title: 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-1, 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. NG-nitro-L-arginine methyl ester (L-NAME, 30 micrograms kg-1 min-1, i.v., n = 5) significantly prevented the recovery of RBF after I/R injury. Similarly, inhibition of prostanoid formation with indomethacin (5 mg kg-1, i.v., n = 4) significantly enhanced the rise in RVR associated with I/R injury. 4. Infusion of L-arginine (L-Arg; 1 or 3 mg kg-1 min-1, i.v., n = 5 and 4, respectively) or D-Arg (1 mg kg-1 min-1, i.v., n = 6), starting 30 min after occlusion, did not improve the recovery of RBF. Furthermore, infusion of L-Arg (20 mg kg-1 min-1 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-1, 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-1, 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.
authors.affiliation: William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London.
authors.forename: J P
authors.initials: JP
authors.lastname: Cristol
authors.forename: C
authors.initials: C
authors.lastname: Thiemermann
authors.forename: J A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: C
authors.initials: C
authors.lastname: Walder
authors.forename: J R
authors.initials: JR
authors.lastname: Vane
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D003907:Dexamethasone; D001120:Arginine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000594:Amino Acid Oxidoreductases; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin