Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney.

The postnatal pattern of renal endothelial nitric oxide synthase (eNOS) is unknown. The purpose of this study was to characterize eNOS expression during maturation and compare this to neuronal NOS (nNOS). The experiments measured whole kidney eNOS mRNA expression by RT-PCR and protein content by Western blot, as well as cortical and medullary protein content in piglets at selected postnatal ages and in adult pigs. Whole kidney eNOS mRNA was compared with nNOS. Whole kidney eNOS expression decreased from the newborn to its lowest at 7 days, returning by 14 days to adult levels. This eNOS mRNA pattern contrasted with nNOS, which was highest at birth, and progressively decreased to its lowest level in the adult. At birth, cortical eNOS protein was greater than medullary, contrasting with the adult pattern of equivalent levels. In conclusion eNOS is developmentally regulated during early renal maturation and may critically participate in renal function during this period. The eNOS developmental pattern differs from nNOS, suggesting that these isoforms may have different regulatory factors and functional contributions in the postnatal kidney.

Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney.

To determine if the developing kidney differs from the adult in the expression of the neuronal nitric oxide synthase, NOS I, these experiments measured mRNA gene expression by RNase protection assay and protein content by Western blot of NOS I in piglets at ages newborn and 3, 7, 10, 14, and 21 days and adult pigs. Whole kidney NOS I mRNA was greatest at birth and decreased progressively during renal maturation to adult levels. NOS I protein content paralleled this developmental pattern. Cortical NOS I protein was equivalent in newborn and 14-day-old piglets and was greater at both ages than the adult. Medullary NOS I protein was relatively greater than cortical in both immature ages and decreased from a peak at birth to adult levels. We conclude the following. 1) During postnatal maturation, renal NOS I mRNA and protein content show a pattern that is developmentally regulated. 2) This developmental pattern of NOS I after birth may, in part, contribute to the enhanced functional role of NO during renal maturation.

Nitric oxide in the developing kidney.

Although nitric oxide (NO) has a well-established role in regulating renal function in the adult, recent studies point to perhaps an even more critical role for NO in maintaining basal renal blood flow (RBF) and glomerular filtration rate (GFR) in the developing kidney. The immature kidney has enhanced renal hemodynamic and functional responses to stimulation and inhibition of NO synthesis when compared with the adult, and these increased responses are not mediated by prostaglandins. Increased intrarenal activity of NO in the developing kidney counter-regulates the highly activated renin angiotensin system by modulating the angiotensin II-mediated vasoconstriction of the developing renal vasculature, the angiotensin II effects on GFR, as well as renin release. Localization studies demonstrate that NO acts on neonatal RBF and stabilization of GFR through an intrarenal distribution of the synthesizing enzyme, nitric oxide synthase, that is different from that of the adult. The developing kidney is dependent on NO to maintain RBF and GFR during periods of hypoxemia, protecting against renal injury, such as acute renal failure. In summary, NO is vital in the developing kidney to maintain normal physiological function and to protect the immature kidney during pathophysiological stress.

Nitric oxide and angiotensin II regulation of renal hemodynamics in the developing piglet.

UNLABELLED: We have previously shown that nitric oxide (NO) is a more important intrarenal vasodilator in the developing animal compared with the adult. The interaction between NO and the renin angiotensin system in the developing kidney is not known. The purpose of this study was to determine the role of NO and angiotensin II in the regulation of developing renal function. We examined the effects of the inhibition of intrarenal NO synthesis with N-nitro-L-arginine methyl ester (L-NAME), 3 micro g/kg/min, intrarenally, administered after intrarenal infusion of either saline or an angiotensin II AT1 receptor antagonist [ATX (A-81988), 0.4 micro g/kg/min] in piglets, age 3 wk, and adult pigs. The developing piglet demonstrated significantly greater renal responses to L-NAME alone. Intrarenal NO synthesis inhibition after saline preinfusion decreased renal blood flow (RBF) in the piglet 29% compared with the adult pig 9%, but only in the piglet decreased GFR 31%, and increased plasma renin activity 57%. Intrarenal infusion of ATX significantly increased RBF in the piglet, 23%, although not altering RBF in the adult. The renal responses to L-NAME were significantly attenuated by ATX preinfusion in both age groups. After ATX pretreatment, L-NAME in piglets decreased RBF 14%, and abolished the change in GFR, whereas in adult pigs decreased RBF only 5%. IN CONCLUSION: 1) angiotensin II may be a more important vasoconstrictor in the developing kidney and 2) NO is a more important regulator of renal function in the developing kidney through modulation of the renin angiotensin system.

