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Perfusion of isolated normal rat kidneys with blood at elevated blood pressure (180-200 mm Hg) followed by perfusion of the renal perfusate through an isolated normal rat liver under venous pressure yielded in the plasma of the hepatic effluent a vasodepressor lipid having the chromatographic and biological characteristics of medullipin II. These findings support the view that medullipin II is the final product of the renohepatic axis of blood pressure control.

Perfusion of normal rat kidneys with 5% human albumin in a balanced salt solution bubbled with oxygen yielded medullipin I (Med I) in the renal venous effluent. The presence of Med I in the renal venous effluent has been established by thin-layer chromatography, by the type of vasodepressor effect when injected intravenously as a bolus into the hypertensive rat, by inhibition of the vasodepressor effect of the renal venous effluent by Tween 20 and SKF 525A (proadifen, inhibitor of cytochrome P-450), and by removal of the liver from the circulation (a procedure that inhibits extracted Med I). Med I so derived lowered blood pressure of spontaneously hypertensive rats when injected into the stomach by an indwelling tube or when given by mouth. The lowering of blood pressure was attended by no change in cardiac output and no change in heart rate. Med I given by mouth to the spontaneously hypertensive rat is a vasodilator that suppresses sympathetic tone, acting in the same way as Med I extracted from renal papillae and given intravenously. Importantly, the antihypertensive action was demonstrated in the spontaneously hypertensive rat, a model of hypertension considered to mimic idiopathic or essential hypertension of humans. Med I is a promising therapeutic agent for hypertension.

The antihypertensive neutral renomedullary lipid, derived from the renal papilla, causes a vasodepressor effect when injected into a peripheral vein, such as the inferior vena cava, after a lag period of 1 to 2 minutes. The blood pressure tracing is skewed (cuplike effect). The lag period is significantly reduced after injection of the antihypertensive lipid into the portal vein. The vasodepressor configuration (cuplike) is the same whether the lipid is injected into the vena cava or portal vein. Removal of the liver from the circulation prevents the depressor effect. Thus, passage through the liver is essential for antihypertensive lipid activity. Renoportal shunting of blood potentiates the antihypertensive function of the kidney after unclipping in the one-kidney, one clip hypertensive rat. Lack of a hepatic circulation prevents the antihypertensive function of the kidney after unclipping. Antihypertensive neutral renomedullary lipid and the renal venous effluent after unclipping have the same biological behavior. We conclude that antihypertensive neutral renomedullary lipid is a promolecule, the putative prohormone of the renal papilla and its renomedullary interstitial cells. The liver converts the antihypertensive prohormone of the kidney to an active antihypertensive substance. A renohepatic axis of blood pressure control appears to exist.

Two antihypertensive lipids can be derived from the renal papilla, the antihypertensive polar (APRL) and the antihypertensive neutral (ANRL) renomedullary lipid. The renal venous effluent of the unclipped kidney contains both ANRL and APRL. This effluent lowers the arterial pressure (AP) of the normal rat when infused i.v. As it lowers the AP the heart rate (HR) and sympathetic nerve activity (SNA) are depressed. ANRL infused i.v. also lowers HR and SNA as it depresses the AP. Conversely, APRL elevates HR and SNA as it lowers the AP. Thus, of the two lipids in the renal venous effluent after unclipping, ANRL appears to be dominant. APRL, however, in the renal venous effluent could potentiate the action of ANRL. The net effect of these observations is to support the view that ANRL is an antihypertensive hormone liberated by the kidney after unclipping. The renomedullary interstitial cells (RIC) degranulate after unclipping. ANRL can be derived from these cells. Thus, the RIC, cells known to exert an endocrine-type antihypertensive function, may well be the source of ANRL in the renal venous effluent after unclipping. The hormonal action of ANRL appears as a major cause of the lowering of the AP after unclipping. It is not known what factors modulate the RIC endocrine system. There is a suggestion that angiotensin may be one of these factors based on the ineffectiveness of these cells toward retarding hypertension when the circulating plasma angiotensin level is high, and their effectiveness when the circulating plasma angiotensin level is low.

1-0-alkyl ethers of phosphatidylcholine having an acetoyl in the second position were derived from fresh renal tissue. The main ether so derived had a 16:0 chain. The C16:0 alkyl ether was synthesized de novo. The renally derived and the synthetic ether exerted a similar and powerful antihypertensive action in hypertensive rabbits when given orally in divided doses. This action was prolonged, requiring more than 60 hours after the last input of the compound for recovery of the arterial pressure. As these ethers exerted their antihypertensive action, there was no evidence of adverse effects. Noteworthy was the failure of these depressor compounds to cause renin release. Diuresis-kaliuresis did not occur. A suggestion of sodium retention was noted.

Antihypertensive polar renomedullary lipid (APRL), a conglomerate of 1-0-alkyl-2-acetoyl-glycero-3-phosphocholine analogs, ws tested in 4- to 6-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats using microcirculatory techniques. APRL (0.5 ug/ml), when added to the solution bathing the cremaster muscle, caused significant changes in the diameter, red blood cell velocity, and blood flow in both groups of rats, for arterioles and venules. Arteriolar changes in diameter were significantly greater (p less than 0.05) in SHR than in WKY. Micropipette application of APRL indicated a dose-dependent response for arterioles and venules in both groups. Moreover, the potent nature of this compound was demonstrated. Relative potency of APRL given intravenously was tested in 10- to 12-week-old SHR and WKY. The response curve was shifted significantly to the left for SHR (p less than 0.01). APRL interaction with known controllers of blood flow was tested in SHR. Blockade of cholinergic, beta-adrenergic, or histaminergic receptors did not inhibit APRL action. blockade of prostaglandin or bradykinin synthesis did not prevent depression of blood pressure by APRL. APRL (40 ug/kg) inhibited (p less than 0.001) the pressor response to norepinephrine (1-10 ug/kg) but not to angiotensin II (4 ug/kg). The present study provides direct evidence that APRL is a vasodilator with increased potency in SHR hypertension. The acute vascular response may be mediated by alpha-adrenergic antagonism.

Two antihypertensive lipids can be extracted from fresh renal medulla. One is polar (the antihypertensive polar renomedullary lipid, or APRL) and the other is nonpolar (the antihypertensive neutral renomedullary lipid, or ANRL). APRL and ANRL differ in their biologic activities: APRL in bolus intravenous injections causes a very rapid decline in the arterial pressure (AP) while ANRL, after a lag of 2 minutes, causes a slower decline in AP. APRL increases heart rate and sympathetic activity. ANRL decreases heart rate and sympathetic activity. ANRL appears to convert to APRL, under certain in vitro circumstances, suggesting that the structure of the two molecules is related. ANRL and APRL appear in the renal venous effluent after unclipping; biologically, ANRL seems dominant. The renal venous effluent of the unclipped isolated kidney lowers the HR and sympathetic activity of the normal rat. Unclipping degranulates the renomedullary interstitial cells (RIC). The antihypertensive effect of unclipping appears due to the secretion of ANRL and APRL by the kidney. It is concluded that ANRL seems to be the antihypertensive hormone of the RIC.