title: Angiotensin II blockade augments renal cortical microvascular pO2 indicating a novel, potentially renoprotective action.
abstract: BACKGROUND
  The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO(2) and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney.
  
  
  METHODS
  Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO(2 )was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 microg/kg i.v.) or candesartan (40 microg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO(2).
  
  
  RESULTS
  After a 30-min stabilisation period there was a slow decline in pO(2 )from 48.6 +/- 4.1 to 38.5 +/- 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO(2) levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO(2) had fallen by 5 mm Hg, resulted in a rise in RBF and pO(2 )within 15 min with pO(2) remaining elevated for up to 60 min post-injection. The angiotensin II AT(1) receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO(2).
  
  
  CONCLUSIONS
  These studies indicate that blockade of AII raises pO(2 )in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.
authors.affiliation: Centre for Nephrology, Department of Medicine, Royal Free and University College Medical School, London, UK. rmhajtn@ucl.ac.uk
authors.forename: Jill T
authors.initials: JT
authors.lastname: Norman
authors.forename: Ray
authors.initials: R
authors.lastname: Stidwill
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: Leon G
authors.initials: LG
authors.lastname: Fine
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D015773:Enalaprilat / Q000627:therapeutic use; D006973:Hypertension / Q000517:prevention & control; D000860:Hypoxia / Q000517:prevention & control; D007672:Kidney Cortex / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D010313:Partial Pressure; D010865:Pilot Projects; D011166:Porphyrins / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011166:Porphyrins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D015773:Enalaprilat; D010100:Oxygen; C081643:candesartan