TXA2, a potent vasoconstrictor, plays a key role in endotoxin-induced ARF [123], and TXA2 receptor blockade can prevent renal vasoconstriction in ischemic ARF in rats [124]. These promising animal studies have not yet been verified in clinical trials. The neonatal efficacy of TXA2 blockade remains to be elucidated.
ANP release is stimulated by hypoxemia and by vasoconstrictor substances such as ET and All [125]. This suggests a vasodilatory action of ANP. The same conclusion was drawn from the finding of elevated serum ANP levels in asphyxiated newborns with RDS. In this setting ANP seems to have a protective role as it causes renal vasodilation and an increase in GFR [126]. These protective effects of ANP may, however, only apply at pharmacological doses. The far less-pronounced physiological increases in plasma ANP levels encountered in experimental hypoxia in the newborn rabbit neither prevent nor improve neonatal renal dysfunction [127]. Because of the profound effect of ANP on the systemic circulation, this renal vasodilatory and natriuretic peptide is unlikely to be useful in the prevention of VMNP/ARF [128].
The effects of TP are not mediated by cyclic AMP phosphodiesterase, since in newborn rabbits the protective action of TP occurs at micromolar plasma concentrations that are not high enough to inhibit cyclic AMP/phosphodiesterase [37]. The diuretic effect of TP can be attributed to a direct effect on the adenosine receptors in the renal medulla or to stimulation of renal PG production [37]. Other effects of TP are probably mediated through improvement in cardiovascular function. Common adverse effects of TP treatment (in adults) are nausea and vomiting, whereas at toxic blood levels hypotension, tachycardia, and seizures can occur. Presumably because of careful monitoring of serum drug concentrations, the side effects of TP are less common in premature newborns. This monitoring is mandatory because of the prolonged plasma half-life of TP in preterm infants [45].
The ACE inhibitor perindoprilat prevented hypo-xemic renal vasoconstriction in hypoxemic newborn rabbits [117]. Captopril gave similar protection in nephro-toxic ARF [118]. The role of All in the development of ischemic and aminoglycoside-induced ARF could, however, not be confirmed [119, 120]. To date no experimental data are available on the protective effect of All receptor antagonists. It seems that neither ACE inhibition or All receptor blockade are effective tools in the management of neonatal ARE
ET has been implicated as a mediator of postischemic and/or endotoxemic ARF [121]. Exogenous ET causes renal vasoconstriction in the newborn rabbit; this vasoconstriction is similar to that seen in hypoxemia [12]. The glomerular dysfunction of hypoxemic newborn rabbits is not prevented by pretreatment with ET antiserum [122]. ET may, however, play a role in other forms of neonatal renal failure (e.g., due to sepsis), and ET antagonists may therefore still prove to be useful protectors of ARF.
Renal cellular injury
Events leading to the morphological renal changes of established ARF have been the subject of intensive research during the last decade. The main pathophysiologi-cal processes implicated in renal cell injury of different origin have been reviewed by Brezis [129], who emphasized the susceptibility of specific nephron segments of the adult animal to hypoperfusion and hypoxemia, particularly the S3 segment of the proximal tubule and the thick ascending limb of the loop of Henle. The immature kidney is less sensitive to this kind of hypoxemic insult.
Intrarenal hypoperfusion and hypoxia/ischemia affects mainly the renal medulla that has a partial oxygen pressure of 10-20 mmHg [130]. The metabolic effects of renal ischemic injury have been described in detail by Siegel et al. [131]. Oxygen deprivation causes
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