mol/l and the response did not vary with age. In 5-week-old SHR, the dose-response relationship was similar in shape and in the extent of the maximum response but was shifted one half-logarithmic step to the right, indicating decreased sensitivity to Ang II. In contrast, the dose-response relationship was shifted one half-logarithmic step to the left in 12-week-old SHR compared with WKY. Alterations in the responsiveness of the proximal tubule to Ang II in young SHR could contribute to sodium retention observed during development of hypertension in these rats.