11-12-epoxy-5-8-14-eicosatrienoic-acid and candesartan

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.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Arachidonic Acid; Arterioles; Benzimidazoles; Biphenyl Compounds; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Endothelium, Vascular; Humans; Imidazoles; In Vitro Techniques; Kidney Glomerulus; Large-Conductance Calcium-Activated Potassium Channels; Male; Norepinephrine; Perfusion; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Calcium-Activated; Pyridines; Rabbits; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetraethylammonium; Tetrazoles; Vasoconstrictor Agents; Vasodilator Agents