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.
Département de Physiologie et Pharmacologie Clinique, CNRS ESA 5014, Faculté de Pharmacie, Lyon, France.
I
I
Messer-Létienne
N
N
Bernard
D
D
Benzoni
J
J
Sassard
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007677:Kidney Function Tests; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium