Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.

Once-daily fosinopril in the treatment of hypertension.

This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter, patients could enter the long-term, open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone, if needed. After 4 weeks of monotherapy, the average decreases in supine diastolic blood pressure were 9% (10 mg), 11.5% (40 mg), and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks, the average decreases, with or without diuretic therapy, were 12.5-18.2%, compared with 10.8% with placebo. Blood pressure continued to be well controlled, and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment. Fosinopril was well tolerated. During the short-term phase, no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase, nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension, once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose.

Effects of nadolol beta-blockade on blood pressure in hypertension.

Nadolol, a nonselective beta adrenoceptor antagonist, was evaluated in 9 normal sybjects with essential hypertension for ability to inhibit exercise-induced changes in double-product (systolic pressure x heart rate). Propranolol and placebo were included as positive and negative controls. The beta antagonists were administered orally in single doses at 10, 20, 40, and 80 mg on a crossover basis. Both nadolol and propranolol induced comparable dose-related inhibition of double-product. Duration of beta receptor blockade was greater with nadolol than with propranolol; significant inhibition of double-product occurred 24 hr after a single 80-mg dose of nadolol. The antihypertensive effect of nadolol was evaluated in another series of 46 subjects with essential hypertension. The dose of nadolol ranged from 80 to 320 mg once daily. Consistent decreases in supine heart rate (20%) and diastolic blood pressure (9%) from baseline were observed. During steady state, the oral daily dose of nadolol was proportional to the minimum steady-state serum concentration (Cmin) of nadolol (r = 0.75, p less than 0.001) obtained just before the next dose of nadolol. Statistically significant correlation was observed between the antihypertensive effect and the Cmin for nadolol (r = 0.45, p less than 0.05).

Pharmacokinetics of fosinopril in patients with various degrees of renal function.

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance, so that total clearance was maintained. After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.

Renal handling of captopril: effect of probenecid.

14C-Captopril was given intravenously to four normal subjects in a 4-mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid. Steady-state levels of unchanged captopril were obtained between 1.5 and 3.5 hr. In the presence of probenecid, the average steady-state blood levels of total radioactivity were higher (36%) than on captopril alone. Unchanged captopril levels were slightly higher (14%) in the presence of probenecid. Kinetic evaluations were carried out exclusively on data for unchanged captopril. The average total body clearance (ClT) and renal clearance (ClR) of captopril in the absence of probenecid were 775 and 388 ml/kg/hr. The corresponding values for captopril with probenecid (631 and 217 ml/kg/hr) were lower. The average ratio of ClR to ClT for captopril alone was 0.50 and fell to 0.35 in the presence of probenecid. When captopril alone was given, a minimum of 78% of the renal excretion of captopril during steady-state could be attributed to net tubular secretion, but when captopril was given with probenecid, net tubular secretion was only 56%. The volume of distribution of captopril during steady state was not altered by probenecid. For the first 3.5 hr, cumulative renal excretion of total radioactivity with and without probenecid was 55% and 60%, but cumulative excretion of unchanged captopril was higher after captopril alone (36% of dose) than after the combination (21% of dose).

Captopril kinetics.

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and 2 l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of captopril averaged 0.8 l/kg/hr and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drug, excretion of radioactivity accounted for 87% and 61% of dose. In the 0- to 24-hr urine, averages of 38% (intravenous) and 24% (oral) of the doses were excreted as unchanged captopril. Absolute absorption of the radioactive oral dose was 71% and the absolute oral bioavailability of captopril was 62%.

The antihypertensive effect of captopril in essential hypertension: relationship to prostaglandins and the kallikrein-kinin system.

