Paradoxical endogenous synthesis of a coronary dilating substance from arachidonate.
Isolated bovine, canine, and human coronary arteries exhibited dose dependent contractions to prostaglandin (PG) E2 and F2alpha (50 ng/ml to 10mug/ml). The ED50 value for both PGE2 and PGF2alpha was 500 ng/ml in the bovine and human coronary arteries. Paradoxically, although PGE2 and gf2alpha are vasoconstrictors, administration of their precursor, arachidonate (100 ng/ml to 10 mug/ml) caused relaxation of the bovine, canine and human coronary arteries. This observation suggests that arachidonate is not being converted by the coronary PG synthetase to PGE2 or PGF2alpha. However, the arachidonate induced coronary relaxation was inhibited by pretreatment with PG synthetase inhibitors, indomethacin, meclofenemate and aspirin. Indomethacin addition to the strips previously relaxed by arachidonate caused contraction. In contrast to other PGs (E2 and F2alpha), PGE1 (10 ng/ml to 10 mug/ml) caused dose dependent relaxation of the bovine coronary arteries (ED50 = 100 ng/ml). Indomethacin induced further relaxation of the blood vessels previously relaxed by PGE1. Since PGE1 cannot arise from arachidonate, the arachidonate coronary dilation and reversal by indomethacin must be independent of PGE1 formation. Linolenate (100 ng/ml to 10 mug/ml) and oleate (100 ng/ml to 10 mug/ml) also caused relaxation of the bovine coronary blood vessels both before and after indomethacin, thereby eliminating a direct non-specific fatty acid effect as the cause of the arachidonate relaxation. These results suggest that in isolated coronaries, arachidonate undergoes a novel conversion, possibly by PG synthetase, to a dilating substance which exerts different contractile effects than exogenously administered PGE2, PGF2alpha and PGE1.
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008042:Linolenic Acids / Q000494:pharmacology; D008469:Meclofenamic Acid / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009829:Oleic Acids / Q000494:pharmacology; D011458:Prostaglandins E / Q000008:administration & dosage / Q000494:pharmacology*; D011460:Prostaglandins F / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000096:biosynthesis*
D001095:Arachidonic Acids; D008042:Linolenic Acids; D009829:Oleic Acids; D011458:Prostaglandins E; D011460:Prostaglandins F; D014665:Vasodilator Agents; D008469:Meclofenamic Acid; D001241:Aspirin; D007213:Indomethacin