Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit.

Studies were performed in pregnant rabbits to assess the effect of inhibition of prostaglandin synthesis on uterine blood flow. Cardiac output and uteroplacental blood flow (UPBF) were measured using radiolabeled microspheres. Prostaglandin E (PGE) concentration was measured by radioimmunoassay in the uterine vein and peripheral artery of the pregnant nephrectomized rabbit. Either meclofenamate or indomethacin 2 mg/kg were utilized to inhibit prostaglandin synthesis. Systemic arterial pressure increased from 86 mm Hg to 98 mm Hg (P less than0.0001) after prostaglandin inhibition. Cardiac output was unchanged after the inhibition of prostaglandin synthesis, 326 ml/min to 7.8 ml/min. Uterine vein PGE concentration was extremely high, 172.4 ng/ml, with concomitant peripheral arterial PGE 2.1 NG/ML. Intravenous administration of either meclofenamate or indomethacin reduced uterine vein PGE to 23 ng/ml (P less than 0.01) and arterial PGE to 1.0 ng/ml (P less than 0.05). Male and nonpregnant female rabbits had lower arterial PGE, 0.37 ng/ml (P less 0.05). Studies in non-nephrectomized pregnant animals demonstrated that uteroplacental secretion of PGE was greater than five times renal secretion. These studies demonstrate that the rabbit uteroplacental unit is a rich source of PGE and suggest that production of the vasoactive lipid may have a key role in regulating UPBF during pregnancy.

The effect of changes in perfusion pressure on uteroplacental blood flow in the pregnant rabbit.

The effect of perfusion pressure on uteroplacental blood flow was determined in pregnant rabbits utilizing the radioactive microsphere method. Control mean arterial pressure, 93 mm Hg +/- 2.6 SEM, was raised by carotid ligation to 109 +/- 4.1 mm Hg and then reduced with antihypertensive drugs to 74 +/- 1.3 mm Hg. Over this range of pressure there was no significant change in cardiac output, 605 +/- 36, 523 +/- 37, and 540 +/- 39 ml/min; or uteroplacental blood flow, 30 +/- 3.2, 27 +/- 5.2, and 29 +/- 4.5 ml/min, respectively. When prostaglandin synthesis was inhibited with either indomethacin or meclofenamate (2 mg/kg), uterine vascular resistance was higher but maintenance of uteroplacental flow occurred over a perfusion pressure of 89 +/- 6.7-115 +/- 9.3 mm Hg. With more severe hypotension induced with trimethaphan, control arterial pressure fell from 92 +/- 2.4 to 39 +/- 0.9 mm Hg, cardiac output fell from 514 +/- 17 to 407 +/- 22 ml/min (P less than 0.025) and uteroplacental blood flow fell from 6.1 +/- 0.9 to 2.5 +/- 0.9% of cardiac output (P less than 0.05), which represented an absolute fall from 32.4 +/- 5 to 10.6 +/- 3 ml/min (P less than 0.025). There was no significant change in renal blood flow expressed as percentage of cardiac output, 14.9 +/- 2 and 13 +/- 1.5%, or in absolute flow, 75 +/- 7.7 and 54 +/- 7 ml/min with trimethaphan-induced hypotension. These studies indicate that uteroplacental blood flow is maintained relatively constant over a range of perfusion pressure of 60-140 mm Hg in both normal and prostaglandin-inhibited pregnant rabbits. However, with reduction in pressure to 36-42 mm Hg, uteroplacental blood flow falls, expressed as a percentage of cardiac output and in absolute flow.

Postpartum hemolytic uremic syndrome in a patient with preexisting hypertension and resolving preeclampsia.

Postpartum hemolytic uremic syndrome (PHUS) is an uncommon and potentially devastating complication of pregnancy. We report a case of PHUS in a patient with chronic hypertension and preceding preeclampsia. Since early and appropriate therapy results in remission in most patients with PHUS, the sometimes subtle differences between this syndrome and preeclampsia are reviewed.

Acute renal failure secondary to interstitial lupus nephritis.

A patient with systemic lupus erythematosus (SLE), followed up over a six-month period, exhibited numerous immunologic abnormalities and varied renal pathologic features. Initial findings included minimal glomerular lesions, serum antibodies directed solely against nuclear RNA protein, and lupus band test showing pure IgM deposition. These findings suggested a good prognosis. Subsequently, the patient developed acute renal failure secondary to an interstitial lupus nephritis, without progression of the glomerular abnormality. Serum antibodies to the nuclear non-nucleic acid macromolecule and single stranded and native DNA were demonstrated concurrently. New skin deposits of IgG and IgA in addition to IgM also were observed. This patient demonstrates the potential progression of lupus renal disease despite the initial favorable prognostic indicators.

