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CARDIOVASCULAR AND RENAL HEMODYNAMIC EFFECTS OF DOPEXAMINE: COMPARISON WITH DOPAMINE
British Journal of Anaesthesia 1990; 65: 380-387
CARDIOVASCULAR AND RENAL HAEMODYNAMIC EFFECTS OF DOPEXAMINE: COMPARISON WITH DOPAMINE H. STEPHAN, H. SONNTAG, H. HENNING AND K. YOSHIMINE
We have studied the effects of dopexamine and dopamine on systemic and renal haemodynamics in 20 male patients undergoing elective coronary artery bypass surgery. Patients were allocated randomly to two groups (n = 10) who were treated with incremental doses of either dopexamine 1, 2 and 4 pg kg'1 min~1, or dopamine 2.5 and5 ng kg~' min~', each dose being maintained for 15 min. Measurements were performed before administration of the drug and at the end of the infusion period at each dose. Fentanyl and midazolam were used as anaesthetic agents. Renal blood flow was measured with the argon washin technique. Dopexamine 4 fig kg'1 min'1 produced an increase in cardiac index of 117% caused by a 65% reduction in after/oad and an increase in heart rate by 61%. Dopamine 5 pig kg~1 min~1 caused a 40% increase in cardiac index as a result of an increase in stroke volume. Renal vascular resistance decreased more than systemic vascular resistance with dopamine. With dopexamine, the increase in renal blood flow (66%) was less than the increase in cardiac index, while renal vascular resistance and systemic vascular resistance declined to a/most the same extent. The results show that dopexamine exerts systemic and renal effects mainly via stimulation of ^-receptors. An action of dopexamine at renal DA,-receptors could not be demonstrated in this study.
I). It acts as a strong agonist at Pj-adrenoreceptors and stimulates peripheral dopamine receptors; its potency at vascular DA^receptors is 33 % that of dopamine and its activity at prejunctional DA2receptors is four to six times less. Dopexamine has no a-adrenergic and only weak Pi-adrenergic effects and inhibits active neuronal reuptake of catecholamines (uptake-1) [1, 2]. Dopexamine reduces systemic vascular resistance and thus afterload and this is followed by an increase in cardiac output; it has specific renal vasodilating properties, with only little direct and indirect positive inotropic and chronotropic effects [1, 3, 4]. This profile suggests dopexamine may be superior to dopamine in treatment of low cardiac output states, when the usefulness of the latter is often limited by vasoconstriction, excessive tachycardia and arrhythmias [5, 6]. The aim of this study was to investigate the effects of dopexamine on general and renal haemodynamics in patients about to undergo aorto-coronary bypass surgery and to determine if these effects are superior to those of dopamine in cardiac patients. PATIENTS AND METHODS
We studied 20 male patients (ages 43-62 yr, weight 66-102 kg) undergoing elective coronary artery bypass surgery. The study was approved by the Gottingen University Human Subjects Review Committee and written informed consent was obtained from each patient. Patients were
KEY WORDS Heart: dopamine, dopexamine, cardiac output. Kidney: blood flow. Surgery: coronary artery bypass.
Dopexamine hydrochJoride is a new synthetic dopamine analogue with properties and receptor activities different from those of dopamine (table
H. STEPHAN, M.D.; H. SONNTAG, M.D.; H. HENNING, M.D.;
Department of Anaesthesiology, University of Gottingen, Robert Koch-Str. 40, D-3400 Gottingen, W. Germany. K. YOSHIMINE, M.D., Department of Anaesthesiology, Kagoshima University, Usuki-Cho 1208-1, Kagoshima-Shi, 890 Japan. Accepted for Publication: February 16, 1990. Correspondence to H. Stephan.
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SUMMARY
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS TABLE I. Receptor activitiei of dopexamine and dopamine. — = No activity; ( + ) = weak; + = mild; + + = moderate; + + + = strong stimulation [1—4]
Receptor DA, DA,
Dopexamine
Dopamine
381
body temperature and vascular pressures (Statham P23IA) were monitored continuously and recorded simultaneously on a 10-channel chart recorder (Hellige, Freiburg). Measurements and anaesthesia
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Anaesthesia was induced with fentanyl 6 |ig kg"1 and midazolam 0.2 mg kg"1 and maintained with fentanyl 0.15 |ig kg"1 min"1 and Uptake-1 midazolam 3 (ig kg"1 min"1. Pancuronium 8 mg inhibition was administered to facilitate tracheal intubation and the lungs were ventilated with 30 % oxygen in allocated randomly to one of two groups treated air using a constant volume ventilator (Engstrom with either dopexamine (n = 10) or dopamine (« ER 300). After induction of anaesthesia and a 15-min = 10). There were no significant differences in age, weight, body surface area and ASA physical period of rest, control measurements were perstatus between the groups. No patient gave a formed. Subsequently, incremental doses of either history of congestive heart failure or valvular dopexamine 1, 2 and 4 ug kg"1 min"1 or dopamine heart disease. Ejection fraction was greater than 2.5 and 5 (ig kg"1 min"1 were administered, each 0.4. None of the patients had either a history or maintained for 15 min, and measurements were clinical evidence of metabolic disorders, liver repeated at the end of the infusion period at each disease or renal impairment. All patients were dose. The doses of dopamine and dopexamine receiving maintenance doses of calcium-channel were chosen on the basis of expected renal blocking drugs and nitrates. Two patients in the equipotency. dopexamine group and three patients in the Renal blood flow (RBF) was measured using dopamine group were treated with P-adreno- the argon washin technique (coefficient of varireceptor antagonists. The last doses of all drugs ation ±5 %), a modification of the Kety-Schmidt were administered in the morning of the op- technique [7] which includes simultaneous blood eration. All patients were premedicated with sampling from the renal vein and the radial artery flunitrazepam 2 mg orally and promethazine during a 5-min period of inhalation of a standard 50 mg i.m. 1 h before arrival in the anaesthetic concentration of argon. Immediately before and room. after each measurement of RBF, arterial and renal venous blood samples were taken and analysed for Catheterization procedure haemoglobin concentration, oxygen saturation Upon arrival in the anaesthetic room ECG and content (CO-Oximeter IL 282 and Lex-Ojleads (lead II) were attached. Using the Seldinger Con, Instrumentation Lab.), blood-gas tensions technique under local anaesthesia, the following (standard electrodes, Radiometer) and electrolyte catheters were positioned: a 20-gauge catheter concentrations (atom absorption spectrophotoconnected to a Goodale-Lubin catheter (USCI, metry, Perkin Elmer 303). 6F) in the radial artery of the non-dominant hand Cardiac output was measured by thermoto monitor arterial pressure and for blood sam- dilution (Fischer BN 7206). Cardiac index (CI) pling; a second Goodale-Lubin (USCI, 6F) via was calculated by dividing cardiac output by the the right internal jugular vein into the right renal body surface area, and stroke volume index (SVI) vein for measurement of blood flow and with- by dividing CI by heart rate. Systemic vascular drawal of blood samples; a pulmonary artery resistance (SVR) and pulmonary vascular recatheter (Edwards quadruple thermodilution sistance (PVR) were derived from standard model No. 93A 131-7F) flow-directed via an formulae, and renal vascular resistance (RVR) was antecubital vein into the pulmonary artery for calculated by dividing mean arterial pressure measurement of pulmonary artery and wedge (MAP) minus renal venous pressure by RBF. pressures and cardiac output; and a polyethylene Statistical analysis of the data obtained in each catheter into the superior vena cava for admin- group was performed using the Wilcoxon istration of drugs and infusions. The positions of matched-pairs signed-ranks test; P < 0.05 was all catheters were confirmed radiologically. ECG, considered significant.
