Renomedullary antihypertensive function in accelerated (malignant) hypertension. Observations on renomedullary interstitial cells.

The antihypertensive function of the renal medulla was tested on accelerated (malignant) hypertension of the rabbit. A procedure for the development of accelerated hypertension of the rabbit of lethal proportions within 3 wk was established. This procedure consisted of the application of a rigid clip with a fixed and unyielding gap to the left renal artery and removal of the right kidney. Three additional manipulations, other than simple nephrectomy, were performed on the right kidney after application of the rigid clip to the left renal artery. These were: (a) a sham operation, (b) removal of the kidney and separation of the renal cortex and its autotransplantation in a fragmented state, and (c) removal of the kidney and separation of the renal medulla and its autotransplantation in a fragmented state. After the sham-operated kidney and autotransplanted renal medulla, the standardized accelerated hypertension did not develop, whereas after autotransplanted renal cortex it did. After a period of protection against accelerated hypertension, removal of either the sham-operated kidney or the renomedullary transplants was followed by a prompt rise in arterial pressure and death of the animal. Thus, the antihypertensive action of renomedullary tissue was similar to that of the whole kidney. The main cell type noted in the protective renomedullary transplants had the microscopic characteristics of the lipid-containing interstitial cells. These cells occurred in clusters, often were near capillaries, and appeared hyperplastic. It is suggested that the renomedullary interstitial cell is the most eligible cell for exertion of the renomedullary antihypertensive action. Since vasoactive lipids are extractable from the renal medulla and its interstitial cells, the hypothesis that interstitial cells secrete antihypertensive substance(s) is attractive.

Short-term therapy of severe hypertension. Hemodynamic correlates of the antihypertensive response in man.

Ten severely hypertensive patients were randomized into five treatment groups: vasodilators; vasodilators plus diuretics; sympatholytics; sympatholytics plus diuretics; and sympatholytics, diuretics, and vasodialtors. Cardiac index was measured daily by echocardiography, and total peripheral resistance (TPR) calculated. Plasma renin activity (PRA) and creatinine clearance (CCR) were measured every other day. There was no difference in antihypertensive response. Seven patients, whose initial TPR was high, responded to treatment with a fall in TPR, regardless of regimen. Three patients with a high pretreatment cardiac index responded with a fall in cardiac index. Changes in TPR or cardiac index were not related to changes in CCR. There was no correlation between PRA and either blood pressure or TPR. It is concluded that the pretreatment hemodynamic status of severely hypertensive patients is the major determinant of the hemodynamic response to antihypertensive therapy.

The liver converts the antihypertensive hormone of the kidney. The renohepatic axis.

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.

The antihypertensive function of the kidney. Its elucidation by captopril plus unclipping.

Unclipping the one-kidney, one-clip hypertensive rat during a free flow of urine caused the blood pressure to return to normal levels within about 3 hours. We found that administration of captopril plus unclipping caused the blood pressure to return to normal in minutes (17 +/- 4). Ureterocaval anastomosis plus captopril plus unclipping also caused the blood pressure to return to normal in minutes (8.8 +/- 2). Thus, the potentiation of the drop in blood pressure does not seem to be due to a volume effect. Administration of indomethacin and aprotinin did not prevent a rapid decline of the blood pressure after unclipping, but the decline was less rapid than that occurring after captopril and unclipping, which suggests that prostaglandin may have some effect on this mechanism. Saralasin administration did not potentiate the antihypertensive action of captopril plus unclipping. Chemical papillectomy prevented the drop in blood pressure after unclipping. The bolus dose of captopril to the hypertensive rat often caused a transient depressor effect resembling that due to the antihypertensive neutral renomedullary lipid, which suggests secretion of this lipid into the blood. The renomedullary interstitial cells accumulated large lipid granules after captopril administration. These cells also degranulated after unclipping. These findings are consistent with the hypothesis that the renal papilla secretes an antihypertensive hormone after unclipping. At present, antihypertensive neutral renomedullary lipid is the main putative hormone.

Alkyl ether analogs of phosphatidylcholine are orally active in hypertensive rabbits.

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.

Analogs of phosphatidylcholine: alpha-adrenergic antagonists from the renal medulla.

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.

Degranulation of renomedullary interstitial cells during reversal of hypertension.

