(Radiology. 2001;219:419-426.)
© RSNA, 2001
Renal Blood Flow Changes Induced with Endothelin-1 and Fenoldopam Mesylate at Quantitative Doppler US: Initial Results in a Canine Study1
Chandra M. Sehgal, PhD,
Peter H. Arger, MD,
Anthony C. Silver, BS,
Jill A. Patton, MS,
H. Mark Saunders, VMD,
Amit Bhattacharyya, PhD and
Caroline P. Bell, PhD
1 From the Department of Radiology, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104-6086 (C.M.S., P.H.A., J.A.P., H.M.S.); and SmithKline Beecham, King of Prussia, Pa (A.C.S., A.B., C.P.B.). Received March 9, 2000; revision requested April 25; revision received October 24; accepted November 14. Address correspondence to C.M.S. (e-mail: sehgal@oasis.rad.upenn .edu).
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ABSTRACT
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PURPOSE: To evaluate quantitative Doppler ultrasonography (US) for assessing renal blood flow changes induced with endothelin-1 (ET-1) and fenoldopam mesylate in conscious dogs.
MATERIALS AND METHODS: A blood flow probe was surgically implanted around the renal artery in eight adult dogs. Color and power Doppler US images were acquired in conscious restrained dogs during intravenous infusion of ET-1 and fenoldopam mesylate. Simultaneous with imaging, blood flow through the renal artery was measured with the implanted probe. The color level of the images within the region representing the kidney was analyzed to derive flow indices. These indices were compared with direct-flow measurements.
RESULTS: The flow indices, color-weighted flow area (CWFA), and percentage of area of color, derived from color and power Doppler US images, correlated linearly with direct flow. The mean color level of color and power Doppler US images correlated weakly with direct flow. Pre- versus postinfusion CWFA decreased with all ET-1 infusions (P 
.032). Infusion of fenoldopam mesylate increased CWFA in all cases (P .032).
CONCLUSION: Quantitative Doppler US enabled successful measurement of the flow changes induced with ET-1 and fenoldopam mesylate. Quantitative Doppler US is potentially useful as a noninvasive surrogate endpoint in evaluating the action of various therapeutic agents.
Index terms: Kidney, blood supply, 81.12981, 81.12982, 81.12983, 81.12984 • Kidney, perfusion, 81.12981, 81.12982, 81.12983, 81.12984 • Kidney, US, 81.12981, 81.12982, 81.12983, 81.12984 • Ultrasound (US), experimental studies, 81.12981, 81.12982, 81.12983, 81.12984
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INTRODUCTION
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Many compounds occurring naturally within the body, and certain pharmaceuticals, are known to affect and regulate blood flow. Despite rapid technologic advances in radiologic medicine, the role of diagnostic imaging in evaluating the action of various pharmaceuticals remains in its infancy and is still relatively unexplored. Our interest has been in using diagnostic ultrasonography (US) to develop image markers that can be used as surrogate end points for evaluating the action of various pharmaceuticals. In our previous studies (1–3), we demonstrated the use of Doppler US for quantifying the vascularity of breast masses, thyroid glands, and kidneys. In this study, we explored the potential use of these quantitative methods to evaluate the action of pharmaceuticals on blood flow in the kidneys.
Two classes of compounds, endothelin-1 (ET-1) and fenoldopam mesylate, were investigated. These compounds have opposite effects on renal blood flow (4–8). Whereas the infusion of ET-1 induces a decrease in renal blood flow, the infusion of fenoldopam mesylate, a selective and specific dopamine DA-1 receptor agonist, increases renal blood flow and is used to manage severe hypertension. In an earlier study, Insana et al (9) demonstrated ET-1 infusion as reducing the mean diameter of arterioles in the renal cortex. This was also accompanied by a decrease in blood flow. The purpose of our study was to evaluate quantitative Doppler US for assessing changes in renal blood flow induced with ET-1 and fenoldopam mesylate in conscious dogs.