The conscious instrumented rabbit: a model for the study of mechanisms of blood pressure regulation during pregnancy.

Conscious pregnant and nonpregnant rabbits were used to further evaluate the role of prostaglandin (PG) and plasma renin activity (PRA) in the systemic hemodynamics of pregnancy. Pregnant rabbits had high peripheral blood levels of both PGE2 and PRA. Systemic blood pressure was not affected in either pregnant or nonpregnant by the administration of an inhibitor of prostaglandin synthesis. Pregnant rabbits, however, had a much larger decrease in blood pressure than nonpregnant animals when given the angiotensin I (AI)-converting-enzyme inhibitor, captopril. Pregnant rabbits were more resistant to the pressor effect of exogenous AII than nonpregnant animals. The pressor effect of AII increased in pregnant rabbits after the administration of meclofenamate and parturition but was not changed by volume expansion. In contrast, the sensitivity of nonpregnant rabbits to AII increased after volume expansion, but not after treatment with inhibitors of prostaglandin synthesis. These studies demonstrate that a remarkable similarity exists between pregnant rabbits and pregnant women in the pressor response to AII. This study is the first to correlate the vasopressor response to AII with PRA and the level of a circulating vasopressor prostaglandin in pregnant animals. The results strongly suggest that this model will be fruitful in further attempts to define the factors controlling systemic hemodynamics during pregnancy.

Pharmacokinetics and clinical tolerance of intravenous and oral cyclosporine in the immediate postoperative period.

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 +/- 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 +/- 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 +/- 0.1 L/min and a volume of distribution of 2.88 +/- 1.1 L/kg, whereas the elimination half-life was 12.8 +/- 3.8 hours and the mean residence time was 9.5 +/- 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 +/- 0.13 and 0.30 +/- 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.

Nephrotoxicity and hyperkalemia in patients with acquired immunodeficiency syndrome treated with pentamidine.

INTRODUCTION: Recently, the use of pentamidine has risen because of its efficacy in managing patients with acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii infection. We undertook a retrospective analysis of the charts of 22 patients with AIDS given pentamidine when they were hospitalized over a two-year period. PATIENTS AND METHODS: Collectively, these 22 patients were admitted 28 times during this period and received a total of 23 courses of pentamidine. During five of these admissions, pentamidine was not given. The duration of therapy ranged from five to 33 days (mean: 13.4 days). Three admissions were excluded because of insufficient laboratory data or concomitant use of therapies that could affect the parameters being studied. RESULTS: In 19 of the remaining 20 admissions, the patients treated with pentamidine were observed to have elevations of potassium (5.1 to 8.7 mEq/L), creatinine (1.5 to 11.8 mg/dL), and blood urea nitrogen (27 to 183 mg/dL), and a decrease in serum bicarbonate (14 to 21 mEq/L). Of the 19 patients exhibiting these abnormalities, most required sodium polystyrene sulfonate and two required dialysis. During the admissions when pentamidine was not given, hyperkalemia was not observed. After discontinuation of pentamidine therapy, these metabolic derangements normalized in all patients except for one who died while still in acute renal failure. Four patients received more than one course of therapy and upon reinstitution of pentamidine treatment, the same metabolic abnormalities recurred. CONCLUSION: In conclusion, pentamidine is more nephrotoxic in patients with AIDS than previously reported in other subjects and can cause life-threatening hyperkalemia.

Abdominal pain associated with IgA nephropathy. Possible mechanism.

A 36-year-old man presented with IgA nephropathy (Berger's disease) and acute abdominal pain. Surgical biopsy of the ileum revealed deposits of IgA, C3, and fibrin in segments of the wall of submucosal arteries. The immune deposits appeared associated with areas of fibrinoid necrosis. These findings support the hypothesis that Berger's disease is a systemic disease, and provide a possible explanation for the abdominal pain associated with IgA nephropathy.

Heroin nephropathy. A clinicopathologic and epidemiologic study.

