Cardiovascular Function During Induced Hypotension by Fenoldopam or Sodium Nitroprusside in Anesthetized Dogs Nguyen D. Gen, PhD, Peter G. Moore, MB, PhD, and Rory s. Jaffe, MD Department of Anesthesiology, University of California, School of Medicine, Davis, California

Fenoldopam, a selective dopamine, receptor agonist, has been recommended for induced hypotension because it effectively lowers arterial blood pressure and improves renal perfusion. We examined cardiovascular functions during hypotension induced by fenoldopam or sodium nitroprusside. In eight halothane-anesthetized dogs, the left ventricle (LV) was instrumented with pressure and ultrasonic dimension transducers for the assessment of LV contractility using the analysis of the pressure-diameter relationship. Blood flow distribution was measured by radioactive microspheres. Doses of fenoldopam and nitroprusside were titrated to reduce mean arterial blood pressure to 60 mm Hg. After 40 min of hypotension, fenoldopam and nitroprusside caused similar increases in heart rate (17% ? 4% vs 19% f lo%, respectively) and decreases in systemic vascular resistance (-24% & 5% vs -27% f 4%).Hypotension induced by fenoldopam was associated with higher LV end-diastolic pressure (4.4 0.6 vs 2.5 ? 1.1 mm Hg) and end-systolic meridional wall stress (33.0 4.3 vs 17.8 f 2.1 g/cm2)when compared with nitroprusside. There were no significant changes in cardiac output and cardiac contractility as expressed

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*

I

nduced hypotension is used to reduce intraoperative blood loss and to improve the surgical field (1).When arterial blood pressure decreases below a critical level, normal perfusion to vital organs is no longer maintained, particularly when vascular autoregulatory mechanisms are attenuated by anesthetics. Therefore, there is a continuing search for a hypotensive agent that can effectively lower arterial blood pressure while preserving blood flow to vital organs. Recently fenoldopam has been proposed for in-

Presented in part at the Sixty-Fourth Congress of the International Anesthesia Research Society, Honolulu, Hawaii, March 1990. Accepted for publication August 26, 1991. Address correspondence to Dr. Ken, Department of Anesthesiology, TB-170, School of Medicine, University of California, Davis, CA 95616.

by the slope (EeJ of the LV end-systolic pressurediameter relationship, velocity of shortening of the diameter, and percentage of wall thickening of the LV. In contrast to nitroprusside, which decreased renal blood flow from 197 f 19 to 163 f 15 mL/min, renal blood flow increased during fenoldopaminduced hypotension from 187 f 20 to 239 f 18 mL/min. The increase in renal perfusion was similar in upper, middle, and lower regions of the kidney; however, it was more in the medulla compared with the cortex (37% 17% vs 25% f 7%). Both fenoldopam and nitroprusside decreased splenic blood flow, but neither altered flow to the brain, skin, or myocardium. Muscle and hepatic arterial blood flow were significantly less with fenoldopam than with nitroprusside. Fenoldopam was associated with significantly larger increases in plasma renin activity compared with nitroprusside. The results of this study show an increase in renal blood flow during fenoldopam infusion that may be of advantage particularly when renal hypoperfusion should be avoided.

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(Anesth Analg 1992;74:72-8)

duced hypotension (2) because of its ability to decrease arterial blood pressure and to enhance renal perfusion and function (3-5). Vasodilation induced by fenoldopam is mediated by activation of the dopamine, (DA,) receptor, a subtype of the dopaminergic receptors (6). The presence of these receptors in the cerebral, coronary, mesenteric, and other vascular beds suggests that vasodilation may not be limited to the kidney; however, supporting data are lacking. The present study was designed to test the hypothesis that, during significant reduction in arterial blood pressure, perfusion to the heart, brain, kidney, and mesentery is maintained or possibly increased with fenoldopam. We evaluated fenoldopam as a hypotensive agent by comparing the effects of equipotent doses of fenoldopam and nitropmsside on cardiac performance and output distribution in dogs during halothane anesthesia. 01992 by the International Anesthesia Research Society

