Michael J. Solhaug

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

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 withN-nitro-L-arginine methyl ester (L-NAME), 3 μg/kg/min, intrarenally, administered after intrarenal infusion of either saline or an angiotensin II AT1 receptor antagonist [ATX (A-81988), 0.4 μg/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.

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.

Nitric oxide in the developing kidney

Abstract. 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.

Endothelium-Derived Nitric Oxide Modulates Renal Hemodynamics in the Developing Piglet

ABSTRACT: 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 μg/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-μg/kg/min L-NAME dose did not change mean arterial pressure. The developing piglet exhibited significantly greater changes at all doses. After the 50-μg/kg/min infusion, piglet RBF decreased 45% and adult pig RBF decreased 29%; piglet RVR increased 128% and adult pig RVR increased 51%. After a 5-μg/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 μ/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. The results of this study suggest that EDNO participates in the regulation of basal renal hemodynamics in the developing piglet and adult pig. Furthermore, it appears that EDNO may play a greater role in maintaining basal renal hemodynamics in the developing piglet than in the adult pig.

Angiotensin II regulates NOS expression in afferent arterioles of the developing porcine kidney.

NO protection is crucial against angiotensin II (ANG II) mediated vasoconstriction in postnatal preglomerular resistance vessels. Although whole kidney NOS is developmentally regulated, NOS regulation in developing renal resistance vessels is unknown. The hypothesis was NOS expression and function in developing afferent arterioles are regulated by ANG II through AT1 and AT2 receptors. Afferent arterioles from porcine kidneys, ages newborn, 7, 21 d, and adult, were dissected using a polybead perfusion technique. Dissected afferent arterioles were treated with ANG II and with either the AT1 receptor inhibitor candesartan or the AT2 receptor inhibitor PD 123319 and evaluated for NOS isoform expression and NOS enzymatic activity. Although NOS activity and neuronal NOS (nNOS) expression were greater in the newborn than in the adult, endothelial NOS (eNOS) expression was greater in the adult. ANG II increased NOS activity and eNOS expression at all ages, but nNOS expression only in developing afferents. AT1 and AT2 receptor blockade significantly attenuated NOS activity and eNOS expression at all ages, but nNOS expression only in developing afferents. ANG II regulates nNOS and eNOS expression and NOS activity in afferent arterioles of the developing kidney via AT1 and AT2 receptors.

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.

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

ABSTRACT: 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 (>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 µmol/ 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. The results of our study indicate that the piglet does not exhibit a normal adult RIHP response to VE. The absence of any discernible increase in RIHP during VE may explain, in part, why piglets have a limited ability to excrete a saline load.

Neuronal nitric oxide synthase, nNOS, regulates renal hemodynamics in the postnatal developing piglet

Introduction:Nitric oxide (NO) vasodilation critically modulates renal hemodynamics in the neonate compared with the adult. Based on the postnatal expression pattern of renal neuronal nitric oxide synthase (nNOS), the hypothesis was that nNOS is the major NOS isoform regulating renal hemodynamics in the immature, but not mature, kidney.Results:NOS inhibitors did not alter mean arterial pressure (MAP) in either group. Intrarenal S-methyl-L-thiocitrulline (L-SMTC) in newborns significantly reduced renal blood flow (RBF) 38 ± 4%, glomerular filtration rate (GFR) 42 ± 6%, and increased renal vascular resistance (RVR) 37 ± 7%, whereas intrarenal L-nitro-arginine methyl ester (L-NAME) affected RBF, GFR, and RVR equivalent to L-SMTC treatment. When L-NAME was administered after L-SMTC treatment, newborn renal hemodynamic changes were not further altered from what was observed when L-SMTC was administered alone. In contrast, in the adult, only intrarenal L-NAME, and not L-SMTC, affected renal hemodynamic responses.Discussion:In conclusion, these studies demonstrate that nNOS is an important regulator of renal hemodynamics in the newborn kidney, but not in the adult.Methods:Experiments compared renal hemodynamic responses with intrarenal infusion of L-NAME, an inhibitor of all NOS isoforms, with the selective nNOS inhibitor L-SMTC in the newborn piglet and the adult pig.

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.

INTRARENAL LOCALIZATION OF NITRIC OXIDE SYNTHASE IN THE DEVELOPING PIGLET. † 2204

Nitric oxide (NO) may play a more important vasoactive role in the developing kidney than the adult, perhaps related to a different developmental intrarenal distribution of the NO synthesizing enzyme, nitric oxide synthase(NOS). These experiments determined the intrarenal histochemical localization of NOS in developing piglets ages 2 days, 1 week, 3 weeks and adult pigs. Kidneys were fixed by in-vivo perfusion, and placed in increasing sucrose concentrations for 72 hr. 15 micron cryostat sections were stained with the NADPH-diaphorase technique, which demonstrates the catalytic activity of NOS by the enzymatic reduction of nitro blue tetrazolium, NBT, in the presence of NADPH. Localization of NOS in the immature kidney differed from the adult in three major patterns: 1. NOS was present in the macula densa at all stages of nephron development, identifying the morphologic formation of this segment. 2. NOS localized to glomerular resistance arterioles in the developing kidney, most intensely in the 1 and 3 week old piglets. 3. All developing age groups intensely demonstrated NOS in segments of the thick ascending limb. In the adult, NOS was confined primarily to the macula densa, with faint staining of resistance arterioles and thick ascending limb. Summary: Intrarenal histochemical localization of NOS reveals distinct developmental localization patterns for the macula densa, glomerular resistance arterioles and tubular segments in the immature kidney that differ from the adult.Conclusion: The identification of NOS in these locations supports the role of NO as an important participant in developing renal function.