The existence of a nephropathy secondary to intravenous narcotic use remains a matter of debate. To determine whether heroin use and renal disease are associated, a clinicopathologic and epidemiologic study was undertaken in the Buffalo Standard Metropolitan Statistical Area (Buffalo-SMSA). Over the past 10 years, 23 addicts presented with the nephrotic syndrome and/or renal insufficiency. All patients were black men 18 to 45 years of age. Kidney biopsies performed on 21 patients uniformly showed sclerosing glomerulonephritis. End stage renal disease (ESRD) developd in 15 of these patients. In the epidemiologic evaluation which spanned four and a half years, heroin use was highly correlated with both sclerosing glomerulonephritis and ESRD. A history of intravenous heroin use was found in 26 per cent of the new cases of sclerosing glomerulonephritis and in 13 per cent of the new cases of ESRD in patients aged 18 to 45 years (p less than 0.000001). This investigation confirms the existence of heroin-associated sclerosing glomerulonephritis in black men. Heroin use appears to be a major risk factor for ESRD in the Buffalo-SMSA.

Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients.

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of methylprednisolone in elderly and young healthy males.

OBJECTIVE: To characterize and compare the pharmacokinetics of a single intravenous dose of methylprednisolone in elderly and young healthy males. DESIGN: A randomized, parallel pharmacokinetic trial. SETTING: A public university-affiliated hospital. SUBJECTS: Seven healthy, elderly white males (aged 69 to 82 years) and five healthy, young white males (aged 24 to 37 years) who gave informed consent and fulfilled all screening criteria. MEASUREMENTS: Serial blood samples were obtained over a 24-hour study period after intravenous administration of a 10-mg dose of methylprednisolone. Serum methylprednisolone concentrations were determined by high performance liquid chromatography and utilized to determine the pharmacokinetic parameters. RESULTS: Methylprednisolone serum concentrations declined in a linear manner in both groups. However, 4 hours after the dose, the mean serum concentration of methylprednisolone was 50.9 +/- 15.1 ng/mL in the elderly group and 37.6 +/- 7.5 (P = 0.07) ng/mL in the young group. The clearance of methylprednisolone was 237 +/- 62 mL/h/kg, with a volume of distribution of 1.10 +/- 0.07 L/kg, for the elderly group, whereas the young males had a mean drug clearance of 359 +/- 90 mL/h/kg (P < 0.05) and a mean volume of distribution of 1.28 +/- 0.34 L/kg. The half-life of methylprednisolone ranged from 1.90 to 5.40 hours in the elderly group; the range was 1.99 to 3.31 hour (P = 0.016) in the young group. CONCLUSION: A slower methylprednisolone clearance was noted in the elderly group compared with the young counterparts. This pharmacokinetic alteration seen in healthy elderly subjects may contribute to the increased incidence of adverse effects from chronic glucocorticoid therapy that has been observed among elderly patients.

Cortisol pharmacodynamics after methylprednisolone administration in young and elderly males.

Glucocorticoids are commonly prescribed in the elderly on an empiric basis with little consideration for the age-related alterations in pharmacologic response. The objectives of this study were to compare the effect of methylprednisolone on cortisol patterns in elderly and young healthy men, to define the relationship between pharmacokinetic parameters of methylprednisolone and pharmacodynamics of cortisol in the elderly and young men. Seven healthy, elderly males (69-82 years old) and five healthy, young males (24-37 years old) participated in a 24-hour pharmacodynamic trial with randomized assignment to a control period (Phase 1) and a methylprednisolone period (Phase II). Serial blood samples were obtained throughout both study periods. Cortisol measurements included the total area under the concentration-time curve (AUC), return AUC, and suppression ratio. During Phase I, a circadian pattern was noted in both groups. After exposure to methylprednisolone (Phase II), a linear decline in serum concentrations of cortisol was observed in both groups. The return AUC of cortisol (425 +/- 357 ng.hr/mL [elderly] versus 854 +/- 216 ng.mL [young]) and the total AUC 764 +/- 340 ng.h/mL [elderly] versus 1,230 +/- 258 ng.hr/mL [young]) were significantly lower in the older men. In addition, a significant decline in total AUC and nadir concentration of cortisol from Phase I to Phase II was noted within both groups. The suppression ratio was significantly greater in the elderly men (mean, 0.38 versus 0.58 in young), which indicates a greater degree of adrenal suppression after administration of methylprednisolone. Exposure to methylprednisolone, as measured by AUC, was 554 +/- 215 ng.hr/kg (elderly) and 389 +/- 102 ng.hr/kg (young). The greater exposure to methylprednisolone noted in the elderly yielded significant combined correlations for both groups with AUC, return AUC, and suppression ratio of cortisol. A more significant response of cortisol to the exogenous glucocorticoid was apparent in the elderly men. In addition, a slower clearance of methylprednisolone was noted in the elderly group compared with their young counterparts. The effect of reduced clearance of methylprednisolone on the suppression ratio indicates the interrelationship between the disposition of a single dose of an exogenous glucocorticoid and response patterns of cortisol.