It was demonstrated earlier that the renal venous effluent of one-kidney, one clip hypertensive rats contained a vasodepressor lipid resembling the antihypertensive neutral renomedullary lipid (ANRL), following unclipping and as the arterial pressure (MAP) was lowered. Consequently, the sham-unclipped (clip-intact) and the unclipped kidney (CK and UCK) were studied by electronmicroscopy and morphometrically (Weibel's techniques). Renomedullary interstitial cells (RIC) of the CK had abundant granules. The collecting duct (CD) had tall lining cells containing pale granules and displayed intercellular channels. Following unclipping, the RIC degranulated and the CD cells became flattened, lost their pale granules, and the intercellular channels disappeared as the MAP decreased. These changes were evident by EM appearance and volume density measurements. The renopapillary changes occurred as the kidney secreted the ANRL-like substance into the blood.

Medullipin system. Generation of medullipin II by isolated kidney-liver perfusion.

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.

Antihypertensive action of medullipin I given by mouth.

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.

Antihypertensive polar and neutral renopapillary lipids. Which is a hormone?

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.

Regional hemodynamic effects of antihypertensive renomedullary lipids in conscious rats.

Renomedullary tissue has been proposed to exert an antihypertensive endocrine-like action. The antihypertensive polar renomedullary lipids (APRL) and neutral renomedullary lipids (ANRL) are potential mediators of this action. We evaluated the blood pressure and regional hemodynamic responses to APRL administered peripherally (i.v.) and to the central nervous system (CNS) in normal rats and rats with sinoaortic deafferentation (SAD) to remove baroreflex buffering. Rats were chronically instrumented with Doppler flow probes for measurement of mesenteric, renal, and hind-quarter vascular resistance, with arterial pressure and intravenous catheters, and with lateral cerebroventricular cannuli for intracerebroventricular (i.c.v.) administration. Intravenous APRL (0.01 to 1.0 micrograms) produced a dose-dependent decrease in blood pressure, tachycardia, and dilation of all vascular beds studied. The dose-response relationships were shifted to the left in SAD animals. APRL administered i.c.v. had no effect on intact or SAD rats. Pressor and regional vasoconstrictor responses to norepinephrine, angiotensin, and vasopressin were markedly reduced in SAD animals during constant infusion of APRL. In a second group of conscious SAD animals instrumented for blood pressure and heart rate measurements, intravenous ANRL (500 micrograms) decreased both arterial pressure (-45 +/- 16 mm Hg) and heart rate (-50 +/- 16 bpm). When given i.c.v., however, ANRL (10-100 micrograms) had no significant effect on resting blood pressure or heart rate. These studies suggest that APRL and ANRL produce no significant cardiovascular effects that are mediated through the CNS. However, both lipids are potent depressor agents, and APRL exhibits a strong peripheral vasodilator action and nonspecifically reduces reactivity to vasoconstrictor agents.

Hemodynamic and antihypertensive effects of captopril, an orally active angiotensin converting enzyme inhibitor.

Captopril inhibits angiotensin II formation and bradykinin degradation in vivo. Eleven patients with essential hypertension (EH) and four patients with renovascular hypertension (RVH) were treated with captopril for periods ranging from 3 days to 12 months. All patients had a diastolic blood pressure (DBP) over 95 mm Hg after receiving a placebo for 3 days. Captopril given in ascending doses (10-1000 mg/day) caused normalization of blood pressure in all but three patients, one with severe RVH whose pressure fell 11%, one patient with severe EH, whose pressure fell 27%, and one with EH whose blood pressure fell 8.5%. The average control DBP in patients with EH was 113.7 +/- 5.5 (SE) mm Hg and fell to 89.9 +/- 3.6 mm Hg (p less than 0.001), while DBP in patients with RVH fell from 110.7 +/- 7.6 mm Hg to 94.5 +/- 8.2 (p less than 0.005). All patients were studied in balance on a 100 mEq sodium (Na) diet. Plasma renin activity (PRA) versus 24-hour urinary Na excretion increased sevenfold during therapy while converting enzyme activity fell by about one half. The magnitude of the blood pressure response was not related to control PRA. Cardiac output was estimated by echocardiography during placebo administration and during maintenance therapy with captopril. A significant change was not observed. Total peripheral resistance fell an average of 18.9% (p less than 0.05) in 11 of the 13 patients in whom the measurement could be made. It is concluded that captopril effectively lowers blood pressure in patients with EH or RHV by reducing total peripheral resistance.