Two groups, each with nine essential hypertensive patients, were maintained on 10 mmol sodium daily over 14-17 days and treated in this sequence: placebo; captopril (25 or 50 mg given thrice daily) or indomethacin (50 mg given thrice daily) alone; captopril plus indomethacin, and (4) captopril alone. The initial fall in mean blood pressure induced by captopril (118 +/- 1 to 102 +/- 1 mmHg) was unaffected by the addition of indomethacin. However, if indomethacin treatment preceded captopril, the antihypertensive effect was attenuated (116 +/- 4 to 109 +/- 4), and was associated with significant reductions in urinary prostaglandin and kinin excretion. Addition of captopril to indomethacin returned kinin excretion to placebo levels but did not affect indomethacin-induced reduction in prostaglandin excretion. Captopril alone stimulated plasma renin activity (PRA) fivefold; aldosterone excretion was lowered by 25% and further reduced by indomethacin. Thus, when captopril and indomethacin are administered together, the order of administration is critical to the antihypertensive effect of captopril.

Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)

Effectiveness of low-dose nadolol for ventricular arrhythmias.

To determine the minimal effective dose of nadolol to suppress frequent ventricular premature complexes (VPCs), 23 patients with at least 30 VPCs/hour on 2 baseline 24-hour Holter recordings were studied. The initial dose of nadolol was 10 mg/day orally, and this dose was doubled at weekly intervals until arrhythmia suppression was achieved, adverse effects appeared, or a maximal dose of 160 mg/day was reached. After each dose level a 24-hour ambulatory Holter monitor was recorded. A pharmacokinetic trial was conducted in patients who responded to nadolol treatment. Frequent VPCs were suppressed at least 75% by nadolol in 11 of 23 patients (48%) and the minimal effective dose was 10 mg/day in 3 patients, 20 mg/day in 4, 40 mg/day in 3 and 80 mg/day in 1 patient. At these doses, minimal steady-state levels of nadolol in serum (Cmin) ranged from 3.9 to 47.0 ng/ml, and these serum concentrations were proportional to the oral dose of nadolol (r = 0.753, p less than 0.001). No relation, however, was observed between Cmin levels and percent reduction of VPCs. Cmin and heart rate changes were comparable between responders and nonresponders, suggesting that the degree of beta blockade was similar between these 2 groups. Adverse reactions were noted in 6 patients, and 2 had an asymptomatic increase in the frequency of VPCs and 1 patient an increase in beats of ventricular tachycardia. This study details the importance of selecting an individualized dose for nadolol for control of ventricular arrhythmias; in more than half of the patients doses of 20 mg/day or less were effective.

The effect of captopril on renal hemodynamics in hypertensive patients.

The effects of captopril (50 or 100 mg t.i.d.) with and without hydrochlorothiazide (25 or 50 mg/day) on renal blood flow, glomerular filtration rate, and the renin-angiotensin system were determined in 20 patients with mild to moderate essential hypertension. Normalization of blood pressure (supine diastolic blood pressure less than 90 mm Hg) was achieved in 12 patients after four or six weeks of captopril alone (147 +/- 3/100 +/- 3 mm Hg after a two-week placebo lead-in vs. 135 +/- 4/83 +/- 1 mm Hg after captopril, P less than 0.01/P less than 0.001). In these 12 patients, no significant alterations in renal blood flow or glomerular filtration rate were observed. Plasma renin activity increased two- to threefold above baseline levels, whereas serum and urinary aldosterone decreased by 23 and 35 per cent, respectively. Eight other patients remained hypertensive after four weeks of captopril alone (165 +/- 6/110 +/- 3 vs. 156 +/- 8/102 +/- 4 mmHg, P greater than 0.05/P less than 0.05). With addition of hydrochlorothiazide, blood pressure fell (P less than 0.001) to 129 +/- 7/84 +/- 3 mm Hg. Captopril alone or in combination with diuretic had no significant effect on renal hemodynamics. In the eight patients requiring diuretic, plasma renin activity remained constant after captopril monotherapy, but rose threefold after hydrochlorothiazide was added. The combination of these two antihypertensive agents significantly lowered serum aldosterone levels and urinary aldosterone excretion by 53 and 50 per cent, respectively. In summary, captopril with and without a thiazide diuretic reduced blood pressure without altering renal hemodynamics.

Comparison of bumetanide and hydrochlorothiazide on renal potassium and hydrogen ion excretion.

