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Unclipping the Goldblatt hypertensive rat lowers the blood pressure by cells in the renal papilla, the renomedullary interstitial cells (RIC), secreting a hormone that is part of a vasodilator system. A vasodilator, termed medullipin I, can be extracted from the renal papilla. Medullipin I and the renal venous effluent following unclipping have identical biologic properties. Medullipin I appears to be the agent secreted by the kidney following unclipping. Both medullipin I and the renal venous effluent must traverse the liver to be active. Medullipin I is converted in the liver to its active form, medullipin II. The blood pressure-lowering effect of both medullipin I and the renal venous effluent after unclipping are blocked by SKF 525A, the inhibitor of cytochrome P- 450. The relation of the kidney to the liver was tested using the rate of decline of the blood pressure after unclipping as an index of the endocrine antihypertensive function of the kidney − acceleration of the decline being considered as increased function, decrease of the decline as decreased function. Five compounds: BW755C, phenobarbital, ketoconazole, eicosatetraynoic acid (ETYA) and butylated hydroxytoluene (BHT), and two manipulations: uretero-caval anastomosis (UCA) and removal of the liver from the circulation were used followed by unclipping. BW755C, inhibitor of both cyclo-oxygenase and lipoxygenase, potentiated the antihypertensive function to a maximum. It is reasoned that inhibition of the first two pathways of arachidonic acid metabolism potentiates the third pathway, the cytochrome P−450 pathway. BW755C and phenobarbital maintained their potentiation after UCA indicating that their action is not mediated by volume loss. Both lost their effect when the liver was removed from the circulation indicating the necessity of the hepatic action. Inhibitors of cytochrome P-450, ketoconazole and ETYA, prevented the decline of the blood pressure after unclipping indicating an involvement of cytochrome P-450-dependent system. BHT blocked the decline of the blood pressure after unclipping supporting the existence of an oxidative step in the activation of medullipin I to medullipin. II. Medullipin I could be a product of arachidonic acid metabolism that is converted to medullipin II by the cytochrome P-450-dependent enzyme system of the liver.