Renomedullary deficiency in partial nephrectomy-salt hypertension.

Partial nephrectomy-salt hypertension (PN-SH) of the rat is associated with Na volume loading. As the hypertensive state evolves, the renomedullary interstitial cells (RIC) of the renal nubbin undergo major changes, decreasing significantly in number while the remaining ones exhibit degenerative changes. The antihypertensive action of the RIC in the renal nubbin, as measured by transplants of fragmented papillae into hypertensive recipients, virtually disappears as the hypertension develops. The changes in the RIC occur whether vascular disease of the kidney is or is not overtly present. It is suggested that deficiency of the antihypertensive action of the RIC allows the prohypertensive effects of Na volume loading to operate without proper control. Thus, the sustained hypertensive state of this model does not appear to be due solely to volume expansion. Rather, it appears due to a combination of the effects of Na and volume and a renomedullary deficiency of hormonal type. The specific cause(s) of the changes in the RIC was not determined. It seems evident that it is related to the high salt intake since the partial nephrectomy procedure without the added salt load did not alter the appearance of the RIC.

Cardiovascular effects of antihypertensive polar and neutral renomedullary lipids.

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.

Secretion of medullipin I by the kidney involves the cytochrome P-450 enzyme system.

OBJECTIVE: To determine whether secretion of medullipin I by the kidney is dependent on the cytochrome P-450 enzyme system in Sprague-Dawley and spontaneously hypertensive rats (SHR). METHODS: Isolated kidneys from Sprague-Dawley rats were perfused with 5% human albumin gassed with 95% O2 and 5% CO2 at 185 mmHg. The resultant renal venous effluent was tested in the SHR for medullipin I-type vasodepressor activity. The kidneys were then treated with ketoconazole, and inhibitor of the cytochrome P-450 enzyme system. After rinsing with 50 ml saline, the last 10 ml of which was saved for a control test (see below), the kidneys were reperfused with 50 ml human albumin and the resultant renal venous effluent was tested for vasodepressor activity. One milliliter of the saline rinse was administered to the SHR and the preketoconazole renal venous effluent was administered after 15 min. The medullipin I-type vasodepression occurred. Thus, inhibition of vasodepression after ketoconazole treatment was not due to residual ketoconazole in the post-treatment renal venous effluent. RESULTS: Treatment of isolated kidneys with ketoconazole prevented secretion of medullipin I which had been induced by 5% human albumin. CONCLUSION: The cytochrome P-450 enzyme system is involved in two major metabolic steps of the medullipin system: synthesis of medullipin I by the kidney and conversion of medullipin I to medullipin II by the liver as shown previously.

Secretion of medullipin I by the kidney requires oxygen.

OBJECTIVE: To test the hypothesis that the secretion of medullipin I by the kidney involves an oxidative step. DESIGN: Medullipin I is secreted by kidney renomedullary interstitial cells and is converted to medullipin II by the liver. Medullipin I can be derived from the kidney in the renal venous effluent by perfusing normal rat kidneys with 95% O2- 5% CO2 at an elevated pressure (180 mmHg). To evaluate whether the secretion of medullipin I involves an oxidative step normal rat kidneys were perfused at an elevated pressure in the presence of O2, in the absence of O2 and after treatment of the kidneys with a powerful antioxidant. METHODS: Normal rat kidneys were perfused with 5% albumin bubbled with O2-CO2 at 180 mmHg. This was the control procedure for each of the three approaches. In approach (1), the kidneys were perfused with 5% albumin bubbled with N2. In approach (2), the kidneys were perfused with 'blood' treated with carbon monoxide. In approach (3), the kidneys were treated with the antioxidant butylated hydroxytoluene then perfused with 5% albumin bubbled with O2-CO2. Each perfusate was tested for medullipin I activity by rapid intravenous injection into the SHR. RESULTS: All three approaches, which exclude the action of molecular O2, prevented the secretion of medullipin I by the kidneys. CONCLUSION: The secretion of medullipin I by the kidneys involves an oxidative step.

Renal function in rats with angiotensin II-salt-induced hypertension: effect of thromboxane synthesis inhibition and receptor blockade.