The purpose of this study was to compare the renal electrolyte excretion pattern of bumetanide with that of hydrochlorothiazide in dogs anesthetized with pentobarbital. In bumetanide-treated animals, mean sodium excretion rose to 12 per cent of the filtered load, while hydrochlorothiazide increased sodium excretion to 4 per cent of the filtered load. After bumetanide, urine pH fell from 6.1 to 5.1 and net hydrogenion excretion increased significantly. After hydrochlorothiazide, urinary pH went from 6.4 to 7.4, and there was no change in net hydrogen ion excretion. Potassium excretion rose to 106+/-22 muEq/min with bumetanide and to 99+/-17 muEq/min with hydrochlorothiazide. These changes in electrolyte excretion occurred despite lack of changes in arterial blood gases, arterial blood pressure, and glomerular filtration rate. In addition, bumetanide did not exert an inhibitory effect on potassium excretion under conditions of potassium loading. It is concluded that bumetanide produces a higher urinary Na+:K+ ratio with a lower pH than hydrochlorothiazide and that renal potassium ion excretion in response to sulfamoyl diuretics is not solely dependent on the rate of sodium excretion.

Preserved renal perfusion during treatment of essential hypertension with the beta blocker nadolol.

Several beta-adrenergic antagonists impair renal perfusion during treatment of hypertension in man. The acute and chronic effects of a new noncardioselective beta blocker, nadolol, on renal hemodynamics, intravascular volume, and renal electrolyte excretion were studied in 10 men with essential hypertension. Oral nadolol normalized systemic blood pressure without impairment of glomerular filtration rate or renal blood flow, indicating preserved renal blood flow and glomerular filtration rate autoregulation. Intravascular volume and renal excretion of electrolytes were similarly unaltered. Once-daily nadolol lowers blood pressure without renal hemodynamic of functional embarrassment.

Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects.

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin-converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose-tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once-daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P less than or equal to .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.

Phase I dose-escalation pharmacokinetics of AZT-P-ddI (IVX-E-59) in patients with human immunodeficiency virus.

3'-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI, IVX-E-59, Scriptene) is a heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (zidovudine or AZT) and one molecule of 2',3'-dideoxyinosine (didanosine or ddI) linked through their 5' positions by a phosphate bond. AZT-P-ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT-P-ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)-AZT-P-(3H)-ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450-mg oral dose of AZT-P-ddI. Plasma levels of unchanged AZT-P-ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The beta-glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3'-amino-3'-deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI-M, was detected in plasma and urine. Analysis by high-field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI-M as being R(-)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT-P-ddI compared with the intravenous infusion, with an area under the concentration-time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI-M exhibited sustained plasma levels for extended time periods with an apparent elimination half-life (t1/2) of approximately 10 hours after oral administration of AZT-P-ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT-P-ddI. The oral bioavailability of AZT (64.7-67.3%) and ddI (33.6-42.9%) and the other pharmacokinetic parameters were consistent with previous data reported with each nucleoside analog alone or in combination therapy.

Acute electrophysiologic effects of nadolol.

The acute effects of intravenous nadolol (0.01 and 0.02 mg/kg) on cardiac electrophysiologic parameters were assessed with His bundle recording and programmed atrial stimulation. The higher dose of nadolol reduced resting heart rate (71 vs. 65 beats/min, P less than 0.02), and the degree of slowing was related to the initial heart rate (r = -0.68, P less than 0.05). Atrioventricular conduction time as defined by the paced A-H interval, rose by 12 msec (P less than 0.001) after nadolol (0.02 mg/kg) administration. Atrial refractoriness increased (by 10 msec, P less than 0.02) only at the higher dose level with nadolol. At both dose levels, atrioventricular nodal effective and functional refractory periods were increased (P less than 0.02) by a mean of 45 and 21 msec, respectively, suggesting greater sensitivity of atrioventricular nodal refractoriness to beta-adrenergic blockade. Nadolol's effects were generally similar to those of previously reported studies with other beta-adrenergic blockers. These data suggest that nadolol slows conduction through the atrioventricular node and increases atrial and atrioventricular nodal refractoriness.

