Glomerular and tubular responses toN^G-nitro-l-arginine methyl ester are age dependent in conscious lambs

Abstract

Sener, Alp, and Francine G. Smith. Glomerular and tubular responses to N G -nitro-L-arginine methyl ester are age dependent in conscious lambs. Am J Physiol Regulatory Integrative Comp Physiol 282: R1512-R1520, 2002 10.1152/ ajpregu.00628.2001.-The present experiments were carried out to investigate the role of endogenously produced NO in modulating renal function during postnatal maturation under physiological conditions. In conscious, chronically instrumented lambs aged ϳ1 (n ϭ 8) and ϳ6 wk (n ϭ 8) of postnatal life, various parameters of glomerular and tubular function were measured for 1 h before and 1 h after intravenous injection of 20 mg/kg of N G -nitro-L-arginine methyl ester (L-NAME; experiment 1) or its inactive isomer D-NAME (experiment 2). After administration of L-NAME to 1-wk-old lambs, glomerular filtration rate (GFR) and filtration factor (FF) decreased by ϳ50% at 20 min, remaining decreased at 60 min. In 6-wk-old lambs, GFR and FF remained constant after L-NAME. Proximal fractional Na ϩ reabsorption decreased after L-NAME administration to lambs aged 6 wk, resulting in a prompt natriuresis; this was sustained for 60 min. There were no effects of L-NAME on proximal fractional Na ϩ reabsorption in 1-wk-old lambs. In 6-wk-old lambs, urinary flow rate increased by ϳ500%, free water clearance increased by ϳ50%, and urinary osmolality decreased by ϳ60% after L-NAME administration; no effects on these variables were measured in 1-wk-old lambs. The diuresis after L-NAME administration to 6-wk-old lambs was unaccompanied by any changes in plasma levels of arginine vasopressin. There were no effects of D-NAME on any of the measured variables. We conclude that endogenously produced nitric oxide modulates glomerular and tubular function in an age-dependent manner.newborn; perinatal; nitric oxide; renal function; glomerular filtration rate; sodium excretion; plasma renin activity; endothelin-1; arginine vasopressin; renal vascular resistance THE ENDOTHELIUM-DERIVED RELAXING FACTOR, nitric oxide (NO), is synthesized in various tissues in the body under basal conditions and normally influences a variety of physiological processes. Through its effects on vascular smooth muscle, NO is involved in the maintenance of organ blood flow, thereby influencing blood pressure. In addition, NO modulates renal hemodynamics and function, possesses immunomodulatory as well as cytotoxic effects, and may act as a neurotransmitter in the central nervous system. NO production is regulated by NO synthase (NOS), of which there are three different isoforms: endothelial (eNOS) and neuronal (nNOS) isoforms are constitutive, whereas the third isoform is inducible (iNOS).In previous studies carried out in conscious, chronically instrumented lambs, we provided evidence that some of the physiological effects of NO produced by the constitutive isoforms of NOS are developmentally regulated (30-32). For example, administration of the L-arginine analog, N G -nitro-L-arginine methyl ester (L-NAME), which competitively inhibits both n-and e...

Effects of ibuprofen treatment on the developing preterm baboon kidney

“…NSAID treatment increases renal vascular resistance, reduces renal blood flow (14,30), decreases glomerular filtration rate (1,22), and is an independent risk factor for the development of acute renal failure (4). Similarly, NOS inhibition has been shown to significantly reduce renal blood flow, glomerular filtration rate, and alter tubular function in neonatal animals (27). Furthermore, a combination of a NOS inhibitor and NSAID treatment has been shown to produce significant renal side effects (such as increased serum creatinine) in human preterm neonates (16).…”

“…Of particular importance, in human infants exposed in utero to NSAIDs, changes in renal morphology have been described (15,33) which are similar to the glomerulocystic changes observed in the preterm baboon kidney. NOS inhibitors elicit a similar physiological response as NSAIDS, such as reduction in renal blood flow and urine output (27); however, the effects on nephrogenesis have not been previously investigated. Therefore, the aim of this study was to determine the effects of ibuprofen treatment on renal development and morphology in the preterm baboon kidney both alone and in combination with a NOS inhibitor.…”

Reduced sensitivity of the renal vasculature to angiotensin II in young rats: the role of the angiotensin type 2 receptor

“…In further support of this conjecture, it is well established that the AT 2 R functions via a nitric oxide (NO)-mediated pathway to produce cyclic GMP and increase vasodilatation (20). Certainly, there is abundant evidence in the literature that NO plays a significantly greater role in the maintenance of hemodynamic function in the neonatal vs. adult kidney, including providing protection against the vasoconstrictor effects of AngII in the newborn (21)(22)(23)(24). Furthermore, there are reports that NO production in the renal vasculature is significantly greater in the newborn vs. adult renal vasculature under normal physiological conditions (4).…”

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

“…Solhaug et al were the first to show an enhanced role for NO in the neonate in 1993, when intrarenal infusion of the nonspecific NOS inhibitor l-NAME into porcine caused significantly greater changes in RVR, RBF, and GFR in the newborn, than in the adult (6). This finding by Solhaug et al was confirmed in other animal models (lambs and rabbits) in which nonspecific NOS inhibition increased RVR while decreasing RBF and GFR much more significantly in neonates than in adult kidneys (4,5,8). These early studies demonstrated that the renal hemodynamics of the neonate is much more dependent on NO than that of the adult to maintain normal physiological function; however, the characteristics and exact nature of the enhanced role of NO remain unidentified.…”

“…Various studies have shown that nitric oxide (NO) plays a much more pronounced role in the neonate's hemodynamic state, as compared with the adult's, and NO counterbalances the highly activated reninangiotensin system (RAS), protecting the immature kidney from the deleterious effects of adverse perinatal events that lead to vasomotor acute renal failure (2)(3)(4)(5)(6)(7). The immature renal vasculature is highly responsive to intrarenal NO stimulation with acetylcholine and NO inhibition with the nonselective nitric oxide synthase (NOS) inhibitor L-nitro-arginine methyl ester (l-NAME) (8)(9)(10)(11), producing significantly greater increases in RVR and decreases in RBF and GFR in the immature kidney, as compared with the adult.…”