Adulterants in heroin/cocaine: implications concerning heroin-associated nephropathy.

Heroin-associated nephropathy (HAN) is a complication of the intravenous use of heroin or cocaine. It has been postulated that one of the substances used to adulterate these drugs may be responsible for the renal injury. We examined data provided by the Drug Enforcement Administration (DEA) concerning the laboratory analysis of 12 366 samples of heroin/cocaine. These street-grade drugs were analyzed for the presence of various adulterants or secondary substances. Eleven adulterants were identified with a frequency of occurrence that exceeded 5%. Quinine, mannitol, lactose and procaine were the non-narcotic compounds most commonly found. Other substances found included caffeine, inositol, lidocaine, starches, methapyrilene, sucrose, acetylprocaine and dextrose. No specific substance including heroin or cocaine has yet been definitely implicated as causative of HAN. These data suggest that further animal research is needed to determine the effects of repeated intravenous injections of each of these commonly found substances on the kidney.

Racial differences in the pharmacokinetics of methylprednisolone in black and white renal transplant recipients.

STUDY OBJECTIVE: To examine the comparative pharmacokinetics of long-term methylprednisolone therapy in black and white renal transplant recipients. DESIGN: Comprehensive pharmacokinetic evaluations of patients who participated in our glucocorticoid-monitoring program. SETTING: University-based renal transplantation clinic. PATIENTS: Six white renal transplant recipients with stable renal function, sex- and (approximate) age-matched with six preselected black patients. INTERVENTIONS: The daily oral methylprednisolone dose for each patient was administered intravenously, and serial plasma samples were obtained over 24 hours. MEASUREMENTS AND MAIN RESULTS: Methylprednisolone was analyzed by high-performance liquid chromatography. The drug's pharmacokinetics in black and white patients, respectively, were as follows: mean clearance 234 +/- 124 and 472 +/- 180 ml/hr/kg (p < 0.05); volume of distribution 0.3-2.0 and 0.8-2.0 L/kg; and elimination rate constant 0.13-0.41 and 0.27-0.42 hour-1 (p < 0.06). No statistical difference was noted in the last two parameters. The mean half-life of 3.4 +/- 1.4 hours in black patients compared with 2.1 +/- 0.3 hours in white patients approached statistical significance (p < 0.08). CONCLUSIONS: These preliminary observations suggest that the disposition of methylprednisolone differs between black and white renal transplant recipients. The current method of prescribing glucocorticoids employs a fixed-dose regimen that does not take these possible interracial differences into consideration. Incorporating the differences may allow for more individualized dosing and more efficacious use of the agent in this patient population.

Cortisol pharmacodynamic response to long-term methylprednisolone in renal transplant recipients.

STUDY OBJECTIVE: To examine the pharmacodynamic patterns of cortisol and pharmacokinetic values of long-term methylprednisolone in renal transplant recipients. DESIGN: Twenty-four-hour pharmacokinetic and pharmacodynamic evaluation of patients who participated in a glucocorticoid-monitoring program. SETTING: University-based renal transplant clinic. PATIENTS: Fourteen renal transplant recipients studied during a clinically stable period. INTERVENTIONS: The daily oral methylprednisolone dose for each patient was administered intravenously, and serial plasma cortisol and methylprednisolone samples were obtained over 24 hours. MEASUREMENTS AND MAIN RESULTS: Methylprednisolone was analyzed by high-performance liquid chromatography. The baseline morning cortisol serum concentrations ranged from 9.8-210.7 ng/ml. After the drug was administered, cortisol declined in a linear fashion with a mean suppression half-life of 2.4 +/- 0.9 hours. The cortisol nadir was reached at 12-16 hours in 11 of 14 patients. The return cortisol area under the curve (AUC-Cret) was noted in all patients and ranged from 57-987 ng.hr/ml. The total cortisol area under the curve was greater in patients who had been transplanted for longer than 2 years (1676 +/- 252 vs 836 +/- 405 ng.hr/ml; p < 0.05) compared with more recently transplanted patients. Methylprednisolone clearance ranged from 100-1181 ml/hr/kg with a mean volume of distribution of 1.3 +/- 0.6 L/kg. The methylprednisolone half-life ranged from 1.2-4.7 hours. The correlation between AUC-Cret and methylprednisolone AUC was -0.64 (p < 0.05). CONCLUSIONS: The pharmacodynamic response of cortisol in renal transplant recipients may be associated in part with long-term steroid exposure. However, the interrelationship between the endocrine and immune system may also affect cortisol's disposition and subsequent recovery patterns in this population. Considerable interpatient variability was apparent in both the cortisol pharmacodynamic response as well as the pharmacokinetics of methylprednisolone. These findings suggest a more individualized dosing method may be necessary to optimize the immunosuppressive effect of glucocorticoids and minimize clinical toxicity.

