The renal medulla is sensitive to hypoxia, and a depression of medullary circulation, e.g. in response to angiotensin II (Ang II), could endanger the function of this zone. Earlier data on Ang II effects on medullary vasculature were contradictory. The effects of Ang II on total renal blood flow (RBF), and cortical and medullary blood flow (CBF and MBF: by laser‐Doppler flux) were studied in anaesthetised rats. Ang II infusion (30 ng kg⁻¹ min⁻¹i.v.) decreased RBF 27 ± 2 % (mean ±s.e.m.), whereas MBF increased 12 ± 2 % (both P < 0.001). Non‐selective blockade of Ang II receptors with saralasin (3 μg kg⁻¹ min⁻¹i.v.) increased RBF 12 ± 2 % and decreased MBF 8 ± 2 % (P < 0.001). Blockade of AT₁ receptors with losartan (10 mg kg⁻¹) increased CBF 10 ± 2 % (P < 0.002) and did not change MBF. Losartan given during Ang II infusion significantly increased RBF (53 ± 7 %) and decreased MBF (27 ± 7 %). Blockade of AT₂ receptors with PD 123319 (50 μg kg⁻¹ min⁻¹i.v.) did not change CBF or MBF. Intramedullary infusion of PD 123319 (10 μg min⁻¹) superimposed on intravenous Ang II infusion did not change RBF, but slightly decreased MBF (4 ± 2 %, P < 0.05). We conclude that in anaesthetised surgically prepared rats, exogenous or endogenous Ang II may not depress medullary circulation. In contrast to the usual vasoconstriction in the cortex, vasodilatation was observed, possibly related to secondary activation of vasodilator paracrine agents rather than to a direct action via AT₂ receptors.

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague–Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.

Summary: The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). Ren‐2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II‐dependent hypertension. Soluble epoxide hydrolase was inhibited using cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy]benzoic acid (c‐AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham‐operated normotensive transgene‐negative Hannover Sprague‐Dawley (HanSD) rats served as controls. When applied in TGR subjected to 5/6 NX, c‐AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ‐protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham‐operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII‐dependent hypertension, and that restoration of intrarenal availability of EETs using long‐term c‐AUCB treatment exhibits substantial renoprotective actions.