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0003-2999/92/$3.50

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Methods Experimental Preparation Eight adult mongrel dogs of either sex (21-26 kg) were anesthetized with intravenous thiamylal (15 mg/kg); anesthesia was maintained with inhaled 1.5% halothane in oxygen after tracheal intubation. Halothane concentration was measured at endexpiration by mass spectrometry (AIMT, St. Louis, Mo.). Ventilation was controlled using a Harvard respirator to maintain normal arterial blood gas tensions. A semirigid catheter was inserted into the abdominal aorta through a femoral artery for aortic pressure measurement and reference blood sampling. Blood pressure was measured using a Statham pressure transducer (model 23dB, Hato Rey, Puerto Rico). Cardiac output was measured by thermodilution using a pulmonary arterial catheter and an Edwards computer (model COM-1, Santa Ana, Calif.) with 5 mL of iced saline as the indicator. Values of cardiac output were averaged from triplicate measurements. Through a left thoracotomy in the fifth intercostal space, the pericardium was opened and a flexible polyethylene catheter was inserted into the left atrium through the appendage for microsphere injection. A solid-state Konigsberg transducer (model P7, Pasadena, Calif.) was placed in the left ventricular (LV) cavity through a stab wound in the apex for measurements of LV pressure and LV end-diastolic pressure. The Konigsberg transducer was calibrated in vitro against a mercury manometer and in vivo against systolic arterial and left atrial pressures. U1trasonic dimension crystals were implanted in pairs to measure the wall thickness of the LV freewall and the anterior-posterior transverse diameter of the left ventricle. Proper alignment of the crystals was confirmed with a high-frequency Tektronix oscilloscope (model RM647, Beaverton, Ore.). Ventricular dimensions were monitored with a Triton sonomicrometer (model 120, San Diego, Calif.). Electrical drift in the measurement system was minimized by frequent calibration during the experiment. Vascular occluders were placed around both venae cavae for varying preload during assessment of LV contractility. An electromagnetic flow probe was placed around the artery of the left kidney and connected to a Zepeda flowmeter (model SWF5RD, Seattle, Wash.) for continuous measurement of renal blood flow (RBF). Regional blood flow was measured using radioactive microspheres as previously described (7). Radioactive microspheres (3M, St. Paul, Minn.) 15 pm in diameter and labeled with 14'Ce, 85Sr, 95Nb, or 46Sc were suspended in 10% Dextran in saline containing 0.01% Tween 80. Before injection, the microsphere

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suspension was ultrasonically and mechanically agitated to achieve complete dispersion. The lack of aggregation of microspheres was verified by microscopic examination. The suspending solution was tested to confirm the absence of any adverse effect on cardiovascular function. Approximately 2-3 million microspheres were injected into the left atrium over 20 s and the injection catheter was flushed with warm normal saline. A reference blood sample was withdrawn from an arterial catheter starting 15 s before the microsphere injection to ensure steady sampling rate and continuing for 2 min at a constant rate of 7.75 mL/min. At the end of the experiment, the animal was killed with halothane overdose and intravenous injection of saturated KCI. The sampled organs were then removed, sectioned, weighed, and counted for radioactivity. Regional blood flow was calculated from the ratio of radioactive count of measured sample over that of reference blood sample and expressed in milliliters per minute per 100 g.

Data Analysis The data were recorded on a direct writing Gould oscillograph (model 2800S, Cleveland, Ohio) and on magnetic tape (Kyowa, model RTP-GOOB, Tokyo, Japan). Physiologic signals were digitized at 5-ms intervals using a Techmar 12-bit analog-to-digital converter and stored on floppy disks. Data were analyzed using a modified Asyst program (Asyst, Rochester, N.Y.) and an 80386 microprocessor. Variable parameters, including mean arterial blood pressure, stroke volume, and systemic vascular resistance were calculated using standard formulas. Percent of systolic shortening was calculated as the ratio of systolic dimension change to diastolic dimension. Velocity of shortening of the LV diameter was derived from the diameter signal using a differentiator. Calibration of the differentiator was made by substituting a triangular wave for the diameter signal. Left ventricular end-systolic meridional wall stress was calculated as described by Colan et al. (8):