Pharmacokinetics of lopamidol after intrathecal administration in humans.

The kinetics of iopamidol, a new nonionic radiocontrast agent, were evaluated in 10 patients undergoing lumbar myelography. The doses of iopamidol administered intrathecally were 11 and 15 ml of a 200-mg iodine per ml solution in one and nine patients, respectively. Radiographs were made within 30 to 40 min and CTs were taken at about 1, 6, and 23 hr after iopamidol administration. The diagnostic quality and usefulness of the conventional and CT myelograms were considered excellent. In the lumbosacral subarachnoid space, the densitometry CT readings were maximal at 1 hr, whereas in the cervical subarachnoid space, peak CT values were reached at 6 hr. Plasma and urine samples were taken at frequent intervals up to 48 hr after the contrast agent was administered. Peak plasma levels of iopamidol were observed at 2.9 hr and were no longer detectable at 48 hr. The 48-hr urinary recovery for all patients averaged 66 +/- 8% of the dose. In all but one patient, iopamidol was cleared almost completely from the CSF within 24 hr. Side effects after iopamidol administration were transient and minor, and were not related to the CT readings or its systemic clearance.

Distribution of intracortical renal blood flow induced by bumetanide in the dog.

Experiments were performed in hydropenic, anesthetized dogs to investigate the effect of two dose levels of bumetanide on sodium excretion, urinary concentration, total renal blood flow and intracortical distribution of blood flow using the radioactive microsphere technique. Intravenous administration of bumetanide (0.025 mg/kg followed by 0.025 mg/min) did not alter blood flow within the kidney. A higher dose of bumetanide (0.1 mg/kg followed by 0.1 mg/min) significantly increased total renal blood flow and lowered renal vascular resistance. The rise in renal blood flow after bumetanide was due entirely to an increase in perfusion to the midcortical and juxtamedullary regions. A transient rise in plasma renin activity was measured only after the higher dose of bumetanide. Both doses of bumetanide increased sodium excretion and depressed solute free water reabsorption, although natriuresis was greater in response to the high dose. The results indicate that higher dose levels of bumetanide can increase total renal blood flow to the inner cortex. However, changes in renal blood flow were apparently not essential for the diuretic action of bumetanide because a significant natriuresis was observed in a setting where no change in intrarenal hemodynamics could be detected.

Glomerular filtration during furosemide diuresis in the dog.

Simultaneous clearance and micropuncture experiments were performed in pentobarbital-anesthetized dogs to determine the effect of furosemide (F; 5 mg/kg) on some of the determinants of GFR during replacement of urine losses. Glomerular capillary pressure (PG) was estimated from stop flow pressure (SFP) plus systemic colloid osmotic pressure (pi alpha). Because renal vasodilation during F administration occurs more often when blood pressure is elevated, two groups of dogs were studied. At endogenous renal perfusion pressure (RPP) of 130 mm Hg, one group responded to F with a 28% increase in renal blood flow (RBF). PG rose (a rise of 18 mm Hg) in proportion to the rise in proximal tubule pressure (PT) (a rise of 20 mm Hg). Thus, the difference in pressures (PG - PT) was unchanged, as was GFR. The second group had RPP lowered by renal artery constriction to a point near the lower limit of autoregulation (104 mm Hg). These dogs responded to F with no increase in RBF; PG was lower and remained constant during F, PT, however, increased (a rise of 10 mm Hg). The difference in pressures (delta P) decreased by 30%, and GFR decreased by 40%. Single nephron glomerular filtration rate (SNGFR) also decreased, and estimated Kf, the ultrafiltration coefficient, actually rose slightly. The major reason for the fall in GFR and SNGFR was due to a decrease in delta P rather than a decrease in Kf. The decrease in delta P can be attributed to failure of the renal vasculature to dilate because PG and RBF remained constant. It is likely that these events will be observed less often at hypertensive BP than at normal BP where renal vascular resistence is already close to a minimum value.