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MATERIALS AND METHODS
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Surgical Procedures: Flow Probe Implantation
Eight healthy adult male beagle dogs (Marshall Farms, North Rose, NY) were used. Prior to imaging, a renal blood flow probe was implanted in each dog by following institutional guidelines for animal care. First, paralumbar laparotomy was performed. The left kidney was identified and retracted ventrally to facilitate identification of the left renal artery. The renal artery was identified with palpation and isolated with blunt dissection. A 4-mm renal blood flow probe (Transonic System, Ithaca, NY) was then placed around the renal artery, the "latch" slid into the closed position, and the set screw tightened. The placement of the probe and the security of the probe around the artery were again checked. The titanium connector button and cable were then tunneled subcutaneously to exit at the upper margin of the scapula through a small stab incision in the skin. The flow probe was then connected to the flow meter to check that pulsatile flow was measured, and the collar was placed onto the skin button.
US Imaging and Flow Measurements
US was performed in conscious restrained dogs after their recovery from surgery. The dogs were lightly sedated with subcutaneous injection of 0.5 mg of acepromazine maleate (PromAce; Ayerst, Rouses Point, NY) per kilogram of body weight at 1.0 mL/kg 5 minutes prior to the start of imaging. The kidneys were scanned by using a curved linear-array C7-4 MHz broadband transducer (ATL 5000; Advanced Technology Laboratory, Bothell, Wash). The transducer was mounted on a fixed stand with a flexible arm. An optimum plane of imaging, often coronal, encompassing the entire kidney was chosen, and the position of the transducer was locked to prevent its movement. If the animal moved, the transducer was repositioned manually to the chosen plane.
During each infusion, Doppler US images were recorded on a time-coded videotape by alternating between color and power Doppler US modes on the scanner. All imaging parameters were kept constant during each study. For color Doppler US, a pulse repetition frequency of 2,000 Hz, a medium wall filter, and color map 1 were used. For power Doppler US, a pulse-repetition frequency of 1,000 Hz, a medium wall filter, and color map 1 were used. ET-1–related imaging was performed with a color gain setting of 81% for both color and power Doppler US. A color gain setting of 72% was used for fenoldopam mesylate infusion. The lower color gain setting was necessary to avoid saturation of color level because of anticipated flow increase during fenoldopam mesylate infusion. The beginning of infusion was marked on the videotape. This marking, combined with time encoding on the tape, was used to determine time relative to the start of infusion.
Simultaneous with imaging, blood flow was measured directly through the renal artery by using the implanted renal blood flow probe. For this purpose, the flow sensor was connected to the flow detection unit by means of a flexible cable that was attached to the renal blood flow button exiting through the skin of the animal. The mean flow through the renal artery in milliliters per minute was recorded in 10-second intervals, and the data were captured with an acquisition system (Po-Ne-Mah; Gould Instrument Systems, Valley View, Ohio). The time was adjusted to synchronize with the scanner clock.
Changes in blood flow were induced with intravenous infusions of ET-1 (1.5–2.4 g/mL at 0.5 mL/kg/h) and fenoldopam mesylate (SmithKline, King of Prussia, Pa) (0.3 µg/mL at 0.5 mL/kg/h). The choice of these doses was based on in-house experience and on the results of an earlier study by Mann et al (10). Infusion was stopped when the flow either decreased by 45%–70% after ET-1 treatment or increased by 40%–130% after fenoldopam mesylate treatment. Changes in flow were measured relative to the preinfusion value. Drugs were infused on separate days, with at least 1 week between dosings.