where cr,, is the LV end-systolic wall stress in grams per square centimeter, and P,,, D,,, and he, are LV pressure, internal diameter, and wall thickness at end-systole, respectively. Cardiac contractility was assessed using the slope E,, of the linear regression of the LV end-systolic pressure-diameter relation. Ten to fifteen consecutive heart beats during vena caval occlusion were analyzed at end-systole. The respirator was turned off

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KIENETAL. FENOLDOFAM VERSUS NITROPRUSSIDE FOR INDUCED HYPOTENSION

momentarily during contractility assessment to eliminate respiratory influence on hemodynamic measurements. Ectopic beats and heart beats with RR intervals varying more than 10% during vena caval occlusion were excluded from analysis. Analysis of each cardiac cycle was performed by computer gating. End-systole was defined as the time at which the LV pressure/diameter ratio was maximal and enddiastole as the initial increase in the positive LV dP/dt. The LV pressure-diameter data were fit to the following equation: P,, = E,, (D,, - Do), where P,, and Des are LV end-systolic pressure and diameter respectively, Do is the intercept of the diameter axis, and E,, is the slope. This slope has been reported to be independent of loading conditions and closely related to cardiac inotropy (9-11).

Experimental Protocol The end-tidal halothane concentration was reduced to 1.0% after completion of the surgical preparation. Experiments were conducted after cardiovascular stability and normal arterial blood gas tensions were observed for 30 min. After a baseline recording, either nitroprusside or fenoldopam was infused using a variable-speed Harvard pump. The infusion dose was titrated to decrease mean arterial blood pressure to 60 mm Hg and recording was made after 40 min of infusion. The drug infusion was then stopped and a 60-min period was allowed for recovery. After a second baseline recording, the second drug was infused to produce an equivalent hypotension and recording was repeated as above. Microspheres were injected at baselines and at 40 min of the nitroprusside and fenoldopam infusions. The sequence of radioactive isotopes and the order of drugs were alternated randomly so each dog served as its own control. Blood samples were collected before microsphere injections and analyzed for plasma renin activity using radioimmunoassay (GAMMACOAT [-1251] Plasma Renin Activity Radioimmunoassay Kit). Data from eight dogs were analyzed using BMDP software and summarized as mean ? SEM. Statistical analysis of data included analysis of variance for repeated measures followed by t-test with Bonferroni modification. Probability values less than 0.05 were considered statistically significant. This study was approved by our institutional committee on the care and use of laboratory animals. The use of animals followed the guidelines of "Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Resources, National Council (DHHS publication No [NIH] 85-23, 1985).