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TABLE II: Dopexamine: cardiovascular and renal haemodynamc effects (mean (SDj). HR = Heart rate; SAP = systolic arterial pressure; DAP = diastolic arterial pressure; MAP = mean arterial pressure; PCWP = pulmonary capillary wedge pressure; MPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; CI = cardiac index; SVI = stroke volume index; RBF = renal bloodflow;RVR = renal vascular resistance. P < 0.05 compared with: * control; + 2 fig kg'1 min~l Dose of dopexamine (ng kg"1 min *)
1
1
59 (10) 117(20) 68(12) 83(15) 2.8(1.9) 6.5(3.1) 12.5 (5.0) 110(59) 1424 (228) 2.40 (0.49) 42(9) 314 (49) 0.26 (0.06)
67(11)* 109 (20) 55 (15)* 71 (15)* 2.8(1.9) 7.1 (3.0) 14.2 (5.2) 81 (35)* 780 (238)* 3.86 (0.87)* 58(11)* 442 (87)* 0.15(0.04)*
4
2
75 (17)* 112(19) 55(13)* 71(13)* 3.2 (2.0) 6.9 (2.4) 14 (4.6) 74 (36)* 706 (288)* 4.29 (0.90)* 58(11)* 469 (109)* 0.15(0.05)*
95 (39)*+ 102 (12)* 48(9)* 65(11)* 4.2 (2.7) 8.3 (2.0) 17.8(3.1) 79 (27)* 503 (148)*+ 5.21 (1.17)*+ 58(11)* 521 (147)* 0.12(0.03)*
TABLE III. Dopamine: cardiovascular and renal haemodynamic effects (mean (SD)). For abbreviations see table II. P < 0.05 compared with: * control; + 2.5 fig kg'1 min'1 Dose of dopamine (Hg kg"1 min"1)
1
HR (beat min" ) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) RAP (mm Hg) PCWP (mm Hg) MPAP (mm Hg) PVR (dyn s cm"*) SVR (dyn s cm"5) CI (litre min-1 m"1) SVI (ml m"») RBF ((ml/100 g) min-1) RVR (mm Hg/(ml/100 g) min-1)
Control
2.5
56(7) 108(18) 61(8) 78 (12) 2.8(1.0) 6.3(2.3) 12.3(3.1) 100 (28) 1230(179) 2.46(0.35) 45(8) 309(46) 0.24 (0.06)
57 (13) 126 (23)* 65 (10) 86 (16)* 3.9 (2.0)* 8.9 (3.5)* 16.3(5.6)* 97(30) 1079 (190)* 3.07 (0.36)* 55 (10)* 445 (84)* 0.19(0.04)*
RESULTS
Cardiovascular effects
With increasing doses of dopexamine (table II), heart rate increased significantly and almost linearly by up to 61 % at 4 ug kg"1 min"1. SVR declined in a dose-dependent manner, by 45 % with the smallest dose and by 65 % with dopexamine 4 ug kg"1 min"1, which resulted in significant decreases in diastolic arterial pressure (DAP) (19% and 29%, respectively). While systolic arterial pressure (SAP) decreased sig-
5
59(13) 155 (19)*+ 76(15)*+ 101 (14)*+ 5.1(2.2)* 12.5 (5.5)*+ 22.7(12.8)*+ 121 (96) 1134(191) 3.45 (0.53)*+
60 (10)* 559 (88)*+ 0.17(0.04)*
nificantly (—13%) only with the greatest dose, MAP declined less than DAP (-14%) with the smallest dose of dopexamine and remained essentially unchanged with increasing doses. Right atrial, mean pulmonary arterial and wedge pressures changed little during the entire study period, while PVR decreased by 26 % with the low dose; increasing doses of dopexamine did not have any further effect. The marked reduction in afterload led to a 38% increase in SVI with the smallest dose, but increasing doses of dopexamine caused such a great increase in heart rate that, although
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HR (beat min" ) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) RAP (mm Hg) PCWP (mm Hg) MPAP (mm Hg) PVR (dyn s cm"5) SVR (dyn s cm-6) CI (litre min-1 m"1) SVI (ml m"1) RBF ((ml/100 g) min-1) RVR (mm Hg/(ml/100 g) min"1)
Control
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS
383
Dopexamine 3 ug kg' 1 min' 1
AP
jiOmmHg
FIG. 1. ECG (lead II), arterial pressure (AP) and pulmonary artery pressure CPAP) of a patient before (A) and during (B) administration of dopexamine 3 ng kg"1 min"1. Vertical scales: mm Hg.
Dopexamine (pg kg' 1 min"1)
_
0
1
2
4
-50QSVR
o-100 J Dopamine (|jgkg^min' 1 ) Change f rom cont rol U>
2.5
5
*
•
-50-
-100-
FIG. 2. Percentage changes in RVR and SVR compared with control values with increasing doses of dopexamine and dopamine. P < 0.05 compaxed with: * control; fall values.
