8-11-14-eicosatrienoic-acid and candesartan

The effects of blockade of the renin-angiotensin system on the renal metabolism of arachidonic acid (AA) were examined. Male Sprague-Dawley rats were treated with vehicle, captopril (25 mg x kg(-1) x day(-1)), enalapril (10 mg x kg(-1) x day(-1)), or candesartan (1 mg x kg(-1) x day(-1)) for 1 wk. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) by renal cortical microsomes increased in rats treated with captopril by 59 and 24% and by 90 and 58% in rats treated with enalapril. Captopril and enalapril increased 20-HETE production in the outer medulla by 100 and 143%, respectively. In contrast, blockade of ANG II type 1 receptors with candesartan had no effect on the renal metabolism of AA. Captopril and enalapril increased cytochrome P-450 (CYP450) reductase protein levels in the renal cortex and outer medulla and the expression of CYP450 4A protein in the outer medulla. The effects of captopril on the renal metabolism of AA were prevented by the bradykinin-receptor antagonist, HOE-140, or the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results suggest that angiotensin-converting enzyme inhibitors may increase the formation of 20-HETE and EETs secondary to increases in the intrarenal levels of kinins and NO.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arachidonic Acid; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Desoxycorticosterone; Enalapril; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Kidney; Kidney Cortex; Kidney Medulla; Male; Microsomes; Mixed Function Oxygenases; NADPH-Ferrihemoprotein Reductase; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Spironolactone; Tetrazoles

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