20-Hydroxyeicosatetraenoic acid and renal function in Lyon hypertensive rats.

To evaluate the contribution of cytochrome P450 (CYP450) metabolites of arachidonic acid in the increased renal vascular resistance and blunted pressure-natriuresis response exhibited by Lyon hypertensive (LH) rats, the effects of an intrarenal infusion of 17-octadecynoic acid (3 microM), an inhibitor of the formation of epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids, were compared in 8-week-old LH and low blood pressure (LL) control rats. 17-Octadecynoic acid failed to affect renal function in LL rats. In contrast, it reduced renal vascular resistance and shifted the pressure-natriuresis relationship to lower pressures in LH rats. Blockade of thromboxane-endoperoxide (TP) receptors with GR 32191B prevented the renal vasodilator response to 17-octadecynoic acid but not its natriuretic action. Miconazole (1 microM), an inhibitor of epoxygenase activity, had no effect on renal function in LH rats. These results indicate that CYP450 metabolites of arachidonic acid, likely 20-hydroxyeicosatetraenoic acid, contribute to the resetting of the pressure-natriuresis relation in LH rats and that the renal vasoconstrictor effects of 20-hydroxyeicosatetraenoic acid in LH rats may be related to activation of TP receptors.

Cytochrome P-450 arachidonate metabolite inhibition improves renal function in Lyon hypertensive rats.

The present study evaluated the effects of miconazole, a selective inhibitor of epoxygenase activity, on renal hemodynamics and the pressure-natriuresis response of saline-drinking, uninephrectomized Lyon hypertensive (LH) and Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentration, 1 micromol/L) into the renal artery had no effect on the renal function of LL rats over a range of renal perfusion pressures (RPP) from 100 to 140 mm Hg. In contrast, miconazole lowered renal vascular resistance (RVR, 17.9 +/- 1.1 v 26.3 +/- 1.5 mm Hg/mL/min/g, P < .01) and increased urinary sodium excretion (6.4 +/- 1.2 v 4.2 +/- 0.8 micromol/min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrienoic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 32191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole into the renal artery in LH rats. GR 32191B decreased basal RVR and prevented the dilation induced by miconazole. It did not, however, alter its natriuretic effect. The renal metabolism of arachidonic acid was also compared in LH and LL rats. The production of epoxygenase metabolites was 25% lower in microsomes prepared from the renal cortex of LH versus LL rats. Miconazole (1 micromol/L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabolites of arachidonic acid may serve as a substrate for the formation of vasoconstrictor endoperoxides that interact with TP receptors in LH rats and contribute to the enhanced renal vascular tone but not the blunted pressure-natriuresis response.

Effects of L-type calcium channel activation on renal vascular resistances in the Lyon hypertensive rat.

This study aimed to evaluate the role of L-type calcium channels in the increased renal vascular resistance (RVR) of the Lyon hypertensive (LH) rat before and after normalization of its blood pressure (BP) by angiotensin-converting enzyme inhibition with perindopril. Concentration-response curves to Bay K 8644 (from 0.1 nM to 1 microM), a selective agonist of L-type calcium channels, were obtained in single-pass perfused kidneys isolated from groups of eight untreated or perindopril-treated (3 mg/kg/day, p.o., from age 3 to 7 weeks) LH and low-BP (LL) control rats. In untreated rats, the negative logarithm of the molar concentration of Bay K 8644 required to produce a half-maximal effect (pD2) values for Bay K 8644 did not differ between the two strains, whereas the maximal RVR response was higher in LH than in LL kidneys (28.0+/-4.9 vs. 12.9+/-0.8 mm Hg/ml/min/g, respectively). Perindopril normalized BP and RVR in LH rats and suppressed the interstrain differences in the maximal RVR responses (11.4+/-0.6 vs. 10.5+/-1.2 mm Hg/ml/min/g in LH and LL rats, respectively). These results demonstrate that LH rats exhibit an increased maximal contractile response to Bay K 8644 compared with LL controls, and that this alteration is not a primary defect because it disappears after normalization of BP level.

Cytochrome P-450-dependent arachidonate metabolites and renal functions in the Lyon hypertensive rat.

1. The present work aimed to assess the role of cytochrome P-450 (CP-450) metabolites of arachidonic acid such as epoxy-eicosatrienoic (EET) and hydroxyeicosatetraenoic acids (HETE) in the renal vasoconstriction and decreased natriuresis exhibited by genetically hypertensive (LH) rats of the Lyon strain. 2. The experiment was performed on single-pass isolated perfused kidney preparations from 8-week-old male LH rats and their low blood pressure (LL) controls. The effects of miconazole (an inhibitor of the formation of EET) and of 17-octadecynoic acid (17-ODYA, an inhibitor of both EET and HETE synthesis) were studied before and after stimulation of the kidneys with two noradrenaline (NA) infusions (65 and 110 nmol/L). 3. Unstimulated LH kidneys (n = 12) differed from LL (n = 12) by increased vascular resistance (RVR) and decreased glomerular filtration rate and urinary sodium excretion (UNaV). 4. Miconazole (1 mumol/L) did not change the functions of LH and LL unstimulated kidneys, but blunted the vasoconstrictor response to NA (110 nmol/L), the difference being significant in LH kidneys only (1.7 +/- 0.2 vs 3.6 +/- 1.2 mmHg/mL per min per g; P < 0.05). 5. Addition of 17-ODYA (3 mumol/L) to miconazole did not modify RVR in LH and LL kidneys or the response to NA infusion. On the contrary, it increased UNaV, the differences being significant in LH kidneys only (22.9 +/- 1.4 vs 17.5 +/- 1.4 mumol/min per g; P < 0.05 after NA 110 nmol/L). 6. It is suggested that EET may contribute to the elevated RVR and HETE to the reduced ability to excrete sodium, of LH kidneys.