CI was further increased by up to 117% with 4 ng kg"1 min"1, SVI did not show any further changes. The cardiovascular effects of dopamine (table III) differed substantially from those of dopexamine. While heart rate did not change with each dose of dopamine, SAP increased by 17% with
2.5 Hg kg"1 min-1 and by 44% with 5ugkg" x min"1. DAP and MAP increased, but only by 25 % and 29 %, respectively, with the high dose. There were marked dose-dependent increases in mean pulmonary arterial and wedge pressures, reaching almost twice the baseline values with 5 Hg kg"1 min"1, while PVR and SVR were influenced little. Heart rate remained unchanged throughout the study period; CI and SVI increased by 25% and 22%, respectively, with the low dose and by 40 % and 33 %, respectively, with the high dose of dopamine. Two patients in the dopexamine group developed ST-segment suppression. In one, heart rate increased from 62 beat min"1 to 79 beat min"1 and MAP and DAP decreased from 70 and 50 mm Hg to 50 and 40 mm Hg, respectively, with 4 ug kg"1 min"1. The second patient (fig. 1) had an increase in heart rate from 53 beat min"1 to 85 beat min"1 with dopexamine 3 ug kg"1 min"1, accompanied by decreases in MAP and DAP from 90 and 68 mm Hg to 50 and 40 mm Hg, respectively. Only one patient in the dopamine group developed ST-segment suppression with 5 ug kg"1 min"1: at a stable heart rate of 55 beat min"1, MAP increased from 85 to 105 mm Hg and DAP from 65 to 75 mm Hg. In three patients, the administration of dopamine 5 ug kg"1 min"1 was associated with arrhythmia: one patient developed atrial fibrillation, the second had supraventricular ectopic beats and the third, ventricular ectopic beats.
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PAP
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100 -,
50.
5 o 2 Dopexamine
100
50-
CO
IRBF
O
2.5
5
Dopamine (|jg kg" 1 min"1)
FIG. 3. Percentage changes in CI and RBF compared with control values, with increasing doses of dopexamine and dopamine. P < 0.05 compared with: * control; fall values.
Renal haemodynamics
In spite of their different effects on cardiovascular dynamics, both drugs affected RBF and RVR similarly (tables II, III). Figure 2 illustrates the changes in RVR and SVR with increasing doses of dopexamine and dopamine expressed as percentages from control values. With dopexamine the ratio between RVR and SVR remained essentially unchanged, whereas increasing doses of dopamine had more effect on RVR than on SVR. While increasing doses of dopexamine improved CI more than RBF, such that the renal fraction of CI (RBF/CI x 100) decreased from 13 % to 10%, dopamine had more effect on RBF than on CI at increasing doses, with the renal fraction of CI increasing from 13% to 16% (fig. 3). DISCUSSION
Haemodynamic effects
The results of this study demonstrate that both dopexamine and dopamine increased cardiac out-
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1
put, but via different mechanisms. Dopamine exerted its effects mainly by increasing stroke volume, attributed to activity at cardiac p r receptors [8, 9] resulting in increased contractility [9—11]. Dopexamine had little influence on stroke volume, but affected cardiac index by increasing heart rate and reducing SVR. Studies in dogs confirmed that the marked decrease in SVR is caused by stimulation of DA15 DA, and p s receptors, while tachycardia is caused mainly by a pj-mediated baroreceptor reflex [1-3]. In contrast with the data of the present study, Mousdale and colleagues [12] found an increase in SAP with dopexamine 1, 2 and 4 |ig kg"1 min"1 in six healthy, awake volunteers. One may assume that awake subjects in a study are subjected to increased sympathetic tone, leading to a-receptormediated vasoconstriction in the peripheral vascular bed and thus attenuation of the vasodilating effects of dopexamine. On the other hand, patients in the present study were receiving maintenance doses of calcium-channel blocking drugs, which may have enhanced the vasodilating properties of dopexamine. Patients with congestive heart failure are known to have high plasma concentrations of noradrenaline [13]. Increased exposure of the failing heart to noradrenaline is an explanation for selective Px-receptor downregulation, while selective P2-receptors retain near full inotropic activity mediated through a P2 population that is not significantly decreased [14]. Moreover, in chronic heart failure the baroreflex is generally blunted [15], which reduces the ability of dopexamine to stimulate the failing heart through baroreflex activation. However, because plasma concentrations of noradrenaline are increased, uptake-1 block by dopexamine may potentiate the cardiac effects of noradrenaline, and stimulation of cardiac P2-receptors by dopexamine may become clinically important. All these mechanisms may lead to increased inotropy and decreased chronotropy with dopexamine in the failing heart compared with the actions of this drug in the non-failing heart [4]. This may also explain why arterial pressure remained relatively unaffected by dopexamine in patients with congestive heart failure [16, 17] whilst arterial pressure decreased in the present study, in which patients suffered from coronary heart disease but not from heart failure. Mean pulmonary artery pressure and right and left atrial pressures remained unchanged and PVR decreased to a lesser extent than SVR, indicating that dopexamine had little influence on venous
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS
Adverse cardiovascular effects
In spite of their different haemodynamic effects, both drugs produced ST-segment depression indicating myocardial ischaemia. With dopamine, augmentation of contractility led to an increase in myocardial oxygen demand, which could not be met by an increase in coronary blood flow in one patient. Dopexamine increases oxygen demand by increasing heart rate, which may be counterbalanced by reduction in afterload and wall stress. It also decreased DAP and thus coronary perfusion pressure and by this mechanism may have induced myocardial ischaemia in two patients. Myocardial ischaemia has been reported with dopamine [21] and with dopexamine [22]. Arrhythmias seem to occur significantly more often with dopamine than with dopexamine and are thought to be principally a Pi-receptor mediated effect. In animals, dopexamine was shown not only to be associated with a lower incidence of late arrhythmias after coronary occlusion than occurs with dopamine, but also to reduce the incidence of early arrhythmias to less than that seen without treatment [23]. The clinical observations of other authors and ourselves confirm these findings [16, 22].
