Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole

J Clin Invest. 1997 Dec 1;100(11):2816-23. doi: 10.1172/JCI119829.

Abstract

Although angiotensin II type 2 (AT2) receptor has recently been cloned, its functional role is not well understood. We tested the hypothesis that selective activation of AT2 receptor causes vasodilation in the preglomerular afferent arteriole (Af-Art), a vascular segment that accounts for most of the preglomerular resistance. We microperfused rabbit Af-Arts at 60 mmHg in vitro, and examined the effect of angiotensin II (Ang II; 10(-11)-10(-8) M) on the luminal diameter in the presence or absence of the Ang II type 1 receptor antagonist CV11974 (CV; 10(-8) M). Ang II was added to both the bath and lumen of preconstricted Af-Arts. Ang II further constricted Af-Arts without CV (by 74+/-7% over the preconstricted level at 10(-8) M; P < 0.01, n = 7). In contrast, in the presence of CV, Ang II caused dose-dependent dilation; Ang II at 10(-8) M increased the diameter by 29+/-2% (n = 7, P < 0.01). This dilation was completely abolished by pretreatment with an AT2 receptor antagonist PD123319 (10(-7) M, n = 6), suggesting that activation of AT2 receptor causes vasodilation in Af-Arts. The dilation was unaffected by inhibiting either nitric oxide synthase (n = 7) or cyclooxygenase (n = 7), however, it was abolished by either disrupting the endothelium (n = 10) or inhibiting the cytochrome P-450 pathway, particularly the synthesis of epoxyeicosatrienoic acids (EETs, n = 7). These results suggest that in the Af-Art activation of the AT2 receptor may cause endothelium-dependent vasodilation via a cytochrome P-450 pathway, possibly by EETs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / pharmacology
  • Angiotensin II / metabolism
  • Angiotensin II / pharmacology*
  • Angiotensin Receptor Antagonists
  • Animals
  • Arachidonic Acid / metabolism*
  • Arterioles / drug effects
  • Arterioles / physiology
  • Benzimidazoles / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Endothelium, Vascular / drug effects
  • Humans
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / physiology
  • Large-Conductance Calcium-Activated Potassium Channels
  • Male
  • Norepinephrine / pharmacology
  • Perfusion
  • Potassium Channel Blockers
  • Potassium Channels / metabolism
  • Potassium Channels, Calcium-Activated*
  • Pyridines / pharmacology
  • Rabbits
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin / agonists
  • Receptors, Angiotensin / metabolism
  • Receptors, Angiotensin / physiology*
  • Tetraethylammonium / pharmacology
  • Tetrazoles / pharmacology
  • Vasoconstrictor Agents / metabolism
  • Vasoconstrictor Agents / pharmacology
  • Vasodilator Agents / metabolism
  • Vasodilator Agents / pharmacology*

Substances

  • Angiotensin Receptor Antagonists
  • Benzimidazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Imidazoles
  • Large-Conductance Calcium-Activated Potassium Channels
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium Channels, Calcium-Activated
  • Pyridines
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Tetrazoles
  • Vasoconstrictor Agents
  • Vasodilator Agents
  • Angiotensin II
  • PD 123319
  • Arachidonic Acid
  • 11,12-epoxy-5,8,14-eicosatrienoic acid
  • Tetraethylammonium
  • Cytochrome P-450 Enzyme System
  • 8,11,14-Eicosatrienoic Acid
  • candesartan
  • Norepinephrine