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
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Research Support, Non-U.S. Gov't
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives
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8,11,14-Eicosatrienoic Acid / pharmacology
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Angiotensin II / metabolism
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Angiotensin II / pharmacology*
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Angiotensin Receptor Antagonists
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Animals
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Arachidonic Acid / metabolism*
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Arterioles / drug effects
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Arterioles / physiology
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Benzimidazoles / pharmacology
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Biphenyl Compounds
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism*
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Endothelium, Vascular / drug effects
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Humans
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Imidazoles / pharmacology
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In Vitro Techniques
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Kidney Glomerulus / blood supply
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Kidney Glomerulus / physiology
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Large-Conductance Calcium-Activated Potassium Channels
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Male
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Norepinephrine / pharmacology
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Perfusion
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Potassium Channel Blockers
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Potassium Channels / metabolism
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Potassium Channels, Calcium-Activated*
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Pyridines / pharmacology
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Rabbits
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin / agonists
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Receptors, Angiotensin / metabolism
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Receptors, Angiotensin / physiology*
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Tetraethylammonium / pharmacology
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Tetrazoles / pharmacology
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Vasoconstrictor Agents / metabolism
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Vasoconstrictor Agents / pharmacology
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Vasodilator Agents / metabolism
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Vasodilator Agents / pharmacology*
Substances
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Angiotensin Receptor Antagonists
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Benzimidazoles
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Biphenyl Compounds
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Cytochrome P-450 Enzyme Inhibitors
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Imidazoles
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Large-Conductance Calcium-Activated Potassium Channels
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Potassium Channel Blockers
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Potassium Channels
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Potassium Channels, Calcium-Activated
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Pyridines
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin
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Tetrazoles
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Vasoconstrictor Agents
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Vasodilator Agents
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Angiotensin II
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PD 123319
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Arachidonic Acid
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11,12-epoxy-5,8,14-eicosatrienoic acid
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Tetraethylammonium
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Cytochrome P-450 Enzyme System
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8,11,14-Eicosatrienoic Acid
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candesartan
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Norepinephrine