Renal haemodynamics
Dopamine causes direct renal vasodilatation; an effect which is not blocked by P2-receptor antagonists [24]. These findings were confirmed by a subsequent study in volunteers, who developed a 57 % increase in RBF at subpressor doses of i.v. dopamine accompanied by a 48 % increase in CI, such that the renal fraction of CI remained unchanged [25]. Rosenblum, Tai and Lawson [21] observed a 26% increase in CI and a 79% increase in RBF at doses between 2.1 and 5.8 ug kg"1 min"1. This finding is consistent with the results of Abrahamsen and colleagues [11], who showed a 27% increase in CI and a 48% increase in RBF, together with an improvement of the renal fraction from 12% to 14%, with dopamine 5 ug kg"1 min"1 in patients with ischaemic heart disease. The 44% and 8 1 % increases in RBF with dopamine 2.5 and 5 ug kg"1 min"1, respectively, obtained by the use of the argon washin technique in the present study, are within the range of values reported by other investigators. These improvements in RBF were caused by 25% and 40% increases in CI and by decreases in RVR by up to 28%, whereas SVR remained essentially unchanged (fig. 2); this is evidence for selective renal vasodilatory effects. The increase in CI was smaller than that in RBF (fig. 3), and MAP remained within the range of autoregulation, suggesting that systemic haemodynamic changes cannot solely account for improved renal haemodynamics. With dopexamine there were greater increases in CI than in RBF (117% vs 66%, respectively, with 4 ug kg"1 min"1) and renal fractions decreased from 13% to 10%, while SVR decreased more than RVR at all doses used, suggesting that the renal effects of dopexamine might be mediated by Pj-receptor stimulation and increase in CI, not necessarily by stimulation of renal DAx-receptors. These results are in contrast with those of Magrini and colleagues [26] in eight hypertensive patients undergoing diagnostic renal vein catheterization. They observed a proportionally greater increase in RBF than in CI (20% vs 13%, respectively, with 3 |ig kg"1 min"1) and a significant reduction in RVR with increasing doses of dopexamine, while SVR remained unchanged. They concluded that dopexamine acted selectively at renal DAXreceptors. These striking differences between those results and our data are difficult to explain,
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capacitance vessels and pulmonary circulation. On the other hand, dopamine produced significant dose-dependent increases in SAP, pulmonary arterial pressure and cardiac filling pressures, with little change in SVR or PVR. This may be attributed to the combined effects of dopamine at a-, P-, and dopaminergic receptors, even at the low dose of 2.5 ug kg"1 min"1 used in the present study. This is in contrast with the results of D'Orio and colleagues [9], who examined dosedependent effects of dopamine and found that, with small doses (< 3 ug kg"1 min"1), the effects of dopamine were limited to those resulting from stimulation of dopaminergic receptors. However, increases in cardiac output have been observed with doses even less than 3 ug kg"1 min"1 [10]. Shebuski, Smith and Ruffolo [18] observed that even low doses of dopamine increased PVR and pulmonary capillary wedge pressure in the propranolol pretreated dog; this was mediated by stimulation of postsynaptic vascular a-receptors in the pulmonary circulation. Thus patients might react differently to the same doses of dopamine, as was shown in hypertensive and aged patients [19, 20].
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ACKNOWLEDGEMENT This study was supported by a grant from Fisons Pharmaceuticals. REFERENCES 1. Brown RA, Dixon J, Farmer JB, Hall JC, Humphries RG, Ince F, O'Connor SE, Simpson WT, Smith GW. Dopexamine: a novel agonist at peripheral dopamine receptors and p,-adrenoreceptors. British Journal of Pharmacology 1985; 85: 599-608. 2. Smith GW, Naya I. Inhibition of uptake-1 in the dog by dopexamine hydrochloride. British Journal of Pharmacology 1987; 92 (Suppl.): 777P. 3. Brown RA, Fanner JB, Hall JC, Humphries RC, O'Connor SE, Smith GW. The effects of dopexamine on the cardiovascular system of the dog. British Journal of Pharmacology 1985; 85: 609-619. 4. Smith GW, O'Connor SE. An introduction to the pharmacologic properties of Dopacard (dopexamine hydrochloride). American Journal of Cardiology 1988; 62: 9C-17C. 5. Goldberg LI, Hsieh YY, Resnekov L. Newer catecholamines for the treatment of heart failure and shock: An update of dopamine and a first look at dobutamine. Progress in Cardiovascular Diseases 1977; 19: 327-340. 6. Mikabali C, Weil MH, Henning RJ. Dobutamine and other sympathomimetic drugs for the treatment of low cardiac output failure. Seminars in Anaesthesia 1982; 1: 63-69. 7. Tauchert M, Kochsiek K, Heiss HW, Rau G, Bretschneider HJ. Technik der Organdurchblutungsmessung mit der Argon-Methode. Zeiuchrift fur Kreislaufforschung 1971; 60: 871-881. 8. Goldberg LI. Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacological Reviews 1972; 24: 1-29. 9. D'Orio V, El Allaf D , Juchmes J, Marcelle R. The use of low doses of dopamine in intensive care medicine. Archives Internationales de Physiologie el de BiochimU 1984; 92: S11-S20.
10. Beregovich J, Bianchi C, Rubier S, Lomnitz E, Cagin N, Levin B. Dose-related hemodynamic and renal effects of dopamine in congestive heart failure. American Heart Journal 1974; 87: 550-557. 11. Abrahamsen AM, Storstein L, Westlie L, Storstein O. Effects of dopamine on hemodynamics and renal function. Acta Medica ScancHnavica 1974; 195: 365-373. 12. Mousedale S, dyburn PA, Mackie AM, Groves N D , Rosen M. Comparison of the effects of dopamine, dobutamine, and dopexamine upon renal blood flow: a study in normal healthy volunteers. British Journal of Clinical Pharmacology 1988; 25: 555-560. 13. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. American Journal of Cardiology 1978; 41: 233-243. 14. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB. [),- and [5,-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective p,-receptor down-regulation in heart failure. Circulation Research 1986; 59: 297-309. 15. Goldstein RE, Beiser GD, Stampfer M, Epstein E. Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circulation Research 1975; 36: 571-578. 16. Svensson G, Sj6gren A, Erhardt L. Short-term haemodynamic effects of dopexamine in patients with chronic congestive heart failure. European Heart Journal 1986; 7: 697-703. 17. Tan LB, Littler WA, Murray RG. Beneficial haemodynamic effects of intravenous dopexamine in patients with low-output heart failure. Journal of Cardiovascular Pharmacology 1987; 10: 280-286. 18. Shebuski RJ, Smith JM, Ruffolo RR jr. Comparison of the renal and pulmonary hemodynamic effects of fenoldopam, dobutamine, dopamine and norepinephrine in the anesthetized dog. Pharmacology 1988; 36: 35-43. 19. Andrejak M, Hary L. Enhanced dopamine renal responsiveness in patients with hypertension. Clinical Pharmacology and Therapeutics 1986; 40: 610-614. 20. Hollenberg NK, Adams DF, Mendell P, Abrams HL, Merrill JP. Renal vascular responses to dopamine: Haemodynamic and angiographic observations in man. Clinical Science and Molecular Medicine 1973; 45: 733742. 21. Rosenblum R, Tai AR, Lawson D. Dopamine in man: Cardiorenal hemodynamics in normotensive patients with heart disease. Journal of Pharmacology and Experimental Therapeutics 1972; 183: 256-263. 22. Dawson JR, Thompson D S , Signy M, Juul SM, Turnbull P, Jenkins BS, Webb-Peploe MM. Acute haemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist, in patients with chronic heart failure. British Heart Journal 1985; 54: 313-320. 23. Parratt JR, Wainwright CL, Fagbemi O. Effect of dopexamine hydrochloride in the early stages of experimental myocardial infarction and comparison with dopamine and dobutamine. American Journal of Cardiology 1988; 62: 18C-23C. 24. McNay JL, McDonald RH, Goldberg LI. Direct renal vasodilation produced by dopamine in the dog. Circulation Research 1965; 16: 510-517. 25. McDonald RH, Goldberg LI, McNay JL, Turtle EP.
