Support of renal blood flow after ischaemic‐reperfusion injury by endogenous formation of nitric oxide and of cyclo‐oxygenase vasodilator metabolites

Abstract

1 Ischaemia-reperfusion injury in the kidney is associated with a loss of autoregulation, an increase in renal vascular resistance (RVR), a decrease of renal blood flow (RBF) and ultimately acute renal failure. The aim of this study was to investigate the role of the release of endogenous nitric oxide (NO) in the recovery of RBF after ischaemic injury of the renal vascular bed.2 Anaesthetized rats (thiopentone sodium; 120 mg kg-', i.p.) were submitted to acute renal ischaemia followed by 2 or 6 h of reperfusion (I/R). Reperfusion was associated with a significant reduction in RBF, an increase in RVR, and an impairment of the vasodilator effect of acetylcholine (ACh).3 N0-nitro-L-arginine methyl ester (L-NAME, 30 iLg kg-' min-, i.v., n = 5) significantly prevented the recovery of RBF after I/R injury. Similarly, inhibition of prostanoid formation with indomethacin (5 mg kg-', i.v., n = 4) significantly enhanced the rise in RVR associated with I/R injury. 4 Infusion of L-arginine (L-Arg; I or 3 mg kg-' min 1, i.v., n = 5 and 4, respectively) or D-Arg (1 mg kg-' min', i.v., n = 6), starting 30 min after occlusion, did not improve the recovery of RBF. Furthermore, infusion of L-Arg (20 mg kg-' min-' for 15 min; n = 4) had no effect on the I/R-induced impairment of the vasodilator responses to ACh. 5 To elucidate the relative importance of the constitutive and inducible NO synthase isoforms for the formation of NO after I/R, calcium-dependent (constitutive) and calcium-independent (inducible) NO synthase activities were measured in kidney homogenates obtained from ischaemic or non-ischaemic kidneys. A calcium-independent NO synthase activity was not detectable in kidney homogenates obtained from either sham-operated control rats or from animals subjected to I/R. Moreover, dexamethasone (3 mg kg-', i.v., 60 min prior to I/R, n = 6), an inhibitor of the induction of NO synthase, had no effect on either RBF or RVR in rats subjected to I/R. In contrast to I/R, lipopolysaccaride (LPS, endotoxin; 5 mg kg-', i.p., n = 3) caused a significant induction of a calcium-independent NO synthase activity in the kidney. 6 These results confirm the importance of the release of vasodilator cyclo-oxygenase metabolites in the compromised renal circulation and indicate that the formation of NO derived from the constitutive, but not the inducible NO synthase, is also important for the maintenance of RBF after I/R injury of the renal vascular bed.

Intrarenal Administration of Molsidomine, a Molecule Releasing Nitric Oxide, Reduces Renal Ischemia-Reperfusion Injury in Rats

“…This factor suggests that the beneficial effects of MOL in I-R injury are not solely mediated by the vasodilator properties of NO in the renal vasculature. Cristol et al have shown an important role for endogenous NO production in the maintenance of renal function after I-R because administration of the NO synthesis blocker Nx-nitro-L-arginine induced a further reduction in renal function (29). In agreement with this observation, some studies report that systemic administration of NO precursors before reperfusion improved renal function and inflammation induced by ischemia (24,25,30).…”

Nebivolol Reduces Experimentally Induced Warm Renal Ischemia Reperfusion Injury in Rats

“…[23] In this study, there was a significant decrease in tissue nitrite levels in kidney of I/R group animals as compared to sham-operated group. Cristol et al [24] have demonstrated the role of endothelial NO after I/R and decrease in renal function after treatment with L-NAME. Moreover, peroxynitrite could initiate lipid peroxidation, which damages the proximal tubular cells, nitration of tyrosine residues (nitrotyrosine), and nitration of cellular proteins, with a subsequent loss of protein structure resulting in reduction of the kidney function.…”

Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion ofpara-aminohippurate after ischemic acute renal failure in rats

“…Prostaglandin E 2 is known to be an important regulator of renal perfusion (10) and its generation is significantly increased in the kidney after I/R injury (19). In the latter, it is thought to restore and stabilize renal perfusion [together with other vasoactive regulators, e.g., nitric oxide (NO) (6,34)]. COX-2, one source of prostaglandin E 2 generation, is induced and activated in a NO-dependent manner (38).…”