Isomers of 12-hydroxy-5,8,10,14-eicosatetraenoic acid reduce renin activity and increase water and electrolyte excretion.
A metabolite of arachidonic acid, 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), which can be formed either in the 12-S or 12-R configuration, has a diversity of biological actions and is generated by a number of tissues including the renal glomerulus and the vasculature. As the two isomers have been shown to differ in their effects on epithelial transport mechanisms and vascular responsiveness, we studied their direct effects on the rat isolated kidney, perfused for four consecutive 15-min clearance periods at a pressure of 90 mm Hg with a modified Krebs' buffer containing oncotic agents. At a dose of 20 nmol, both 12(S)- and 12(R)-HETE doubled urine volume (P less than .05) and sodium and potassium excretion rate in the first, postinjection clearance period. The effects of 12(R)-HETE were sustained during all three post-treatment clearance periods, whereas those of 12(S)-HETE were short-lived, excretion rates being similar to control values by the second post-treatment clearance period. At a higher dose of 40 nmol, 12(R)-HETE significantly reduced the usual rate of decline in glomerular filtration rate, characteristic of the rat isolated kidney, and caused an even greater initial increase in urine volume and sodium excretion rate than that achieved with 20 nmol. Renin concentration in the venous effluent was reduced immediately by 12(R)- and 12(S)-HETE (P less than .01), to approximately half of the control value. Again the response to the (R)-isomer was more prolonged. Thus, a 12-HETE of glomerular origin may alter renal function through direct and indirect tubular and hemodynamic effects.
Quilley
C P
CP
New York Medical College, Department of Pharmacology, Valhalla.
McGiff
J C
JC
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004573:Electrolytes / Q000652:urine; D005919:Glomerular Filtration Rate; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000378:metabolism; D013237:Stereoisomerism; D014655:Vascular Resistance / Q000187:drug effects
D004573:Electrolytes; D006893:Hydroxyeicosatetraenoic Acids; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D012083:Renin