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but might be related to the greater SVR in awake hypertensive patients or the enhanced responsiveness to stimulation of dopaminergic receptors as a result of greater numbers of free dopamine receptors and possible upregulation of their number in hypertensive subjects [19]. Mousdale and colleages [12] compared the effects of dopexamine, dopamine and dobutamine on renal blood flow in six volunteers using the PAH-clearance method. Dopexamine caused a progressive increase in RBF and a reduction in RVR, but to a lesser extent than dopamine at doses up to 5 ug kg"1 min"1. From this the authors concluded that dopexamine had a specific effect on renal artery dopamine receptors, although they did not measure either Cl or SVR, without which conclusions concerning specific dopaminergic activity cannot be drawn.
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS Effects of dopamine in man: Augmentation of sodium cxcretion, glomerular filtration rate and renal plasma flow. Journal of Clinical Investigation 1964; 43: 1116-1124. 26. Magrini F, Foulds R, Roberts N, Macchi G, Mandadori
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C, Zanchetti A. Human renovascular effects of dopexamine hydrochloride: a novel agonist of peripheral dopamine and p^-adreno-receptors. European Journal of Clinical Pharmacology 1987; 32: 1-4.
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CARDIOVASCULAR AND RENAL HAEMODYNAMIC EFFECTS OF DOPEXAMINE: COMPARISON WITH DOPAMINE H. STEPHAN, H. SONNTAG, H. HENNING AND K. YOSHIMINE
We have studied the effects of dopexamine and dopamine on systemic and renal haemodynamics in 20 male patients undergoing elective coronary artery bypass surgery. Patients were allocated randomly to two groups (n = 10) who were treated with incremental doses of either dopexamine 1, 2 and 4 pg kg'1 min~1, or dopamine 2.5 and5 ng kg~' min~', each dose being maintained for 15 min. Measurements were performed before administration of the drug and at the end of the infusion period at each dose. Fentanyl and midazolam were used as anaesthetic agents. Renal blood flow was measured with the argon washin technique. Dopexamine 4 fig kg'1 min'1 produced an increase in cardiac index of 117% caused by a 65% reduction in after/oad and an increase in heart rate by 61%. Dopamine 5 pig kg~1 min~1 caused a 40% increase in cardiac index as a result of an increase in stroke volume. Renal vascular resistance decreased more than systemic vascular resistance with dopamine. With dopexamine, the increase in renal blood flow (66%) was less than the increase in cardiac index, while renal vascular resistance and systemic vascular resistance declined to a/most the same extent. The results show that dopexamine exerts systemic and renal effects mainly via stimulation of ^-receptors. An action of dopexamine at renal DA,-receptors could not be demonstrated in this study.
I). It acts as a strong agonist at Pj-adrenoreceptors and stimulates peripheral dopamine receptors; its potency at vascular DA^receptors is 33 % that of dopamine and its activity at prejunctional DA2receptors is four to six times less. Dopexamine has no a-adrenergic and only weak Pi-adrenergic effects and inhibits active neuronal reuptake of catecholamines (uptake-1) [1, 2]. Dopexamine reduces systemic vascular resistance and thus afterload and this is followed by an increase in cardiac output; it has specific renal vasodilating properties, with only little direct and indirect positive inotropic and chronotropic effects [1, 3, 4]. This profile suggests dopexamine may be superior to dopamine in treatment of low cardiac output states, when the usefulness of the latter is often limited by vasoconstriction, excessive tachycardia and arrhythmias [5, 6]. The aim of this study was to investigate the effects of dopexamine on general and renal haemodynamics in patients about to undergo aorto-coronary bypass surgery and to determine if these effects are superior to those of dopamine in cardiac patients. PATIENTS AND METHODS
We studied 20 male patients (ages 43-62 yr, weight 66-102 kg) undergoing elective coronary artery bypass surgery. The study was approved by the Gottingen University Human Subjects Review Committee and written informed consent was obtained from each patient. Patients were
KEY WORDS Heart: dopamine, dopexamine, cardiac output. Kidney: blood flow. Surgery: coronary artery bypass.
Dopexamine hydrochJoride is a new synthetic dopamine analogue with properties and receptor activities different from those of dopamine (table
H. STEPHAN, M.D.; H. SONNTAG, M.D.; H. HENNING, M.D.;
Department of Anaesthesiology, University of Gottingen, Robert Koch-Str. 40, D-3400 Gottingen, W. Germany. K. YOSHIMINE, M.D., Department of Anaesthesiology, Kagoshima University, Usuki-Cho 1208-1, Kagoshima-Shi, 890 Japan. Accepted for Publication: February 16, 1990. Correspondence to H. Stephan.
