title: Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition.
abstract: BACKGROUND
  Prostanoid products of the cyclo-oxygenase (COX) pathway of arachidonic acid metabolism modulate blood pressure (BP) and sodium homeostasis. Conventional non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit both COX isoforms (COX-1 and -2), cause sodium retention, exacerbate hypertension, and interfere with the efficacy of certain anti-hypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors. While a new class of NSAIDs that specifically inhibit COX-2 is now widely used, the relative contribution of the individual COX isoforms to these untoward effects is not clear.
  
  
  METHODS
  To address this question, we studied mice with targeted disruption of the COX-1 (Ptgs1) gene. Blood pressure, renin mRNA expression, and aldosterone were measured while dietary sodium was varied. To study interactions with the renin-angiotensin system, ACE inhibitors were administered and mice with combined deficiency of COX-1 and the angiotensin II subtype 1A (AT1A) receptor were generated.
  
  
  RESULTS
  On a regular diet, BP in COX-1-/- mice was near normal. However, during low salt feeding, BP values were reduced in COX-1-/- compared to +/+ animals, and this reduction in BP was associated with abnormal natriuresis despite appropriate stimulation of renin and aldosterone. Compared to COX-1+/+ mice, the actions of ACE inhibition were markedly accentuated in COX-1-/- mice. Sodium sensitivity and BP lowering also were enhanced in mice with combined deficiency of COX-1 and AT1A receptor.
  
  
  CONCLUSIONS
  The absence of COX-1 is associated with sodium loss and enhanced sensitivity to ACE inhibition, suggesting that COX-1 inhibition does not cause hypertension and abnormal sodium handling associated with NSAID use.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: K
authors.initials: K
authors.lastname: Athirakul
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: L P
authors.initials: LP
authors.lastname: Audoly
authors.forename: O
authors.initials: O
authors.lastname: Smithies
authors.forename: T M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D051545:Cyclooxygenase 1; D004039:Diet, Sodium-Restricted; D007527:Isoenzymes / Q000172:deficiency*; D007672:Kidney Cortex / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009318:Natriuresis / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency; D012083:Renin / Q000378:metabolism; D012964:Sodium / Q000172:deficiency
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D012964:Sodium; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D012083:Renin