ANESTH ANALG 1992;74:72-8

Results Hypotension induced by either fenoldopam or nitroprusside was similar in onset and recovery times. Steady-state arterial blood pressure was obtained 3.6 t 0.8 min after the start of fenoldopam infusion compared with 5.0 +- 0.9 min with nitroprusside. Arterial blood pressure returned to preinfusion level 11.52 2.5minwithfenoldopamvs. 13.352.8minwith nitroprusside after termination of infusion. From similar baseline mean arterial blood pressures, the dosages of fenoldopam and nitroprusside required to decrease mean arterial blood pressure to 60 mm Hg were 4.5 1.8 and 4.0 2 0.6 pg.kg-'.min-' ,respectively. In two of the eight dogs, large fenoldopam doses were required to maintain hypotension leading to the reported large standard error of the averaged dose of fenoldopam. Hemodynamic data obtained at baseline and during hypotension are summarized in Table 1. There were no significant differences between the two baselines. After 40 min of hypotension with either drug, heart rate increased by 17%, whereas systemic vascular resistance decreased by 24%. No significant changes in cardiac output and stroke volume were observed; however, LV end-diastolic pressure showed a greater decrease ( P < 0.05) during nitroprusside (- 52%) than during fenoldopam (- 15%) infusion as shown in Figure 1. Renal blood flow decreased slightly but significantly with nitroprusside. This decrease in RBF was not accompanied by a significant change in renal vascular resistance. In contrast, fenoldopam increased RBF by 28% concomitant with a 50% decrease in renal vascular resistance. Neither hypotensive agent altered cardiac contractility assessed by either the slope (EeJ of the LV end-systolic pressure-diameter relationship or percent systolic wall thickening or LV diameter shortening velocity. Left ventricular end-systolic meridional wall stress (WS) was reduced to one-half with nitroprusside; in contrast, changes in WS due to fenoldopam were not significantly different from baseline values (Figure 2). Plasma renin activity (PRA) increased during hypotension with both drugs, but the increase in PRA was significantly greater (P < 0.05) during fenoldopam infusion. Except for a decrease in Po, associated with nitroprusside infusion, blood gas tensions remained unchanged from baseline (Table I). Table 2 contains values of organ blood flows measured using radioactive microspheres at baseline and during infusion of either fenoldopam or nitroprusside. There were no significant differences between the two baselines. The transmural blood flow distribution across the LV wall did not change significantly with either agent as shown by the endocardial/ epicardial flow ratio. On the contrary, the ratio of

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KlENETAL. FENOLDOPAM VERSUS NITROPRUSSIDE FOR INDUCED HYPOTENSION

Table 1. Effects of Nitroprusside and Fenoldopam on Baseline Hemodynamics HR (beatdmin) LVP (mm Hg) MAP (mm Hg) LVEDP (mm Hg) CO (L/min) SV (mL) SVR (mm Hg.L-'.min-') RBF (mL/min) RVR (mm Hg.mL-'min-') E,, (mm Hg/mm) VS (D) (mm/s) % WT WS (g/cm') PRA (ng.mL-'.h-') PH Pco, (mm Hg) Po, (mm Hg)

Baseline

Nitroprusside

Baseline

Fenoldopam

108 2 8 110 2 7 82 2 5 6.6 2 0.5 2.61 2 0.18 26 2 3 31.9 2 2.0 197 2 19 0.48 2 0.06 13.8 2 3.3 -28.8 2 6.6 14.9 2 2.3 39.0 2 5.0 4.7 2 1.0 7.37 -t 0.01 40.0 2 2.5 264 rt 35

126 f 9" 79 f 4" 59 f 4" 2.5 2 l.la 2.39 t 0.22 20 f 2 23.1 f 1.6" 163 f 15" 0.39 2 0.12 15.6 t 4.4 -26.4 t 3.3 14.7 f 2.6 17.8 f 2.1" 11.9 t 1.0" 7.33 t 0.01 42.4 t 1.7 137 t 24"

107 t 8 108 t 5 82 f 4 6.7 ? 0.6 2.67 t 0.19 26 f 3 31.1 t 1.6 187 t 20 0.46 t 0.08 14.8 t 2.6 -28.3 t 5.2 15.0 f 2.6 40.6 f 5.3 4.2 t 1.5 7.38 t 0.02 39.6 f 2.9 256 t 29

124 t 8" 89 t 4" 61 f 5" 4.4 ? 0.6",b 2.76 t 0.25 24 t 3 24.4 t 2.3" 239 f Wb 0.24 t 0.07',b 18.4 t 4.9 -26.0 t 4.0 14.4 t 2.1 33.0 t 4.3b 20.4 f 3.64.b 7.34 2 0.03 42 2 2.8 262 t 26b _ _ _ ~

~

Values represent the mean f SEM of eight dogs. HR, heart rate; LVP, left ventricular pressure; MAP, mean arterial blood pressure; LVEDP, left ventricular end-diastolicpressure; CO, cardiac output; SV, stroke volume; SVR, systemic vascular resistance; RBF, renal blood flow measured by a calibrated flow probe; RVR, renal vascular resistance; E,,, slope of the left ventricular pressure-diameter relation; VS (D), velocity of shortening of LV diameter; % WT, percent of wall thickening; WS, left ventricular end-systolic meridional wall stress; PRA, plasma renin activity. "P < 0.05 compared with baseline. bP < 0.05 compared with nitroprusside.

