Cytochrome P-450 Pathway in Renal Function of Normal Rats and Rats with Bilateral Ureteral Obstruction

Abstract

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) are decreased and mean arterial pressure (MAP) and renal vascular resistance (RVR) are increased after unilateral release of bilateral ureteral obstruction (BUO) of 24 hr duration. An imbalance between vasoconstrictor and vasodilator substances may explain these hemodynamic changes. We examined the role of the cytochrome P-450 pathway in this setting. After unilateral release of BUO, GFR and ERPF (ml/min/kg body wt) were significantly lower in these rats than in sham-operated rats (SOR) 1.14 ± 0.09 vs 6.7 ± 0.5 and 3.09 ± 0.2 vs 23.5 ± 3.4, respectively). BUO rats had significantly higher MAP (mm Hg) and RVR (mm Hg/ml/min/kg body wt) than SOR (155 ± 5 vs 120 ± 1 and 29.1 ± 1.7 vs 3.2 ± 0.4, respectively). SOR given 3-methylcholanthrene and β-naphthoflavone to induce the cytochrome P-450 system had no significant changes in renal function, RVR, or MAP. SOR given ketoconazole to inhibit the cytochrome P-450 system had significantly lower GFR (4.8 ± 0.5) than temporal control rats without significant changes in ERPF (21.2 ± 4.6), MAP (127 ± 6), or RVR (4.2 ± 0.9). Rats with BUO given ketoconazole had lower but not significantly different GFR (0.84 ± .1) and ERPF (2.61 ± .4) than BUO controls. Values for MAP did not differ in BUO rats given ketoconazole versus BUO temporal controls. BUO rats given 3-methylcholanthrene and β-naphthoflavone had significantly higher GFR and ERPF (2.01 ± 0.24 and 6.66 ± 1.36, respectively) and significantly lower RVR (14.7 ± 3.9) than control rats with BUO; MAP was unchanged. Microsomal preparations from indomethacin-treated isolated kidneys obtained from BUO rats when compared with preparations obtained from SOR had significantly less activity of the P-450 cytochrome-dependent ω/ω-1 hydroxylase (103 ± 6 vs 130 ± 7 pmol hydroxyeicosatetraenoic acids produced per mg of protein/min, P < 0.02) and the P-450 cytochrome-dependent epoxygenase (11 ± 0.3 vs 30 ± 4 pmol lipoxyeicosatrienoic acids produced per mg of protein/min, P < 0.04). Indomethacin-treated microsomes prepared from kidneys of BUO rats converted significantly less ¹⁴C-arachidonic acid through the P-450-dependent hydroxylases (13.5 ± 0.8 vs 17.0 ± 0.1% of ¹⁴C-arachidonic acid converted to 19- and 20-hydroxyeicosatetraenoic acids, P < 0.02), and significantly less through the epoxygenases (1.4 ± 0.4 vs. 3.8 ± 0.5% of ¹⁴C-arachidonic acid converted to epoxyeicosatrienoic acids). The data suggest that a metabolite(s) of the cytochrome P-450 pathway modifies renal function in vivo in such a way that inhibition or activation of the cytochrome P-450 system is reflected in decreases or increases in GFR and ERPF in BUO rats without affecting mean arterial pressure. We conclude that the cytochrome P-450 pathway plays an important role in renal hemodynamics of normal rats and rats with BUO of 24 hr duration. [P.S.E.B.M. 1992, Vol 201]