Nitric oxide and the immature kidney.

Nitric oxide (NO) is a very potent vasodilator synthesized from L-arginine by endothelial cells. By activating guanylate cyclase, it promotes vasodilatation of adjacent smooth muscle cells. NO is thus involved in the control of vascular tone in various organs. There is increasing evidence that NO is tonically synthesized within the kidney and plays a crucial role in the modulation of renal hemodynamics and excretory function. The blockade of basal NO synthesis has been shown to result in decreases in renal blood flow and, to a lesser extent, in glomerular filtration rate. NO may also be involved in sodium excretion. In the neonatal period, a time associated with a hyperactivation of vasoactive systems, NO seems to play a greater role than in the adult. It could also be implicated in the response to vasoconstrictive stresses, such as perinatal hypoxia, frequently encountered during this period.

Nephrocalcinosis in very low birth weight neonates: sonographic patterns, histologic characteristics, and clinical risk factors.

Fifty infants weighing less than 1200 grams at birth who survived at least 3 weeks were enrolled in this study, of whom 14 (28%) developed sonographic evidence of nephrocalcinosis by 9 weeks, despite median total furosemide dose of only 2 mg/kg. Risk factors for development of neonatal nephrocalcinosis were white race (P < 0.01) and positive family history of kidney stones (P < 0.001). Sonography demonstrated echogenic foci measuring 2 to 9 mm near the papillary tips in most infants with nephrocalcinosis even though the kidneys apparently had not progressed through the stages of diffuse medullary echogenicity that Patriquin and Robitaille postulated are the sonographic correlates of the Anderson-Carr-Randall progression, a leading theory of renal calculus formation. The presence of intratubular calcifications in the two patients studied post mortem also is contrary to the Anderson-Carr-Randall theories that center on interstitial calcium deposition. Although neonatal nephrocalcinosis shares some clinical risk factors (white race and positive family history of renal calculi) with renal calcium deposition in older children and adults, the prevalent theories of renal calcium deposition do not account for its sonographic or histologic manifestations.

Endothelium-derived nitric oxide modulates renal hemodynamics in the developing piglet.

The developing mammal exhibits lower renal blood flow (RBF) and higher renal vascular resistance (RVR) than its adult counterpart. The maturational pattern of renal hemodynamics involves the synchronous increase in RBF and decrease in RVR with age. In spite of considerable investigation, the mechanisms involved in the regulation of renal hemodynamics in the developing animal remain largely unexplained. Specifically, the role of the vasodilator endothelium-derived nitric oxide (EDNO) in the regulation of developing renal hemodynamics is not known. These experiments examined the intrarenal effect on the renal hemodynamics of the developing piglet and adult pig of the EDNO competitive inhibitor N-nitro-L-arginine methylester (L-NAME) at three doses (50, 5, and 3 micrograms/kg/min). During basal conditions, the developing piglet exhibited lower RBF and higher RVR than the adult pig. All doses of intrarenal L-NAME produced significant decreases in RBF and increases in RVR in both groups. The 3-micrograms/kg/min L-NAME dose did not change mean arterial pressure. The developing piglet exhibited significantly greater changes at all doses. After the 50-micrograms/kg/min infusion, piglet RBF decreased 45% and adult pig RBF decrease 29%; piglet RVR increased 128% and adult pig RVR increased 51%. After a 5-micrograms/kg/min infusion, RBF decreased 28% in the piglet and 14% in the adult pig; RVR increased 75% in the piglet compared with 27% in the adult pig. After 3 micrograms/kg/min L-NAME, piglet RBF decreased 29% and adult RBF decreased 9%; RVR increased 47% in the piglet versus 13% in the adult pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Nephrocalcinosis in very low birth weight neonates: family history of kidney stones and ethnicity as independent risk factors.

Serial renal ultrasonography was performed in 50 consecutive neonates with birth weights less than 1200 gm who survived to at least 3 weeks of age. Nephrocalcinosis developed in 8 (67%) of 12 white and only 6 (16%) of 38 nonwhite infants (p < 0.01). Seven (78%) of nine infants with a family history of kidney stones had nephrocalcinosis compared with only 7 (17%) of 41 without a family history of kidney stones (p < 0.001). We conclude that nephrocalcinosis in our population of very low birth weight neonates is significantly and independently associated with a family history of kidney stones and white race.