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Figure 1. Hemodynamic changes from baseline in response to infusion of either fenoldopam or nitroprusside are compared. Except for a greater reduction in left ventricular end-diastolic pressure (LVEDP) with nitroprusside, changes in heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO), and systemic vascular resistance (SVR) are similar between agents. Bars represent mean ? SEM of eight dogs. *P < 0.05 compared with baseline. t P < 0.05 compared with nitroprusside.

myocardial oxygen supply to demand expressed by endocardia1 blood flow over wall stress increased significantly with both fenoldopam and nitroprusside, and a greater (P < 0.05) increase was observed with nitroprusside than fenoldopam. Regional blood flow distribution, expressed as percent change from baseline, showed similar decreases in blood flow to the spleen, whereas blood flow to the brain, small intestine, and skin did not change significantly with either drug. A twofold increase in hepatic arterial blood flow was observed with nitroprusside. In con-

Figure 2. Comparison of myocardial performance during induced hypotension by either fenoldopam or nitroprusside. Changes are in percent from baseline. Myocardial performance assessed by the slope E,, of the left ventricular end-systolic pressure-diameter relationship, percent of wall thickening (%WT), and velocity of shortening of left ventricular diameter [VS(D)] does not change significantly with either drug. Left ventricular end-systolic wall stress (WS) decreases significantly more with nitroprusside than with fenoldopam. Bars represent mean t SEM of eight dogs. *P < 0.05 compared with baseline. t P < 0.05 compared with nitroprusside.

trast, there were significant decreases in blood flow to the hepatic artery and muscle beds with fenoldopam (Figure 3). Figure 4 shows regional distribution of blood flow to the renal bed as percent change from baseline. Renal perfusion decreased significantly with nitroprusside, whereas it increased with fenoldopam. Blood flow to the medulla, compared to the cortex,

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Table 2. Effects of Nitroprusside and Fenoldopam on Blood Flow Distribution Baseline Skin Muscle Liver (arterial Bow) Spleen Right atrium LV endocardium LV epicardium LV septum Right ventricle Small intestine Kidney cortex Kidney medulla Brain EndolEpi Endows

Nitroprusside

2.8 2 0.4 4.7 f 0.3 14.7 f 3.8 198 f 34 78 f 13 88 f 11 78 f 8 73 f 7 59 f 4 6027 673 f 39 74 13 57 2 5 1.09 f 0.05 2.91 f 0.53

2.0 2 0.4 5.4 4 0.5 24.6 Itr 4.8" 124 -t 11" 74 It- 17 92 -t 10 8349 71 4 7 6045 63 -t 10 558 f 32" 63 f 10 57 4 3 1.19 4 0.05 6.40 4 1.54"

*

Baseline

Fenoldopam

2.9 2 0.6 4.5 2 0.6 13.8 t 4.5 226 f 20 81 f 11 95 f 10 85 f 7 79 f 7 65 f 5 66 f 10 649 f 44 71 f 10 55 f 5 1.12 4 0.06 2.90 f 0.62

2.6 f 0.5 3.1 f 0.4b 6.4 f 1.Yb 128 2 9" 77 f 8 85 f 5 78 f 5 70 f 5 61 f 4 76 f 10 804 f 92 f Fb 50 f 5 1.15 f 0.07 3.40 f 0.69b

Values represent the mean 5 SEM in mLmin-'.100 g-' of eight dogs. LV, left ventricular; Endompi, endocardiudepicardium blood flow ratio; EndoMS, endocardial blood flowfleft ventricular end-systolic meridional wall stress ratio. 'P < 0.05 compared with baseline. *P < 0.05 compared with nitroprusside.

