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The renal regulatory role of cytochrome P450 dependent metabolites of arachidonic acid (AA), vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), was examined in anaesthetised rats. We measured renal artery flow (RBF), cortical (CBF) and medullary (MBF) perfusion (laser-Doppler) and medullary tissue nitric oxide (NO, selective electrode), after non-selective inhibition of CYP-450 pathway with 1-aminobenzotriazole (ABT, 10 mg/kg i.v.) or after selective inhibition of 20-HETE synthesis with HET0016 (Taisho Co, Yoshino-cho, Japan), infused into renal artery at 0.3 mg/kg/h or into renal medulla at rates increasing from 0.15 to 1.5 mg/kg/h. ABT caused significant (by 13.7%) decrease in RBF without changing MBF. Renal arterial HET0016 increased MBF (not RBF or CBF) from 152±12 to 174±12 perfusion units (+16%, P<0.001), while medullary tissue nitric oxide was significantly increased (P<0.001). After renal medullary HET0016, renal perfusion indices were significantly higher than after HET0016 solvent (ß-cyclodextrin). Total renal blood flow seems to be under vasodilator control of EETs whereas renal medullary perfusion under tonic suppression by 20-HETE. The data document, for the first in the whole kidney studies, the functional antagonism of 20-HETE and NO.
Selective ligands of both Ang II receptor types are needed to study their relative importance or possible interaction in the control of normal or elevated arterial blood pressure (BP); the knowledge of the role of AT2 is still limited. We examined if a newly synthetised (A. Lipkowski) agonist of vasodilator AT2 receptors (LKP) would affect increase in BP (7 mmHg) which developed during a 10-day exposure of Wistar rats to high-salt diet (HS, 4% Na w/w). With LKP treatment (48 mg/kg/24 h orally) BP increased more (31 mm Hg) than in untreated rats. With combined treatment: LKP + AT1 receptor antagonist (oral losartan (Los), 15 mg/kg/24 h; gift from Adamed Company, Pieńków, Poland), BP increased 19 mm Hg. At the end of studies the response of the total renal blood flow (RBF, Transonic probe) and cortical blood flow (CBF, laser-Doppler superficial probe) to intrarenal infusion of acetylcholine (Ach, 5-10 µg/kg/h) or norepinephrine (NE, 10- 30 µg/kg/h) was determined. In untreated HS rats intrarenal Ach increased RBF 17%, whereas in HS+LKP and HS+LKP+Los groups it decreased RBF 1 and 2%, respectively (NS). LKP treatment did not modify decreases in RBF after NE but limited the decrease in CBF. We conclude that stimulation of AT2 receptors did not effectively oppose the increase in BP elevation, which follows increased Na intake in Wistar rats. At high AT2 activity the renal vascular bed lost its ability to dilate, which suggests a state of substantial basal vasodilation; the ability to constrict was preserved. This suggests that intrarenal microvasculature is more responsive to AT2 stimulation compared to other peripheral vessels, as it is also more responsive to stimulation of vasoconstrictor AT1 species. Supported by the Polish Ministry of Science and Higher Education (grant No. N N 401225634).
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