Cytochrome P450-dependent arachidonate metabolism in renomedullary cells: formation of Na+K+-ATPase inhibitor.

The medullary portion of the thick ascending limb of the loop of Henle (mTALH) has one of the highest concentrations of Na+K+-ATPase found in mammalian tissues, reflecting the importance of this nephron segment in the regulation of extracellular fluid volume, as active sodium transport is driven by Na+K+-ATPase. We have isolated cells derived primarily from the mTALH of the outer medulla of rabbit kidney and have identified a cytochrome P450-dependent mono-oxygenase system which metabolizes arachidonic acid to two biologically active oxygenated peaks, each containing two or more products. One of the peaks potently inhibits cardiac Na+K+-ATPase and the other relaxes blood vessels. We report that formation of these oxygenated arachidonate metabolites is stimulated by arginine vasopressin (AVP) and salmon calcitonin (SCT). In mTALH cells obtained from rabbits made hypertensive by aortic constriction there was a selective increase in P1 and P2 formation compared to other renomedullary cells.