Cardiac and Renal Prostaglandin I₂: BIOSYNTHESIS AND BIOLOGICAL EFFECTS IN ISOLATED PERFUSED RABBIT TISSUES

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Abstract

Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I2. The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI2, 6-keto-PGF1α, in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH2, but not dihomo-γ-linolenic acid and its endoperoxide PGH1, serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI2 but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE2; while the heart converts endogenous arachidonate primarily into PGI2. Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI2 by the heart, and of PGE2 by the kidney. Cardiac PGI2 administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH2 causes an increase in coronary resistance without apparent cardiac conversion to PGI2. The perfused heart rapidly degrades most of the exogenous endoperoxide probably into PGE2, while exogenous PGI2 traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH2 in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI2 synthetase, whereas the more lipid soluble precursor arachidonic acid (exogenous or endogenous) penetrated to the cyclooxygenase, which apparently is tightly coupled to the PGI2 synthetase.

Authors

Philip Needleman, Sue D. Bronson, Angela Wyche, Mark Sivakoff