The metabolism of endothelin-1 and big endothelin-1 by the isolated perfused kidney of the rabbit.
The activity of human big endothelin-1 (bET-1) or endothelin-1 (ET-1) was investigated in the isolated perfused kidney of the rabbit. In some experiments the effluent superfused a rabbit jugular vein (RbJV) or rat colon (RC), and bolus doses of bET-1 or ET-1 were administered either directly over the tissue (OT) or through the kidney (TK). When injected OT, the contractile responses of the RbJV to ET-1 were > or = 100-200 times more than those to bET-1. However, at least 10 times the ET-1 dose given OT was needed TK to produce an equivalent contraction of the RbJV, showing that ET-1 was being inactivated or removed by the kidney. Injections of bET-1 TK produced increases in perfusion pressure of a magnitude 1/25th of those of ET-1. In some experiments administration of bET-1 TK was associated with the release into the perfusate of an ET-1-like factor that contracted the RbJV, but not the RC (used to detect any angiotensin II release), at doses that had little effect when administered OT, suggesting that bET-1 was being activated by the kidney. Phosphoramidon (10 microM) infused TK blocked (92 +/- 1% inhibition) the renal responses to bET-1 and reduced the overflow of ET-1-like material onto the tissues without affecting ET-1-induced renal vasoconstriction. Incubation of bET-1 with rabbit renal cortical microsomes (100 micrograms protein) resulted in the generation of ET-1-like activity, as assessed by bioassay, which was inhibited by phosphoramidon (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Kaw
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S
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, England.
Warner
T D
TD
Vane
J R
JR
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D019332:Endothelin-1; D016232:Endothelins / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011817:Rabbits; D013347:Subcellular Fractions / Q000378:metabolism
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; C008890:phosphoramidon