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SUMMARY
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS TABLE I. Receptor activitiei of dopexamine and dopamine. — = No activity; ( + ) = weak; + = mild; + + = moderate; + + + = strong stimulation [1—4]
Receptor DA, DA,
Dopexamine
Dopamine
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body temperature and vascular pressures (Statham P23IA) were monitored continuously and recorded simultaneously on a 10-channel chart recorder (Hellige, Freiburg). Measurements and anaesthesia
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Anaesthesia was induced with fentanyl 6 |ig kg"1 and midazolam 0.2 mg kg"1 and maintained with fentanyl 0.15 |ig kg"1 min"1 and Uptake-1 midazolam 3 (ig kg"1 min"1. Pancuronium 8 mg inhibition was administered to facilitate tracheal intubation and the lungs were ventilated with 30 % oxygen in allocated randomly to one of two groups treated air using a constant volume ventilator (Engstrom with either dopexamine (n = 10) or dopamine (« ER 300). After induction of anaesthesia and a 15-min = 10). There were no significant differences in age, weight, body surface area and ASA physical period of rest, control measurements were perstatus between the groups. No patient gave a formed. Subsequently, incremental doses of either history of congestive heart failure or valvular dopexamine 1, 2 and 4 ug kg"1 min"1 or dopamine heart disease. Ejection fraction was greater than 2.5 and 5 (ig kg"1 min"1 were administered, each 0.4. None of the patients had either a history or maintained for 15 min, and measurements were clinical evidence of metabolic disorders, liver repeated at the end of the infusion period at each disease or renal impairment. All patients were dose. The doses of dopamine and dopexamine receiving maintenance doses of calcium-channel were chosen on the basis of expected renal blocking drugs and nitrates. Two patients in the equipotency. dopexamine group and three patients in the Renal blood flow (RBF) was measured using dopamine group were treated with P-adreno- the argon washin technique (coefficient of varireceptor antagonists. The last doses of all drugs ation ±5 %), a modification of the Kety-Schmidt were administered in the morning of the op- technique [7] which includes simultaneous blood eration. All patients were premedicated with sampling from the renal vein and the radial artery flunitrazepam 2 mg orally and promethazine during a 5-min period of inhalation of a standard 50 mg i.m. 1 h before arrival in the anaesthetic concentration of argon. Immediately before and room. after each measurement of RBF, arterial and renal venous blood samples were taken and analysed for Catheterization procedure haemoglobin concentration, oxygen saturation Upon arrival in the anaesthetic room ECG and content (CO-Oximeter IL 282 and Lex-Ojleads (lead II) were attached. Using the Seldinger Con, Instrumentation Lab.), blood-gas tensions technique under local anaesthesia, the following (standard electrodes, Radiometer) and electrolyte catheters were positioned: a 20-gauge catheter concentrations (atom absorption spectrophotoconnected to a Goodale-Lubin catheter (USCI, metry, Perkin Elmer 303). 6F) in the radial artery of the non-dominant hand Cardiac output was measured by thermoto monitor arterial pressure and for blood sam- dilution (Fischer BN 7206). Cardiac index (CI) pling; a second Goodale-Lubin (USCI, 6F) via was calculated by dividing cardiac output by the the right internal jugular vein into the right renal body surface area, and stroke volume index (SVI) vein for measurement of blood flow and with- by dividing CI by heart rate. Systemic vascular drawal of blood samples; a pulmonary artery resistance (SVR) and pulmonary vascular recatheter (Edwards quadruple thermodilution sistance (PVR) were derived from standard model No. 93A 131-7F) flow-directed via an formulae, and renal vascular resistance (RVR) was antecubital vein into the pulmonary artery for calculated by dividing mean arterial pressure measurement of pulmonary artery and wedge (MAP) minus renal venous pressure by RBF. pressures and cardiac output; and a polyethylene Statistical analysis of the data obtained in each catheter into the superior vena cava for admin- group was performed using the Wilcoxon istration of drugs and infusions. The positions of matched-pairs signed-ranks test; P < 0.05 was all catheters were confirmed radiologically. ECG, considered significant.
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TABLE II: Dopexamine: cardiovascular and renal haemodynamc effects (mean (SDj). HR = Heart rate; SAP = systolic arterial pressure; DAP = diastolic arterial pressure; MAP = mean arterial pressure; PCWP = pulmonary capillary wedge pressure; MPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; CI = cardiac index; SVI = stroke volume index; RBF = renal bloodflow;RVR = renal vascular resistance. P < 0.05 compared with: * control; + 2 fig kg'1 min~l Dose of dopexamine (ng kg"1 min *)
1
1
59 (10) 117(20) 68(12) 83(15) 2.8(1.9) 6.5(3.1) 12.5 (5.0) 110(59) 1424 (228) 2.40 (0.49) 42(9) 314 (49) 0.26 (0.06)
67(11)* 109 (20) 55 (15)* 71 (15)* 2.8(1.9) 7.1 (3.0) 14.2 (5.2) 81 (35)* 780 (238)* 3.86 (0.87)* 58(11)* 442 (87)* 0.15(0.04)*
4
2
75 (17)* 112(19) 55(13)* 71(13)* 3.2 (2.0) 6.9 (2.4) 14 (4.6) 74 (36)* 706 (288)* 4.29 (0.90)* 58(11)* 469 (109)* 0.15(0.05)*
95 (39)*+ 102 (12)* 48(9)* 65(11)* 4.2 (2.7) 8.3 (2.0) 17.8(3.1) 79 (27)* 503 (148)*+ 5.21 (1.17)*+ 58(11)* 521 (147)* 0.12(0.03)*
TABLE III. Dopamine: cardiovascular and renal haemodynamic effects (mean (SD)). For abbreviations see table II. P < 0.05 compared with: * control; + 2.5 fig kg'1 min'1 Dose of dopamine (Hg kg"1 min"1)
1
HR (beat min" ) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) RAP (mm Hg) PCWP (mm Hg) MPAP (mm Hg) PVR (dyn s cm"*) SVR (dyn s cm"5) CI (litre min-1 m"1) SVI (ml m"») RBF ((ml/100 g) min-1) RVR (mm Hg/(ml/100 g) min-1)
Control
2.5
56(7) 108(18) 61(8) 78 (12) 2.8(1.0) 6.3(2.3) 12.3(3.1) 100 (28) 1230(179) 2.46(0.35) 45(8) 309(46) 0.24 (0.06)
57 (13) 126 (23)* 65 (10) 86 (16)* 3.9 (2.0)* 8.9 (3.5)* 16.3(5.6)* 97(30) 1079 (190)* 3.07 (0.36)* 55 (10)* 445 (84)* 0.19(0.04)*
RESULTS
Cardiovascular effects
With increasing doses of dopexamine (table II), heart rate increased significantly and almost linearly by up to 61 % at 4 ug kg"1 min"1. SVR declined in a dose-dependent manner, by 45 % with the smallest dose and by 65 % with dopexamine 4 ug kg"1 min"1, which resulted in significant decreases in diastolic arterial pressure (DAP) (19% and 29%, respectively). While systolic arterial pressure (SAP) decreased sig-
5
59(13) 155 (19)*+ 76(15)*+ 101 (14)*+ 5.1(2.2)* 12.5 (5.5)*+ 22.7(12.8)*+ 121 (96) 1134(191) 3.45 (0.53)*+
60 (10)* 559 (88)*+ 0.17(0.04)*
nificantly (—13%) only with the greatest dose, MAP declined less than DAP (-14%) with the smallest dose of dopexamine and remained essentially unchanged with increasing doses. Right atrial, mean pulmonary arterial and wedge pressures changed little during the entire study period, while PVR decreased by 26 % with the low dose; increasing doses of dopexamine did not have any further effect. The marked reduction in afterload led to a 38% increase in SVI with the smallest dose, but increasing doses of dopexamine caused such a great increase in heart rate that, although
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HR (beat min" ) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) RAP (mm Hg) PCWP (mm Hg) MPAP (mm Hg) PVR (dyn s cm"5) SVR (dyn s cm-6) CI (litre min-1 m"1) SVI (ml m"1) RBF ((ml/100 g) min-1) RVR (mm Hg/(ml/100 g) min"1)
Control
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Dopexamine 3 ug kg' 1 min' 1
AP
jiOmmHg
FIG. 1. ECG (lead II), arterial pressure (AP) and pulmonary artery pressure CPAP) of a patient before (A) and during (B) administration of dopexamine 3 ng kg"1 min"1. Vertical scales: mm Hg.