Image Analysis
Color and power Doppler US images were digitized from the videotapes at one frame per second. Approximately 720 digital images were acquired for each infusion. The digital images were first reviewed by one of two authors (C.M.S. or J.A.P.), and the images with flash artifact—approximately 2%–3% of the images—were identified and removed. In the remaining images, the region enclosed within the border of the whole kidney was analyzed for flow by using a computer program (University of Pennsylvania, Philadelphia, Pa) to quantify image color levels. Other investigators (11–13) have adopted similar approaches. The first step in quantitative analysis was outlining the kidney on an image. This region of interest was drawn by C.M.S. or J.A.P. on the first image of the series. The computer then replicated the region of interest on all remaining images in the set. Then the images were reviewed, with the regions of interest superimposed. Regions of interest not conforming to the kidney border were redrawn.
Next, the image pixels within the regions of interest were analyzed for flow or color. This involved reading color levels in the color bars of the color and power Doppler US images. The color bar was divided into 100 equal levels. Each level was assigned a value of 0–100 on the basis of its position in the color bar. For color Doppler US, this analysis was repeated for two colors that represented the direction of flow. The signal levels represented in the color bars of power and color Doppler US images are often log compressed and "piecewise" linear with changing slopes, respectively. The precise nature of these functions is generally not known to the end user and varies from scanner to scanner. In this study, the data were reported by using a linear scale. Multiplication with the suitable conversion function could, in principle, be used to convert the data to an absolute signal level.
After mapping of the color bar, the computer was used to identify colored pixels within the regions of interest and assigned a value to each pixel by matching its color to a color within the color bar. From these measurements, three flow indices were determined: (a) mean color level, (b) percentage of area of color, and (c) color-weighted fractional area (CWFA). The properties of these flow indices are summarized in Table 1.
Each of the three indices was measured on a sequence of images acquired at 1-second intervals, and the measurements were averaged over 10 seconds. This step was necessary to compare two groups of measurements: imaging-derived flow indices versus direct flow. Flow indices were compared with direct flow by performing linear regression analysis, and measurements at the inception and conclusion of drug infusions were compared by performing the Student t test to evaluate the null hypothesis that infusion of fenoldopam mesylate and ET-1 did not change flow. The exact version of the Wilcoxon signed-rank test (StatXact-4; Cytel Software, Cambridge, Mass) was performed on the CWFA index of color and power Doppler US versus direct flow measurements.
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RESULTS
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Correlation between Imaging-derived Flow Indices and Direct Flow
Fourteen infusions were performed in eight dogs: seven with ET-1, and seven with fenoldopam mesylate. Two dogs received only one infusion each. The remaining six dogs received both ET-1 and fenoldopam mesylate treatment on separate days. In two of 14 cases, there were technical problems in recording direct flow, and in a third, there were marked image artifacts due to animal motion, and the data were not analyzed. Therefore, data from only 11 infusions are represented in this study.
Figure 1 shows plots of flow indices (mean color level, percentage of area of color, and CWFA) versus mean flow in one dog. Fenoldopam mesylate was used to change flow in this example. Each curve in the figure shows excellent correspondence between the image flow index (y axis) and mean flow (x axis). The data show a high Pearson correlation (r = 0.9) between the two modes of measurement.
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Figure 1. Graphs show correlations between imaging-derived flow indices and true flow as measured with implanted probes. Top panel shows correlation between mean color level and flow. Middle panel shows correlation between a percentage of area of color and flow. Bottom panel shows a correlative relationship between CWFA and mean flow. The data points are from one dog during fenoldopam mesylate infusion. The results show a strong correlation between imaging-derived indices and true flow.
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There were differences in correlation values from one animal to another. The r values for individual infusions are summarized in Tables 2 and 3. The significance of each correlation measurement is represented by the P value that was calculated by performing the Student t test for correlation with N - 2 degrees of freedom, where N is the number of observations. A mean of 45 data points ± 27 (SD) was used for each comparison. In 100% of cases in which both color and power Doppler US were performed, percentage of area of color and CWFA correlated significantly with actual blood flow (P .05) (Tables 2, 3). The mean color level index had a significant association in only 60% of cases (Tables 2, 3). The magnitude of correlation r was consistently lower for mean color level, as compared with the values for percentage of area of color and CWFA. The r coefficients for color and power Doppler US indices were consistently similar in magnitude (Tables 2, 3).