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Figure 3. Changes in regional blood flow distribution in response to fenoldopam and nitroprusside are compared. Note similar reductions in splenic blood flow between the two drugs and significant decreases in blood flow to the muscle and liver (arterial flow) during fenoldopam infusion as compared with nitroprusside. Bars present mean f SEM of eight dogs. *P < 0.05 compared with baseline. t P < 0.05 compared with nitroprusside.

demonstrated a trend toward higher increases with fenoldopam and smaller decreases with nitroprusside. The changes in renal perfusion induced by either fenoldopam or nitroprusside did not vary when measured from the upper, middle, or lower regions of the kidney.

Discussion Data from this study in dogs demonstrate that fenoldopam is as effective as nitroprusside in lowering arterial blood pressure to 60 mm Hg. Fenoldopaminduced hypotension was rapid in onset and abated quickly upon termination of infusion. Despite similar

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Figure 4. Comparison of renal blood flow distribution during hypotension induced by either fenoldopam or nitroprusside. Changes are in percent from baseline with negative signs representing decreases. Cross sections of different regions of the right kidney are divided into cortex (C) and medulla (M). Renal perfusion decreases with nitroprusside, whereas it increases with fenoldopam. Values are mean f SEM. *P < 0.05 compared with nitroprusside. t P < 0.05 compared with fenoldopam.

levels of hypotension, different regional blood flow distributions were demonstrated between the two agents. In particular, hypotension induced by fenoldopam was characterized by a selective 28% increase in renal perfusion without significant changes in coronary and cerebral blood flow or cardiac performance. The reduction in arterial blood pressure with either drug was attributed to a decrease in vascular resistance owing to a direct peripheral vasodilation (7). Because fenoldopam does not cross the blood-brain barrier (12,13), the hypotensive effect of fenoldopam is restricted to peripheral activity. Unlike nitroprusside, which acts as a nonspecific direct dilator on arterial resistance vessels (14),fenoldopam induces

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relaxation of vascular smooth muscle by activation of postsynaptic DA, receptors. This vasodilator effect of fenoldopam is reported to be independent of aadrenergic, padrenergic, cholinergic, or histaminergic receptors, or of catecholamine release (2,13). The venodilator effect of fenoldopam appears to be less intense than that of nitroprusside. At equal hypotensive level, a significantly lower LV end-diastolic pressure was observed with nitroprusside than fenoldopam, indicating a greater venodilation and reduced venous return with nitroprusside (15). Fenoldopam-induced hypotension was not accompanied by increased pulmonary shunting. Arterial oxygen tension remained constant during systemic hypotension with fenoldopam, in contrast to the nearly 50% decrease seen with nitroprusside. Recently, assessment of cardiac contractility has included analysis of the LV end-systolic pressurediameter relationship. This analysis provides an index of contractility that is highly sensitive to inotropic changes (9-1 1). Whether this index remains reliable in extreme loading conditions is subject to controversy (16,17). In the present study, other indices of contractility including percent of systolic shortening and velocity of shortening were also used to support the analysis. The results show that cardiac contractility was not significantly altered during 40 min of stable hypotension with either agent. In contrast, Ventura et al. (3) reported increases in LV ejection rate and velocity of circumferentialfiber shortening in hypertensive patients treated with fenoldopam. However, these changes were not attributed to a direct positive inotropic effect of the drug. Instead, afterload reduction and activation of baroreceptors were thought to be responsible for reflex stimulation of the heart. This explanation agrees with an earlier report demonstrating an absence of inotropic effect of fenoldopam on isolated papillary muscle (13). In the present study, hypotension induced by both drugs was accompanied by a gradual increase in heart rate. Nitroprusside maintains normal heart rate at moderate levels of hypotension (7,18). However, when the cumulative dose of nitroprusside increased, heart rate increased through enhanced sympathetic activity (19,20). Similarly, tachycardia associated with fenoldopam may be due to baroreceptor activation in response to hypotension. Interestingly, increases in heart rate were not observed when fenoldopam was infused in dogs anesthetized with pentobarbital (13) or was infused over a shorter duration (21). Cerebral and coronary blood flows did not change during infusion of either fenoldopam or nitroprusside, suggesting that autoregulatory mechanism in these organs remained intact at this level of hypotension. On the other hand, RBF decreased after 40 min of nitroprusside infusion. The decrease in renal per-