Dopexamine (pg kg' 1 min"1)
_
0
1
2
4
-50QSVR
o-100 J Dopamine (|jgkg^min' 1 ) Change f rom cont rol U>
2.5
5
*
•
-50-
-100-
FIG. 2. Percentage changes in RVR and SVR compared with control values with increasing doses of dopexamine and dopamine. P < 0.05 compaxed with: * control; fall values.
CI was further increased by up to 117% with 4 ng kg"1 min"1, SVI did not show any further changes. The cardiovascular effects of dopamine (table III) differed substantially from those of dopexamine. While heart rate did not change with each dose of dopamine, SAP increased by 17% with
2.5 Hg kg"1 min-1 and by 44% with 5ugkg" x min"1. DAP and MAP increased, but only by 25 % and 29 %, respectively, with the high dose. There were marked dose-dependent increases in mean pulmonary arterial and wedge pressures, reaching almost twice the baseline values with 5 Hg kg"1 min"1, while PVR and SVR were influenced little. Heart rate remained unchanged throughout the study period; CI and SVI increased by 25% and 22%, respectively, with the low dose and by 40 % and 33 %, respectively, with the high dose of dopamine. Two patients in the dopexamine group developed ST-segment suppression. In one, heart rate increased from 62 beat min"1 to 79 beat min"1 and MAP and DAP decreased from 70 and 50 mm Hg to 50 and 40 mm Hg, respectively, with 4 ug kg"1 min"1. The second patient (fig. 1) had an increase in heart rate from 53 beat min"1 to 85 beat min"1 with dopexamine 3 ug kg"1 min"1, accompanied by decreases in MAP and DAP from 90 and 68 mm Hg to 50 and 40 mm Hg, respectively. Only one patient in the dopamine group developed ST-segment suppression with 5 ug kg"1 min"1: at a stable heart rate of 55 beat min"1, MAP increased from 85 to 105 mm Hg and DAP from 65 to 75 mm Hg. In three patients, the administration of dopamine 5 ug kg"1 min"1 was associated with arrhythmia: one patient developed atrial fibrillation, the second had supraventricular ectopic beats and the third, ventricular ectopic beats.
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PAP
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100 -,
50.
5 o 2 Dopexamine
100
50-
CO
IRBF
O
2.5
5
Dopamine (|jg kg" 1 min"1)
FIG. 3. Percentage changes in CI and RBF compared with control values, with increasing doses of dopexamine and dopamine. P < 0.05 compared with: * control; fall values.
Renal haemodynamics
In spite of their different effects on cardiovascular dynamics, both drugs affected RBF and RVR similarly (tables II, III). Figure 2 illustrates the changes in RVR and SVR with increasing doses of dopexamine and dopamine expressed as percentages from control values. With dopexamine the ratio between RVR and SVR remained essentially unchanged, whereas increasing doses of dopamine had more effect on RVR than on SVR. While increasing doses of dopexamine improved CI more than RBF, such that the renal fraction of CI (RBF/CI x 100) decreased from 13 % to 10%, dopamine had more effect on RBF than on CI at increasing doses, with the renal fraction of CI increasing from 13% to 16% (fig. 3). DISCUSSION
Haemodynamic effects
The results of this study demonstrate that both dopexamine and dopamine increased cardiac out-
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1
put, but via different mechanisms. Dopamine exerted its effects mainly by increasing stroke volume, attributed to activity at cardiac p r receptors [8, 9] resulting in increased contractility [9—11]. Dopexamine had little influence on stroke volume, but affected cardiac index by increasing heart rate and reducing SVR. Studies in dogs confirmed that the marked decrease in SVR is caused by stimulation of DA15 DA, and p s receptors, while tachycardia is caused mainly by a pj-mediated baroreceptor reflex [1-3]. In contrast with the data of the present study, Mousdale and colleagues [12] found an increase in SAP with dopexamine 1, 2 and 4 |ig kg"1 min"1 in six healthy, awake volunteers. One may assume that awake subjects in a study are subjected to increased sympathetic tone, leading to a-receptormediated vasoconstriction in the peripheral vascular bed and thus attenuation of the vasodilating effects of dopexamine. On the other hand, patients in the present study were receiving maintenance doses of calcium-channel blocking drugs, which may have enhanced the vasodilating properties of dopexamine. Patients with congestive heart failure are known to have high plasma concentrations of noradrenaline [13]. Increased exposure of the failing heart to noradrenaline is an explanation for selective Px-receptor downregulation, while selective P2-receptors retain near full inotropic activity mediated through a P2 population that is not significantly decreased [14]. Moreover, in chronic heart failure the baroreflex is generally blunted [15], which reduces the ability of dopexamine to stimulate the failing heart through baroreflex activation. However, because plasma concentrations of noradrenaline are increased, uptake-1 block by dopexamine may potentiate the cardiac effects of noradrenaline, and stimulation of cardiac P2-receptors by dopexamine may become clinically important. All these mechanisms may lead to increased inotropy and decreased chronotropy with dopexamine in the failing heart compared with the actions of this drug in the non-failing heart [4]. This may also explain why arterial pressure remained relatively unaffected by dopexamine in patients with congestive heart failure [16, 17] whilst arterial pressure decreased in the present study, in which patients suffered from coronary heart disease but not from heart failure. Mean pulmonary artery pressure and right and left atrial pressures remained unchanged and PVR decreased to a lesser extent than SVR, indicating that dopexamine had little influence on venous
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS
Adverse cardiovascular effects
In spite of their different haemodynamic effects, both drugs produced ST-segment depression indicating myocardial ischaemia. With dopamine, augmentation of contractility led to an increase in myocardial oxygen demand, which could not be met by an increase in coronary blood flow in one patient. Dopexamine increases oxygen demand by increasing heart rate, which may be counterbalanced by reduction in afterload and wall stress. It also decreased DAP and thus coronary perfusion pressure and by this mechanism may have induced myocardial ischaemia in two patients. Myocardial ischaemia has been reported with dopamine [21] and with dopexamine [22]. Arrhythmias seem to occur significantly more often with dopamine than with dopexamine and are thought to be principally a Pi-receptor mediated effect. In animals, dopexamine was shown not only to be associated with a lower incidence of late arrhythmias after coronary occlusion than occurs with dopamine, but also to reduce the incidence of early arrhythmias to less than that seen without treatment [23]. The clinical observations of other authors and ourselves confirm these findings [16, 22].
