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We studied the metabolism and cardiac actions of a polar aminocardenolide, 3-beta-O-(4-amino-4,6-dideoxy-beta-D-galactopyranosyl) digitoxigenin (ASI-222), in conscious, chronically instrumented dogs and compared the cardiac actions of this compound with those of digoxin. Chloroform-soluble metabolites and the excretion patterns of ASI-222 in urine and feces were identified and measured using thin-layer chromatography. The deaminated metabolite of ASI-222 appeared both in the urine and the feces together with the genin, digitoxigenin and the parent drug which constituted the majority of the radioactivity excreted. There was a secondary rise in the plasma concentration of ASI-222 starting 2 hr after the i.v. administration, which strongly suggests its enterohepatic recycling. The secondary increase in the plasma concentration was not seen in the dogs receiving digoxin. ASI-222 produced increases in cardiac contractility and systolic blood pressure which were more rapid in onset and shorter in duration than those produced by an equimolar dose of digoxin. Amplitudes of these physiologic responses to these two compounds in conscious dogs were approximately 2 times higher than the effects previously reported to similar doses in anesthetized dogs.

The function of the nephron, the anatomical unit of the kidney, is segmented; at least 12 segments have been identified that differ in their morphology, transport properties and hormonal responsiveness1. 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 tissues2, reflecting the importance of this nephron segment in the regulation of extracellular fluid volume, as active sodium transport is driven by (Na++ K+)ATPase1. Here, in cells derived primarily from the mTALH of the outer medulla of rabbit kidney, we have identified a cytochrome P450-dependent monooxygenase system3which metabolizes arachidonic acid to two biologically active oxygenated products; one of the products inhibits (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).