Renal interstitial hydrostatic pressure during verapamil-induced natriuresis.

Infusion of calcium antagonists results in significant increases in sodium excretion, an effect that is exacerbated in hypertensive animals. The mechanism responsible for the increase in sodium excretion has not been elucidated. The purpose of this study was to determine the role of renal interstitial hydrostatic pressure (RIHP) in mediating increases in sodium excretion produced by the calcium antagonist verapamil. Changes in renal hemodynamics and electrolyte excretion were examined in response to an intrarenal infusion of verapamil (100 micrograms/min) in normal dogs and in dogs with angiotensin II-induced hypertension. Infusion of verapamil in normal dogs increased renal blood flow by 18% and had no effect on glomerular filtration rate. Renal vascular resistance and filtration fraction both decreased in response to verapamil. Absolute (5.1 +/- 2.3 to 176 +/- 45.8 mueq/min) and fractional excretion of sodium (0.21 +/- 0.13 to 7.36 +/- 3.12%) also increased significantly. Despite renal vasodilation, the natriuresis was not associated with significant increases in RIHP (6.4 +/- 0.9 to 5.8 +/- 0.9 mmHg). Infusion of verapamil into dogs with angiotensin II hypertension resulted in a natriuresis (4.2 +/- 1.6 to 338.7 +/- 78.3 mueq/min) that was much greater than under normal conditions. Although the renal vasodilation was significantly higher in the angiotensin II-hypertensive dogs, the enhanced natriuresis in these animals was not associated with increases in RIHP. The results of this study indicate that increases in RIHP are not responsible for the natriuresis produced by verapamil in normal or angiotensin II-hypertensive dogs.

Role of renal interstitial hydrostatic pressure in the blunted natriuretic response to saline loading in the piglet.

Acute saline volume expansion (VE) in the developing animal is associated with a blunted natriuretic response when compared with that in adults. Recent studies have suggested that renal interstitial hydrostatic pressure (RIHP) plays an important role in mediating VE-induced natriuresis in the adult. The purpose of our study was to determine whether abnormalities in the RIHP response to VE could be involved in the blunted natriuretic response in the developing animal. The effect of an acute saline load (5% body wt) on RIHP and sodium excretion was examined in adult pigs (greater than 70 d) and piglets (26-43 d). In response to an acute saline load, the piglets excreted significantly less sodium than the adults (1.7 +/- 0.5 versus 3.8 +/- 0.7 mumol/min/g kidney wt). The increase in fractional excretion of sodium in response to VE was also significantly less in the piglets. There was no significant change in GFR in either group. Associated with the blunted natriuretic response in the piglet was an absence of an increase in RIHP (6.1 +/- 1.1 versus 6.1 +/- 1.6 mm Hg) in response to VE. In contrast, the adult pig, which exhibited a normal natriuretic response, showed a significant increase in RIHP (8.8 +/- 1.3 to 12.3 +/- 1.5 mm Hg) during VE. When RIHP was prevented from increasing during VE in the adult pigs, the natriuretic response was significantly attenuated, as it was in the piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sodium intake on fasting and postprandial levels of atrial natriuretic factor in humans.

The effect of chronic dietary sodium intake on fasting and postprandial plasma atrial natriuretic factor (ANF) levels was examined in 2 studies of normal humans. In Study I, 3 separate groups of normals (n = 8 for each) received diets of either low (L), normal (N) or high (H) daily sodium intake for 7 days. Twenty-four h urines for sodium were obtained on days 6 and 7. Urine sodium excretion for each group was (L) 13.1 +/- 3.7, (N) 150.1 +/- 19.4 and (H) 271.3 +/- 33.6 mEq/day. On the completion of day 7, fasting plasma ANF showed no change with alteration in sodium intake. In contrast, when blood samples were obtained postprandially, significant increases in plasma ANF were observed in the group maintained on high sodium diet. In Study II, a continuous group of normals (n = 8) received the 3 sodium controlled diets for 7 days sequentially (L/N/H). No significant changes in fasting levels of ANF were detected between L/N/H sodium diets. In conclusion, these studies show that the maintenance of sodium balance during chronic changes in sodium intake can occur despite no significant increase in plasma ANF under normal steady state conditions. However, plasma ANF is significantly elevated during chronic high sodium intake, when measured postprandially.