Renal haemodynamics
Dopamine causes direct renal vasodilatation; an effect which is not blocked by P2-receptor antagonists [24]. These findings were confirmed by a subsequent study in volunteers, who developed a 57 % increase in RBF at subpressor doses of i.v. dopamine accompanied by a 48 % increase in CI, such that the renal fraction of CI remained unchanged [25]. Rosenblum, Tai and Lawson [21] observed a 26% increase in CI and a 79% increase in RBF at doses between 2.1 and 5.8 ug kg"1 min"1. This finding is consistent with the results of Abrahamsen and colleagues [11], who showed a 27% increase in CI and a 48% increase in RBF, together with an improvement of the renal fraction from 12% to 14%, with dopamine 5 ug kg"1 min"1 in patients with ischaemic heart disease. The 44% and 8 1 % increases in RBF with dopamine 2.5 and 5 ug kg"1 min"1, respectively, obtained by the use of the argon washin technique in the present study, are within the range of values reported by other investigators. These improvements in RBF were caused by 25% and 40% increases in CI and by decreases in RVR by up to 28%, whereas SVR remained essentially unchanged (fig. 2); this is evidence for selective renal vasodilatory effects. The increase in CI was smaller than that in RBF (fig. 3), and MAP remained within the range of autoregulation, suggesting that systemic haemodynamic changes cannot solely account for improved renal haemodynamics. With dopexamine there were greater increases in CI than in RBF (117% vs 66%, respectively, with 4 ug kg"1 min"1) and renal fractions decreased from 13% to 10%, while SVR decreased more than RVR at all doses used, suggesting that the renal effects of dopexamine might be mediated by Pj-receptor stimulation and increase in CI, not necessarily by stimulation of renal DAx-receptors. These results are in contrast with those of Magrini and colleagues [26] in eight hypertensive patients undergoing diagnostic renal vein catheterization. They observed a proportionally greater increase in RBF than in CI (20% vs 13%, respectively, with 3 |ig kg"1 min"1) and a significant reduction in RVR with increasing doses of dopexamine, while SVR remained unchanged. They concluded that dopexamine acted selectively at renal DAXreceptors. These striking differences between those results and our data are difficult to explain,
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capacitance vessels and pulmonary circulation. On the other hand, dopamine produced significant dose-dependent increases in SAP, pulmonary arterial pressure and cardiac filling pressures, with little change in SVR or PVR. This may be attributed to the combined effects of dopamine at a-, P-, and dopaminergic receptors, even at the low dose of 2.5 ug kg"1 min"1 used in the present study. This is in contrast with the results of D'Orio and colleagues [9], who examined dosedependent effects of dopamine and found that, with small doses (< 3 ug kg"1 min"1), the effects of dopamine were limited to those resulting from stimulation of dopaminergic receptors. However, increases in cardiac output have been observed with doses even less than 3 ug kg"1 min"1 [10]. Shebuski, Smith and Ruffolo [18] observed that even low doses of dopamine increased PVR and pulmonary capillary wedge pressure in the propranolol pretreated dog; this was mediated by stimulation of postsynaptic vascular a-receptors in the pulmonary circulation. Thus patients might react differently to the same doses of dopamine, as was shown in hypertensive and aged patients [19, 20].
385
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ACKNOWLEDGEMENT This study was supported by a grant from Fisons Pharmaceuticals. REFERENCES 1. Brown RA, Dixon J, Farmer JB, Hall JC, Humphries RG, Ince F, O'Connor SE, Simpson WT, Smith GW. Dopexamine: a novel agonist at peripheral dopamine receptors and p,-adrenoreceptors. British Journal of Pharmacology 1985; 85: 599-608. 2. Smith GW, Naya I. Inhibition of uptake-1 in the dog by dopexamine hydrochloride. British Journal of Pharmacology 1987; 92 (Suppl.): 777P. 3. Brown RA, Fanner JB, Hall JC, Humphries RC, O'Connor SE, Smith GW. The effects of dopexamine on the cardiovascular system of the dog. British Journal of Pharmacology 1985; 85: 609-619. 4. Smith GW, O'Connor SE. An introduction to the pharmacologic properties of Dopacard (dopexamine hydrochloride). American Journal of Cardiology 1988; 62: 9C-17C. 5. Goldberg LI, Hsieh YY, Resnekov L. Newer catecholamines for the treatment of heart failure and shock: An update of dopamine and a first look at dobutamine. Progress in Cardiovascular Diseases 1977; 19: 327-340. 6. Mikabali C, Weil MH, Henning RJ. Dobutamine and other sympathomimetic drugs for the treatment of low cardiac output failure. Seminars in Anaesthesia 1982; 1: 63-69. 7. Tauchert M, Kochsiek K, Heiss HW, Rau G, Bretschneider HJ. Technik der Organdurchblutungsmessung mit der Argon-Methode. Zeiuchrift fur Kreislaufforschung 1971; 60: 871-881. 8. Goldberg LI. Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacological Reviews 1972; 24: 1-29. 9. D'Orio V, El Allaf D , Juchmes J, Marcelle R. The use of low doses of dopamine in intensive care medicine. Archives Internationales de Physiologie el de BiochimU 1984; 92: S11-S20.
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but might be related to the greater SVR in awake hypertensive patients or the enhanced responsiveness to stimulation of dopaminergic receptors as a result of greater numbers of free dopamine receptors and possible upregulation of their number in hypertensive subjects [19]. Mousdale and colleages [12] compared the effects of dopexamine, dopamine and dobutamine on renal blood flow in six volunteers using the PAH-clearance method. Dopexamine caused a progressive increase in RBF and a reduction in RVR, but to a lesser extent than dopamine at doses up to 5 ug kg"1 min"1. From this the authors concluded that dopexamine had a specific effect on renal artery dopamine receptors, although they did not measure either Cl or SVR, without which conclusions concerning specific dopaminergic activity cannot be drawn.
DOPEXAMINE: SYSTEMIC AND RENAL HAEMODYNAMIC EFFECTS Effects of dopamine in man: Augmentation of sodium cxcretion, glomerular filtration rate and renal plasma flow. Journal of Clinical Investigation 1964; 43: 1116-1124. 26. Magrini F, Foulds R, Roberts N, Macchi G, Mandadori
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C, Zanchetti A. Human renovascular effects of dopexamine hydrochloride: a novel agonist of peripheral dopamine and p^-adreno-receptors. European Journal of Clinical Pharmacology 1987; 32: 1-4.
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