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TABLE 2. R Values for Linear Correlation between Imaging-derived Indices and Direct Flow Measurements during Fenoldopam Mesylate Infusion
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TABLE 3. R Values for Linear Correlation between Imaging-derived Indices and Direct Flow Measurements during ET-1 Infusion
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Pre- versus Postinfusion Comparisons of Flow
ET-1 infusion.—In Figure 2, Doppler US images acquired at the beginning of a 12-minute ET-1 infusion are compared with those acquired at the end. The top and bottom panels show power and color Doppler US images, respectively. There were notable differences between the images acquired at the inception and those acquired at the conclusion of ET-1 infusion. Preinfusion images showed well-defined vasculature of the kidney, including the outer cortex. With infusion of ET-1, the flow to the kidneys was markedly reduced. Particularly noticeable was the near-complete loss of cortical flow that was caused by the action of ET-1.
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Figure 2. Doppler US images acquired in a coronal plane of the kidney in a single animal before (left) and after (right) ET-1 infusion (0.15-1.25 µg/kg/h) show a decrease in flow that results from ET-1 infusion. The top and bottom panels represent power and color Doppler images, respectively. All image parameters were kept constant during ET-1 infusion. The time from beginning to end of infusion was 12 minutes.
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The qualitative changes demonstrated in Figure 2 are represented in more detail in Figure 3 as serial measurements of CWFA related to flow for color Doppler US images and to blood volume for power Doppler US images. The upper panels show plots of CWFA of color and power Doppler US images as a function of time during ET-1 infusion. The lower panels show the corresponding change in direct flow as measured with the implanted probe. The color and power Doppler US curves showed a decrease in CWFA with time after an initial delay. The same pattern was observed with direct flow and is shown in the lower panels of Figure 3.
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Figure 3. Graphs of data from a single dog show changes in flow and flow indices from ET-1 infusion. Graphs A and B show changes in CWFA derived from color Doppler US images and changes in mean flow during ET-1 infusion, respectively. Graphs C and D show corresponding changes in CWFA as derived from power Doppler US images and changes in mean flow as measured with the flow probe, respectively. Solid lines were drawn freehand to show the trend. These results show that imaging-derived indices follow the same pattern of change as does mean flow measured directly with a flow probe.
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The CWFA and flow measurements at the beginning and end of infusion in the individual dogs are shown in Figure 4. In each case (seven [100%] of seven dogs), there was a decrease in CWFA and in flow measured directly. The mean decreases in CWFA (black dots in Fig 4) were 68%, as measured with color Doppler US, and 53%, as measured with power Doppler US, versus 54%, as measured with direct flow. Results of the exact version of the Wilcoxon signed-rank test, performed on color and power Doppler US image indices versus on direct flow measurements, showed the CWFA reduction caused by ET-1 as measured with color and power Doppler US to be significant (P .032).
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Figure 4. Graphs show a comparison of CWFA and blood flow in the kidney before and after ET-1 infusion. Individual dogs are represented by open circles. Black circles and thick lines represent mean values. Graphs A and C represent flow measurements on color and power Doppler US images, whereas graphs B and D represent flow changes measured with the flow probe. Each pair of top and bottom panels represents simultaneous measurements. A flow decrease is observed in each case studied, in accordance with imaging-derived and direct measurements.
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Fenoldopam mesylate infusion.—Figure 5 shows changes induced with fenoldopam mesylate on Doppler US images. A noticeable color increase representing a marked enhancement of blood flow through the kidney was seen within 11 minutes of fenoldopam mesylate infusion. The quantitative CWFA changes seen with the two modes of Doppler US are shown in Figures 6A and 6C. In each case, there was a linear increase in flow with infusion. The changes measured with US matched the increase in flow measured with the implanted probe. As compared with true flow, the Doppler US measurements showed greater variation about the least-squares line of fit.
