Effect of heparin on cortical adenylate cyclase activity and on urinary excretion of 3',5'-adenosine monophosphate in rat.
The effect of heparin on the renal adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) system was studied in vitro in renal cortical membrane preparations and in vivo on hormone-stimulated nephrogenous cAMP excretion. The heparin dose dependently inhibited basal and hormone-stimulated rat renal cortical AC activity. The heparin concentration causing 50% inhibition was 45 micrograms/ml for the basal activity and 33 and 85 micrograms/ml for the parathyroid hormone (PTH) and glucagon-stimulated activities, respectively. PTH- and glucagon-stimulated AC activity was inhibited by the non-antithrombotic heparinoid, N-acetylated N-disulfated heparin, but not by a structural analogue of heparin, dextran sulfate. Forskolin- and Mn2(+)-stimulated AC activity was also inhibited by heparin, while NaF stimulated activity was resistant to it. Increasing Mg2+ concentration did not affect the inhibition of basal and PTH-stimulated AC activity by heparin. The urinary excretion of nephrogenous cAMP was determined in parathyroidectomized rats treated with glucagon (group 1), glucagon and heparin (group 2), heparin alone (group 3) and control (group 4). Glucagon induced a significant increase in nephrogenous cAMP excretion. The urinary excretion of nephrogenous cAMP, however, was significantly lower in group 2 (receiving glucagon and heparin) than in group 1 (receiving glucagon alone). There were no significant changes in nephrogenous cAMP in groups 3 and 4. These results suggest that heparin is a potent inhibitor of renal AC in vivo and in vitro. Taken together, our data point out the catalytic unit of the AC system as the site of heparin interaction.
Katzir
Z
Z
Nephrology Services, Hadassah University Hospital, Jerusalem, Israel.
Wald
H
H
Rubinger
D
D
Popovtzer
M M
MM
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000652:urine*; D016264:Dextran Sulfate; D003911:Dextrans / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology*; D008274:Magnesium / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D012969:Sodium Fluoride / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D003911:Dextrans; D010281:Parathyroid Hormone; D005576:Colforsin; D012969:Sodium Fluoride; D006493:Heparin; D005934:Glucagon; D016264:Dextran Sulfate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008274:Magnesium