title: Glomerular autacoids stimulated by bradykinin regulate efferent arteriole tone.
abstract: BACKGROUND
  We have shown that when efferent arterioles are perfused retrograde to avoid the influence of vasoactive autacoids released by the glomerulus, bradykinin causes dilatation via release of cytochrome p450 (cp450) metabolites, probably epoxyeicosatrienoic acids (EETs). Here we tested the hypothesis that the glomerulus releases cyclooxygenase (COX) and cp450 metabolites. These eicosanoids, acting as vasopressor and vasodepressor autacoids, control efferent arteriole resistance downstream from the glomerulus.
  
  
  METHODS
  Rabbit efferent arterioles were perfused orthograde through the glomerulus from the end of the afferent arteriole to determine whether bradykinin induces the release of glomerular autacoids that influence efferent arteriole resistance. Efferent arterioles were preconstricted with norepinephrine, and increasing doses of bradykinin were added to the perfusate in the presence or absence of COX and cp450 inhibitors.
  
  
  RESULTS
  When efferent arterioles were perfused orthograde through the glomerulus, bradykinin at 10 nmol/L caused significant and reproducible dilatation; diameter increased from 8.0 +/- 0.5 to 12.6 +/- 0.4 microm (P < 0.05). This effect was not modified by a nitric oxide synthase (NOS) inhibitor. In the presence of indomethacin, a COX inhibitor, bradykinin-induced dilatation was almost completely blocked (from 8.0 +/- 0.5 to 9.3 +/- 0.6 microm). This blockade was completely reversed by 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), a specific antagonist of the vasoconstrictor cp450 metabolite 20-hydroxyeicosatetraenoic acid (20-HETE); diameter increased from 6.6 +/- 0.7 to 13.2 +/- 0.5 microm. To test the hypothesis that this dilatation was due to EETs, a specific inhibitor of EET synthesis, N-methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH), was added to the arteriolar perfusate. In the presence of indomethacin and 20-HEDE, bradykinin caused dilatation and this effect was completely blocked by MS-PPOH (1 microm) (from 7.6 +/- 0.6 to 7.3 +/- 0.5 microm).
  
  
  CONCLUSIONS
  We concluded that in response to bradykinin, the glomerulus releases COX metabolites (probably prostaglandins) that have a vasodilator effect. When COXs are inhibited, the vasoconstrictor 20-HETE released by the glomerulus is able to oppose the vasodilator effect of bradykinin. This vasodilator effect is mediated by EETs released by the glomerulus and/or the efferent arteriole and does not involve nitric oxide. The balance between these opposing effects of various eicosanoids controls efferent arteriole resistance downstream from the glomerulus.
authors.affiliation: Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Ren
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Kishore V
authors.initials: KV
authors.lastname: Renduchintala
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000098:blood supply*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019899:Paracrine Communication; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000577:Amides; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D014665:Vasodilator Agents; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D001920:Bradykinin