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Figure 5. Doppler US images acquired in a coronal plane of the kidney before and after fenoldopam mesylate infusion are compared and show an increase in flow as a result of fenoldopam mesylate infusion. The top and bottom panels represent power and color Doppler US images, respectively. All imaging parameters were kept constant during fenoldopam mesylate infusion. The time from beginning to end of infusion was approximately 11 minutes.
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Figure 6. Graphs show changes in flow induced with fenoldopam mesylate infusion in a single dog. Graphs A and B show changes in CWFA derived from color Doppler US images and the flow measurements with the flow probe, respectively. Graphs C and D show changes in CWFA as determined with power Doppler US and mean flow as measured with the flow probe. These results show a close similarity between imaging-derived indices and direct flow.
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The beginning and end of infusion are compared in Figure 7. In all cases there was an increase in flow with Doppler US and direct flow measurements. The measured mean maximum increase in flow (black circles in Figure 7) was 144% with color Doppler US and 92% with power Doppler US, as compared with 53% with direct flow. The exact version of the Wilcoxon signed-rank test (StatXact-4) was performed on color and power Doppler US image indices versus on direct flow measurements. It showed that the CWFA increase caused by fenoldopam mesylate as measured with color and power Doppler US was significant (P .032).
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Figure 7. Graphs compare blood flow in the kidney before and after fenoldopam mesylate infusion. Individual dogs are represented by open circles. Black circles and thicker lines represent mean values. Graphs A and C represent flow measurements with color and power Doppler US images, and graphs B and D show flow changes measured with the flow probe. Each pair of top and bottom panels represents simultaneous measurements. A flow increase is observed in each case with imaging-derived and direct measurements.
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DISCUSSION
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ET-1, a potent vasoconstrictor, is involved in many renal disorders (5–7). Fenoldopam mesylate, on the other hand, is a newer class of antihypertensive drug that stimulates renal blood flow (14). Taken together, these two classes of compounds play key roles in renal diseases and their treatment by regulating blood flow. An important question is whether these changes can be monitored noninvasively and in real time. The results of the current study show that color and power Doppler US modes of imaging are valid indicators of flow changes that are induced with ET-1 and fenoldopam mesylate. Three quantitative indices—mean color level, percentage of area of color, and CWFA—were measured for each mode. The values of these indices derived from color and power Doppler US imaging were comparable (Tables 2, 3), a finding that suggests that both modes perform equally well.
Comparison of the panels in Figures 3 and 6 shows that the imaging-derived parameters vary about the mean to a greater degree than do the direct flow measurements. Part of the reason for this difference is that our studies were performed in conscious dogs. Animal movements produced motion-related artifacts in the images and contributed to fluctuation in the data. A more compliant subject is likely to improve the value of the correlation coefficient.
The pre- to postinfusion decrease in CWFA indices with ET-1 matched the true flow measurements: 68% and 53% for color and power Doppler US, respectively, versus 54% for true flow. However, the extent of increase in CWFA with fenoldopam mesylate with imaging was larger than that observed with direct flow: 144% with color Doppler US, and 92% with power Doppler US, versus 53% with direct flow. The reason for this discrepancy is not known. It may be related to the bias caused by the linear scale used for mapping the color bar or may result from increased movement of the animals near the end of infusion, when they tended to be more restless because of the direct effects of the infusions.
In summary, the results of the current study demonstrate that quantitative color and power Doppler US examinations can be successfully performed as surrogate markers for monitoring renal blood flow changes that are induced with vasoactive substances. Although this study focused on demonstrating the effect of vasoactive compounds on renal flow, we believe that the proposed method can be applied to a wide range of clinical applications such as chemotherapy and angiogenic and antiangiogenic drugs and to other related physiologic effects of drugs.
Practical application: Much of the driving force of the current study has been to demonstrate that by performing color and power Doppler US, the effects of vasoactive substances such as ET-1 and fenoldopam mesylate can be reliably assessed. There is currently a need for noninvasive measurements that can be used as end points in evaluating newly emerging agents in preclinical and clinical trials. This study demonstrates that quantitative Doppler US is a suitable candidate for this purpose.