77

fusion was similar to those previously reported at equal or lower levels of hypotension (18,21-23). With less severe hypotension and a shorter duration of nitroprusside infusion, there was a trend toward an increase in RBF (7,24). These findings support the theory that despite the dependence of RBF on perfusion pressure, blood flow to the renal bed may be related to level of hydration and reflex stimulation of sympathetic vasoconstrictor nerves (18,22). In contrast, fenoldopam significantly increased RBF by decreasing renal vascular resistance. Our results show a trend favoring a larger increase in medullary over cortical blood flows. This trend, although not reaching statistical significance, could be related to the regulation of medullary tonicity for the maintenance of Na+ balance in the kidney. Nevertheless, the marked increases in RBF explain the increases in urine and Na+ excretions reported in normal or hypertensive patients treated with fenoldopam (4,25). Fenoldopam is known to act specifically on DA, receptors. These receptors are located in abundance in the renal bed and to a lesser extent in the splanchnic bed, and their activation leads to a marked reduction in vascular smooth muscle tone (2,6,13). Although the renal vasodilation caused by fenoldopam is mainly mediated by the postsynaptic DA, receptors, whether presynaptic DA, receptors are also involved in the vascular activity of this drug remains controversial (13,26). Fenoldopam infusion was accompanied by increased PRA that was significantly greater than that observed with nitroprusside. This increased PRA may account for increases of fenoldopam doses in two dogs to counteract vasoconstrictor effects caused by activation of the renin-angiotensin system. Whereas the increase in PRA may often be viewed as a compensatory response to systemic hypotension (27), fenoldopam-induced increases in PRA have been reported in the absence of blood pressure changes. Moreover, enhanced PRA persisted when fenoldopam was infused into the renal artery of ganglionic-blocked dogs or dogs in which the renal vasculature was maximally dilated (28). These findings strongly support the postulate that fenoldopam increases PRA by stimulating specific DA, receptors located at the juxtaglomerular cells (29,30). Nevertheless, despite elevated PRA, increments of RBF were probably mediated through dilation of renal vasculature secondary to activation of postsynaptic DA, receptors as well as through inhibition of vasoconstriction via presynaptic mechanisms. Absence of rebound hypertension after fenoldopam suggests that the increase in PRA rapidly abates after termination of infusion. In summary, the results of this study show similar effectiveness in induction of hypotension by either

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KIENETAL. FENOLDOPAM VERSUS NITROPRUSSIDE FOR INDUCED HYPOTENSION

fenoldopam or nitroprusside. These hypotensive drugs decreased arterial blood pressure by decreasing vascular resistance, but differences emerged when examining effects on regional blood flow. Importantly, RBF increased significantly with fenoldopam, whereas blood flow to other vital organs was well maintained. This renal vasodilator property may be particularly useful when renal perfusion should be protected during induced hypotension. However, owing to the increase in PRA associated with fenoldopam, angiotensin-converting enzyme inhibitors may be needed with fenoldopam for maintaining stable hypotension when longer infusion periods are necessary. Further study seems warranted for the evaluation of the combination of an angiotensinconverting enzyme inhibitor and fenoldopam, as fenoldopam, because of its selective (especially renal) effects, holds promise for clinical use as a hypotensive agent. We thank Richard Martucci, Collette LaRocque, and Freda Hwang for their technical support, and Lynn Gall for preparing the manuscript. We are grateful for a generous supply of fenoldopam from Smith-French and Kline Laboratories.

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Cardiovascular function during induced hypotension by fenoldopam or sodium nitroprusside in anesthetized dogs.

Fenoldopam, a selective dopamine1 receptor agonist, has been recommended for induced hypotension because it effectively lowers arterial blood pressure...
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