Thromboxane receptors in human kidney tissues.

Thromboxane (TX) A2 effects in the kidneys include contraction of glomerular mesangial cells and intrarenal vascular tissue. A kidney cDNA encoding a TX receptor expressed in rat renal glomeruli and rat renal arterial smooth muscle cells has been reported. However, TXA2 receptors in human kidneys have not been documented. The purpose of this study was to identify and characterize TXA2 receptors in glomeruli and intrarenal arteries isolated from human kidneys. Normal kidneys, not used for transplant because of technical reasons, were kept at -70 degrees C and used for research purposes. The glomeruli and intrarenal arteries were isolated from renal cortical tissue by a mechanical sieving technique. The equilibrium dissociation constant and receptor number were determined by nonlinear analysis of binding inhibition data. The data were generated in radioreceptor assays using [125I]-BOP, a stable analog of TXA2. The dissociation constants (mean +/- SEM) for binding of I-BOP to human glomeruli and intrarenal arterial membranes were 6.6 +/- 1.1 nM (n = 7) and 20 +/- 6 nM (n = 7), respectively (p < 0.05). The receptor number was 311 +/- 91 fmol/mg protein (n = 7) in glomeruli and 74 +/- 16 fmol/mg protein (n = 7) in intrarenal arterial membranes (p < 0.04). The order of specificity of TXA2 analogs for [125I]-BOP binding sites was similar in glomeruli and in arterial membranes and was I-BOP > or = U46619 > or = pinane TXA2 > or = carbocyclic TXA2 > or = PGH2. These findings provide direct evidence for the presence of specific, high-affinity [125I]-BOP binding sites in human renal glomeruli and extraglomerular vascular tissue. These data also indicate that the human binding sites have higher affinity for the TXA2 agonist I-BOP than for PGH2.

A proposed method for the noninvasive evaluation of renal asymmetry in a living-related donor candidate.

This report proposes an adjunctive technique for the evaluation of asymmetry of renal size and function of undetermined etiology, discovered during the assessment of two living-related donor candidates. The method utilizes the observation of renal functional reserve measurement as demonstrated by oral protein loading in patients with normal and diseased kidneys. Renal function was measured as timed Ccr and estimation of differential GFR by technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) scintigraphy. A comparison of renal function before and after protein loading in two such patients demonstrated the anticipated increase in GFR. No change in differential GFR as determined by renal scan in one patient was interpreted as supportive evidence for bilaterally normal parenchymal function. Follow-up of both donors shows continued normal renal function.

Increased peripheral resistance during reduced uterine perfusion pressure hypertension in pregnant rabbits.

The role of an increase in total peripheral resistance (TPR) and the contribution of angiotensin II (ANG II) to the hypertension induced by reduced uterine perfusion pressure (RUPP) was explored in pregnant rabbits. On the 22nd day of gestation, a catheter and a microthermocouple were placed in the aorta to measure mean arterial pressure (MAP) and cardiac output (CO), respectively. Three days later, RUPP was induced by a clip on the aorta proximal to the ovarian and distal to the renal arteries. Mean arterial pressure distal to the clip (uterine perfusion pressure) was reduced to 56 +/- 8% (mean +/- SD) of the initial level. Twenty-four hours later, MAP rose from 65 +/- 3 to 84 +/- 11 mm Hg; CO index decreased from 207 +/- 18 to 169 +/- 27 ml/min/kg; and TPR index increased from 0.32 +/- 0.03 to 0.51 +/- 0.08 mm Hg kg/ml/min, respectively (n = 7, all p less than 0.01). Sham-operated pregnant rabbits (n = 7) and non-P rabbits (n = 5) with a comparable distal aortic pressure reduction experienced no change in MAP or CO. Infusion of a receptor antagonist of angiotensin II (Sar1,Ile8-Ang II, 1 microgram/kg/min for 20 min) decreased MAP in sham-operated pregnant rabbits from 64 +/- 6 to 54 +/- 6 mm Hg (p less than 0.01) but did not change MAP in RUPP hypertensive rabbits (86 +/- 9 mm Hg before and 87 +/- 8 at the end of infusion, n = 6). These data indicate that RUPP in pregnant rabbits leads to a high resistance form of hypertension in which the formation of Ang II is not increased.