This study was designed to assess the contribution of thromboxane (Tx) A2 to the pathogenesis of renal dysfunction in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 mol/l NaCl by infusion of Ang II (125 ng/min, intraperitoneally) for 12 days. Relative to values in water- and saline-drinking rats without Ang II infusion, rats with Ang II-salt hypertension exhibited increased renal vascular resistance, decreased renal blood flow, and increased renal excretion and glomerular synthesis of TxB2. Treatment with an inhibitor of TxA2 synthesis, UK 38,485, had no effect on renal function in normotensive and hypertensive rats. Similarly, the TxA2 and prostaglandin endoperoxide antagonist SQ 29,548 did not affect renal function in normotensive rats. In contrast, in rats with Ang II-salt hypertension of 12 days' duration, SQ 29,548 caused a reduction in renal vascular resistance, allowing for maintenance of renal blood flow in the face of an accompanying reduction in blood pressure. A comparable reduction in renal perfusion pressure, produced by constriction of the abdominal aorta above the renal arteries, was not accompanied by a reduction in renal vascular resistance in Ang II-salt hypertensive rats. Therefore, the SQ 29,548-induced lowering of renal vascular resistance is attributable not to renal blood flow autoregulation, but to blockade of the renal vasoconstrictor actions of TxA2 and/or prostaglandin endoperoxides. This interpretation implies that pressor eicosanoids contribute to increase renal vascular resistance in rats with severe Ang II-salt hypertension.

The renal antihypertensive endocrine function: its relation to cytochrome P-450.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric studies on the rat renal papilla of resistant and sensitive strains in partial nephrectomy salt hypertension.

The renomedullary interstitial cell (RIC) was studied morphometrically in the partial nephrectomy-salt (Chanutin-Ferris) model of hypertension. The RIC were compared in four strains of rat, two of them being resistant to the induction of this form of hypertension and two of them being sensitive. The Dahl salt-resistant (R/JR) rat was compared to a commercial Sprague-Dawley (SD) strain, and a Wistar derived strain discovered in Belgrade by Susic and Kentera (WB) was compared to a commercial Wistar strain (W). In both studies, resistance and sensitivity correlated well with the state of the RIC before the experimental procedure, the resistant strain having more numerous and better granulated RIC than the sensitive strain. It may therefore be possible to predict salt-resistance or sensitivity in rats by morphological examination of the RIC.

Role of changes in renal hemodynamics and P-450 metabolites of arachidonic acid in the reversal of one-kidney, one clip hypertension.

OBJECTIVE: To examine the role of changes in renal hemodynamics and P-450 metabolites of arachidonic acid in the reversal of one-kidney, one clip (1-K,1C) hypertension in rats. DESIGN: The stimulus for the release of an antihypertensive lipid from the kidney is not known. This study examined whether cortical or papillary blood flow is altered after removal of the clip from the renal artery of 1-K,1C hypertensive rats, and the effects of blockade of the renal metabolism of arachidonic acid by P-450 with 17-octadecynoic acid (17-ODYA) on the fall in blood pressure. METHODS: Cortical and medullary blood flows were measured using laser-Doppler flowmetry. 17-ODYA (33 nmol/min) was infused directly into the renal artery to examine the effect of inhibition of renal P-450 activity on reversal of 1-K,1C hypertension. The renal metabolism of arachidonic acid in control and in 1-K,1C hypertensive rats was assessed by incubating microsomes with [14C]-arachidonic acid, the metabolites formed being measured using reverse-phase high-performance liquid chromatography. The antihypertensive effects of these P-450 metabolites of arachidonic acid were compared with those of medullipin I after intravenous administration in conscious spontaneously hypertensive rats (SHR). RESULTS: Cortical and papillary blood flow increased significantly and arterial pressure fell after unclipping the renal artery in the 1-K,1C hypertensive rats. 17-ODYA prevented the fall in blood pressure after unclipping. The production of epoxy- and dihydroxy-eicosatrienoic acids was elevated in microsomes prepared from the renal cortex of the 1-K,1C hypertensive rats. However, intravenous administration of these metabolites did not mimic the effect of medullipin I to lower arterial pressure in SHR. CONCLUSION: Elevations in renal cortical or papillary blood flow, or both, may stimulate the release of a P-450-derived antihypertensive lipid from the kidney after unclipping of the renal artery in 1-K,1C hypertensive rats. However, it is unlikely that this substance is a P-450 metabolite of arachidonic acid.