Cardiac and Renal Prostaglandin I<sub>2</sub>: <i>BIOSYNTHESIS AND BIOLOGICAL EFFECTS IN ISOLATED PERFUSED RABBIT TISSUES</i>

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

doi:10.1172/JCI108998

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

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

Published March 1, 1978 - More info

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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-PGF_1α, 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.