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FOOTNOTES
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Abbreviations: CWFA = color-weighted flow area,
ET-1 = endothelin-1
Author contributions: Guarantor of integrity of entire study, C.M.S.; study concepts, C.M.S., C.P.B.; study design, C.M.S., P.H.A.; literature research, J.A.P., C.M.S.; experimental studies, C.M.S., P.H.A., A.C.S.; data acquisition, C.M.S., A.C.S.; P.H.A., H.M.S.; data analysis/interpretation, C.M.S., J.A.P.; statistical analysis, C.M.S., J.A.P., A.B.; manuscript preparation, C.M.S., C.P.B.; manuscript definition of intellectual content, C.M.S., P.H.A., C.P.B.; manuscript editing, C.M.S., P.H.A., J.A.P., A.C.S., C.P.B.; manuscript revision/review, C.M.S., A.B.; manuscript final version approval, C.M.S.
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REFERENCES
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-
Sehgal CM, Arger PH, Pugh CR, Kirchofer JI, Kotlar EY, Bovee KC. Comparison of power Doppler and B-scan sonography for renal imaging using a sonographic contrast agent. J Ultrasound Med 1998; 17:751-756.[Abstract]
-
Sehgal CM, Arger PH, Rowling SE, Conant EF, Reynolds C, Patton JA. Quantitative vascularity of breast masses by Doppler imaging: regional variations and diagnostic implications. J Ultrasound Med 2000; 19:427-440.[Abstract]
-
Langer JE, Sehgal CM, Mandel S, et al. Color and power Doppler analysis of solid thyroid nodules (abstr). J Ultrasound Med 1999; 18:139.
-
Arger PH, Sehgal CM, Pugh CR, Kirchofer JI, Kotlar EY, Bovee KC. Evaluation of change in blood flow by contrast-enhanced power Doppler imaging during norepinephrine-induced renal vasoconstriction. J Ultrasound Med 1999; 18:843-851.[Abstract]
-
Huggins JP. Endothelins in biology and medicine Boca Raton, Fla: CRC, 1997.
-
Highsmith RF. Endothelins: molecular biology, physiology and pathology Totowa, NJ: Humana, 1998.
-
Jorkasky DK, Andet P, Shusterman N, Ilson B, Hendrich D, Stote RM. Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kidney transplant recipients. Am J Kidney Dis 1992; 19:567-572.[Medline]
-
Murphy MB, McCoy CE, Weber RR, et al. Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine 1 agonist fenoldopam. Circulation 1987; 76:1312-1318.[Abstract/Free Full Text]
-
Insana MF, Wood JG, Hall TJ, Cox GG, Harrison LA. Effects of endothelin-1 on renal microvasculature measured using quantitative ultrasound. Ultrasound Med Biol 1995; 21:1143-1151.[Medline]
-
Mann WA, Kinter LB, Woodward P. Selective DA-1 antagonism of SK&F R-87516-J, fenoldopam, and dopamine-stimulated renal vasodilation in dogs (abstr). Fed Proc 1986; 45:427.
-
Huber S, Delorme S, Knopp MP, et al. Breast tumors: computer-assisted quantitative assessment with color Doppler US. Radiology 1994; 192:797-801.[Abstract/Free Full Text]
-
Meyerowitz CB, Fleischer AC, Pickens DR, et al. Quantification of tumor vascularity and flow with amplitude color Doppler sonography in an experimental model: preliminary results. J Ultrasound Med 1996; 15:827-833.[Abstract]
-
Carson PL, Fowlkes JB, Roubidoux MA, et al. 3-D color Doppler image quantification of breast masses. Ultrasound Med Biol 1998; 24:945-952.[Medline]
-
Elliott WJ, Weber RR, Nelson KS, et al. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 1990; 81:970-977.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
