Role of prostaglandin cyclooxygenase and cytochrome P450 pathways in the mechanism of natriuresis which follows hypertonic saline infusion in the rat.
OBJECTIVE
The prostaglandin cyclooxygenase (COX) and P450 cytochrome (CYP450) pathways of arachidonic acid metabolism are functionally interrelated and both engaged in control of sodium excretion; the study focused on their contribution to the natriuresis which follows hypertonic saline infusion in the rat.


METHODS
In anaesthetized rats, clearance studies were conducted, supplemented with laser-Doppler measurements of the cortical and medullary blood flow (CBF, MBF), and measurement of medullary tissue admittance (Y), an index of interstitial ion concentration.


RESULTS
Indomethacin (Indo), 5 mg kg(-1) i.v. paradoxically enhanced the natriuresis secondary to intra-aortic suprarenal 5% saline load, further increasing sodium excretion by 385 +/- 73% (P < 0.01). After acute clotrimazole, 10 mg kg(-1) i.v. an inhibitor of CYP450 epoxygenase, the increase in natriuresis was smaller and did not differ from that observed after the drug's ethanol solvent. In rats pre-treated with clotrimazole for 3 days, hypertonic saline loading increased sodium excretion (U(Na)V) to 0.94 +/- 0.22 micromol min(-1) , compared with a significantly greater (P < 0.05) increase to 2.76 +/- 0.48 micromol min(-1) measured in untreated controls. Indo increased U(Na)V twofold, similarly in the clotrimazole and in the control group; in the absence or presence of clotrimazole treatment, COX blockade significantly decreased MBF and increased Y.


CONCLUSIONS
The data indicate that blockade of the CYP450 epoxygenase significantly impairs excretion of sodium in rats acutely loaded with hypertonic NaCl solution. The paradoxical post-Indo natriuresis is preserved in clotrimazole treated rats, which speaks against the role of CYP450 pathway in the response.
Kompanowska-Jezierska
E
E
Laboratory of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawiñskiego 5, 02-106 Warsaw, Poland.
Walkowska
A
A
Sadowski
J
J
D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D007261:Infusions, Intra-Arterial / Q000379:methods; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D009318:Natriuresis / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage
D011453:Prostaglandins; D012462:Saline Solution, Hypertonic; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases; D003022:Clotrimazole; D007213:Indomethacin