A significant role for nitric oxide (NO) in proximal tubule physiology and pathophysiology has been revealed by a series of in vivo and in vitro studies. Whether the proximal tubule produces NO under basal conditions is still controversial; however, evidence suggests that the proximal tubule is constantly exposed to NO that might include NO from nonproximal tubule sources. When challenged with a variety of stimuli, including hypoxia, the proximal tubule is able to produce large quantities of NO. In vivo studies generally indicate that NO inhibits fluid and sodium reabsorption by the proximal tubule. However, the final effect of NO on proximal tubular reabsorption appears to depend on the concentration of NO and involve interaction with other regulatory mechanisms. NO regulates Na(+)-K(+)-ATPase, Na(+)/H(+) exchangers, and paracellular permeability of proximal tubular cells, which may contribute to its effect on proximal tubular transport. Enhanced production of NO, perhaps depending on macrophage type inducible NO synthase, participates in hypoxic/ischemic proximal tubular injury. In conclusion, NO plays a fundamental role in both physiology and pathophysiology of the proximal tubule.

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Increased release of renal adenosine and stimulation of renal adenosine receptors have been proposed to be major mechanisms in the development of contrast media-induced acute renal failure (CM-ARF). Patients with diabetes mellitus or preexisting renal disease who have reduced renal function have a markedly increased risk to develop CM-ARF. This increased risk to develop CM-ARF in patients with diabetes mellitus is linked to a higher sensitivity of the renal vasculature to adenosine, since experimental studies have shown increased adenosine-induced vasoconstriction in the kidneys of diabetic animals. Furthermore, recent evidence suggests that administration of adenosine receptor antagonists reduces the risk of development of CM-ARF in both diabetic and nondiabetic patients. The purpose of this review is to discuss the role of adenosine in the development of CM-ARF, particularly in the kidneys of diabetic patients, and to evaluate the therapeutic potential of adenosine receptor antagonists in the prevention of CM-ARF. Selective adenosine A1 receptor antagonists may provide a therapeutic tool to prevent CM-ARF in patients with diabetes mellitus and reduced renal function.

Studies were performed on anesthetized dogs to determine the relationship of interstitial pressure to sodium excretion during renal vein constriction in the presence and absence of volume expansion. Renal interstitial pressure was measured from implanted capsules during basal renal venous pressure and increased pressures of 10, 20, 30, and 40 mmHg. A positive relationship between renal venous pressure and interstitial pressure was demonstrated in hydropenia and in volume expansion, with markedly higher interstitial pressures obtained in volume expansion. A positive correlation was demonstrated between fractional sodium excretion and renal interstitial pressure in hydropenia as compared to a significant negative correlation in volume expansion. Negative correlations were demonstrated in volume expansion between renal interstitial pressure and glomerular filtration rate and renal blood flow as compared to no significant change in these parameters in hydropenia. Accordingly, a positive correlation was demonstrated between renal interstitial pressure and sodium excretion in hydropenia but not in volume expansion. Volume expansion was characterized by higher interstitial pressure and decreased sodium excretion in association with decreased renal blood flow and glomerular filtration rate.

SUMMARY It has long been known that increments in renal perfusion pressure can induce an elevation of urine sodium excretion without changing renal blood flow or glomerular filtration rate. The mechanism underlying this pressure-related natriuresis remains undefined, although the interest in its elucidation has been stimulated by the notion that it may constitute the central phenomenon through which the kidney regulates blood volume and, thereby, blood pressure. Recently, the use of novel experimental techniques has disclosed some important clues about changes in renal hemodynamics that, along with changes in renal humoral regulators, allow us to visualize a possible sequence of events responsible for pressure-related natriuresis. According to this hypothesis, the autoregulatory responses responsible for maintaining glomerular filtration rate are elicited in preglomerular vasculature by changes in renal perfusion pressure. These myogenic responses are coupled through Ca 2+ entry in juxtaglomerular cells with inversely related changes in the release of renin and, consequently, with the amount of angiotensin II generated in renal interstitium. The release of renin from juxtaglomerular cells is modulated by the synthesis of prostaglandin I 2 from the adjacent endothelial cells. Interstitial angiotensin II could influence sodium tubular reabsorption directly by stimulating sodium transport in proximal renal tubules and indirectly by altering medullary blood flow and, thereby, medullary interstitial pressure. In the renal medulla, the effects of interstitial pressure on sodium reabsorption can be amplified by the release of prostaglandin E 2 from interstitial cells. A deficient regulation of this relationship could result in a shift of the pressure-natriuresis curve, leading to hypertension. (Hypertension 11: 724-738, 1988) KEY WORDS • prostaglandins • renin-angiotensin system • medullary blood flow • renal blood flow • glomerular filtration rate • hypertension I T has long been recognized that the kidney alters urine flow and sodium excretion 1 2 in response to acute changes in renal perfusion pressure (RPP).3 4 Since the glomerular filtration rate (GFR) is well autoregulated (Figure 1), pressure-related natriuresis is the result of decreased reabsorption of sodium by the renal tubules rather than increased filtered load. 4 The mechanisms responsible for changes in sodium reabsorption have not been fully denned, but interest in its elucidation has been maintained ever since pressure-related natriuresis was conceptually placed at the

Nitric oxide (NO) reduces the molecular activity of Na+-K+-ATPase in opossum kidney (OK) cells, a proximal tubule cell line. In the present study, we investigated the cellular mechanisms for the inhibitory effect of NO on Na+-K+-ATPase. Sodium nitroprusside (SNP), a NO donor, inhibited Na+-K+-ATPase in OK cells, but not in LLC-PK1 cells, another proximal tubule cell line. Similarly, phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator, inhibited Na+-K+-ATPase in OK, but not in LLC-PK1, cells. PKC inhibitors staurosporine or calphostin C, but not the protein kinase G inhibitor KT-5823, abolished the inhibitory effect of NO on Na+-K+-ATPase in OK cells. Immunoblotting demonstrated that treatment with NO donors caused significant translocation of PKCalpha from cytosolic to particulate fractions in OK, but not in LLC-PK1, cells. Furthermore, the translocation of PKCalpha in OK cells was attenuated by either the phospholipase C inhibitor U-73122 or the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. U-73122 also blunted the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. The phospholipase A2 inhibitor AACOCF3 did not blunt the inhibitory effect of SNP on Na+-K+-ATPase in OK cells. AACOCF3 alone, however, also decreased Na+-K+-ATPase activity in OK cells. In conclusion, our results demonstrate that NO activates PKCalpha in OK, but not in LLC-PK1, cells. The activation of PKCalpha in OK cells by NO is associated with inhibition of Na+-K+-ATPase.

Previous studies in rats have demonstrated that superficial proximal tubule sodium reabsorption does not change in response to alterations in renal perfusion pressure (RPP). The first objective of the present study was to estimate sodium reabsorption in response to acute changes in RPP utilizing fractional lithium reabsorption (FRLi) as an index of fractional sodium reabsorption (FRNa) by the proximal tubule of the kidney as a whole. FRLi decreased in response to increases in RPP, suggesting that sodium reabsorption by the proximal tubule of some nephron population is decreased. Therefore, the second objective of the present study was to test the hypothesis that superficial and deep proximal tubules respond differently to changes in RPP by comparing proximal tubule sodium reabsorption from both nephron populations. In response to an acute change in RPP from 114 +/- 4 to 138 +/- 5 mmHg, FRNa by the proximal tubule and descending limb of Henle's loop in deep nephrons decreased from 71.3 +/- 2.3 to 55.8 +/- 5.6%, but FRNa by the superficial late proximal tubule was not changed: (44.3 +/- 4.8 to 45.1 +/- 3.9%). The urinary fractional reabsorption of sodium decreased from 96.7 +/- 0.6 to 94.5 +/- 0.5%. In summary, these studies demonstrate that increases in RPP have no effect on sodium reabsorption by the proximal tubule of superficial nephrons. In contrast, sodium delivery to the point of micropuncture in the descending limb of Henle's loop of deep nephrons was increased, suggesting inhibition of sodium reabsorption by proximal tubules of deep nephrons in response to increases in RPP.

The newly discovered peptides extracted from cardiac atria, atrial natriuretic factors (ANFs), when administered parenterally cause renal hemodynamic changes and natriuresis. The nephron sites and cellular mechanism accounting for profound increase in Na' excretion in response to ANFs are not yet clarified. In the present study we investigated whether synthetic ANF peptide alters the reabsorption of Na' and reabsorption of solutes cotransported with Na' in the proximal tubules of rats.Synthetic ANF peptide consisting of 26 amino acids, 4 ag/kg body wt/h, or vehicle in controls, was infused to surgically thyroparathyroidectomized anesthetized rats. After determination of the fractional excretion (FE) of electrolytes (Na', K+, P,, Ca2+, Mg2+, HCO3), the kidneys were removed and luminal brush border membrane vesicles (BBMVs) were prepared from renal cortex. Solute transport was measured in BBMVs by rapid filtration techniques. Infusion of ANF peptide increased FENa, FEp,, and FEHCO,; but FEc., FEK, and FEMg were not changed. The increase in FENa was significantly correlated, on the one hand, with increase of FEp, (r = 0.9, n = 7; P < 0.01) and with increase of FEHCO3 (r = 0.89, n = 7; P < 0.01). On the other hand, FEN. did not correlate with FEK, FEca, or with FEM.. The Na+ gradient-dependent uptake of Pi by BBMVs prepared from renal cortex of rats receiving ANF infusion was significantly (P < 0.05) decreased (-25%), whereas the Na+ gradient-dependent uptake of L-13H]proline and of D-I3Higlucose or the diffusional uptake of 22Na+ were not changed. ANF-elicited change in FEn showed a close inverse correlation with decrease of Na+-dependent Pi uptake by BBMVs isolated from infused rats (r = 0.99, n = 7; P < 0.001). Direct addition of ANF to BBMVs in vitro did not change the Na+ gradient-dependent Pi uptake. In rats infused with ANF, the rate of amiloride-sensitive Na+-H+ exchange across the brush border membrane (BBM) was significantly (P < 0.05) decreased (-40%), whereas the diffusional 22Na+ uptake (0.5 min) and the equilibrium (120 min) uptake of 22Na+ were not changed. The inhibition of Na+-H+ exchange after ANF was likely due to alteration of the BBM antiporter itself, in that the H+ conductance of BBMVs was not increased. We conclude that synthetic ANF (a) decreases tubular Na+ reabsorption linked to reabsorption of HCO3 in proximal tubules, and (b) inhibits proximal tubular reabsorption of Pi coupled to Na+ reabsorption, independent of secretion and/or