(Acta Paediatu Jpn 1992; 34: 393
- 397)
Original Article
Circulatory Effects of Denopamine in Newborn Piglets Hideshi Tomita, M.D.1,2,James Y. Coe, M.D. and Peter M. Olley, M.D. 'Department of Pediatrics, University of Alberta, Edmonton, Canada and 'Department of Pediatrics, Sapporo Medical College, Sapporo, Japan
Denopamine is an orally active agonist whose cardiovascular action in the newborn is unknown. We evaluated its circulatory effects during normoxia in newborn piglets less than 7 days of age. The piglets were acutely instrumented under general anesthesia with an electromagnetic flow probe around the main pulmonary artery and catheters in the main pulmonary artery, aorta, left ventricle, and the right and left atria. A Millar high-fidelity catheter was used to measure left ventricular dp/dt. The ductus arteriosus was ligated. Denopamine was administered in the right atrium as a continuous infusion of 2, 4, and 8pg/kg per min for 10 min each. Although cardiac index, heart rate and left ventricular dp/dt increased dose-dependently by 46.0 f 18.2%, 87.1 f 34.9% and 159.9 f 42.4%, respectively, stroke index was not significantly altered. Unlike pulmonary artery pressure (which increased dose-dependently), aortic pressure increased with 2 and 4 pglkg per rnin denopamine, respectively, it fell with 8 pg/kg per rnin denopamine. Similarly, the systemic vascular resistance decreased with the high dose (8pg/kg per min). There was no significant change in pulmonary vascular resistance. Denopamine is potently inotropic in the adult. However, its circulatory effect in the neonate is dependent on its chronotropic action. Furthermore, denopamine is a systemic vasodilator at high doses in the neonatal circulation. Key Words Denopamine, Newborn piglets
Introduction Intravenous infusion of catecholamines such as isoproterenol, dopamine and dobutamine have been used to improve the pump function of the heart, especially when associated with congesReceived November 7, 1991 Revised December 16. 199 1 Accepted February 7, 1992 Correspondence address: Hideshi Tomita, Department of Pediatrics, Sapporo Medical College, South- 1 West-16, Chuo-ku, Sapporo 060, Japan.
tive heart failure. Recently, several new orally active inotropic agents have been developed. Denopamine (TA-064), ( - )-(R)-l-Cp-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl) amino] ethanol is one such orally active inotropic agent that exerts its action via p , agonism [l-51. Although there are several reports regarding its potent inotropic action in adult animals 16-91 and on clinical efficacy in human adults [ 10, 1 11, the cardiovascular effect of denopamine in the newborn is unknown. This study therefore evaluates the cardiovascular effects of denopamine in acutely instrumented anesthetized piglets.
394 ( 1 0 ) Tomita et al.
Materials and Methods Five newborn piglets, 1-6 days old (mean 2 days). weighing 1.5-2.0 kg (mean 1.8 kg) were acutely instrumented as described previously under general anesthesia, nitrous oxide (5 I/min) and halothane (0.5Oh) in oxygen (5 I/min) [12]. Briefly, through a left thoracotomy, an electromagnetic flow probe (C and C Instruments, Culver City, CA, USA) was placed around the main pulmonary artery. Fine polyethylene catheters (PE90, OD = 1.27 mm and ID = 0.80 mm) were introduced into the main pulmonary artery and the left atrium by direct puncture and secured with purse string sutures. The ductus arteriosus was ligated. Similar PE90 catheters were placed in a right carotid artery and bilateral external jugular veins to measure the aortic and right atrial pressures, and to infuse denopamine in the right atrium continuously. A Millar highfidelity catheter was placed in the left ventricle via the contralateral carotid artery. The fluid-filled catheters were connected to Statham P23dB strain gauge transducers, the flow probes to a Gould/Statham SP2202 flowmeter (Gould/Statham, OH, USA), and the Millar high-fidelity catheter to a Millar Transducer Control Unit (model TC510; Millar Investment Inc., TX, USA). All signals (main pulmonary arterial flow; pulmonary, aortic, right atrial, left atrial and left ventricular pressures: and left ventricular dp/dt) were continuously monitored and recorded on a Gould ES2000 physiological recorder for the duration of the denopamine infusion. Arterial blood gases were monitored periodically through each study with a Nova Stat Profile 5 Blood Gas Analyzer
(Nova Biomedical, MA, USA) to maintain normocapneic normoxia. All hernodynamic parameters are expressed as mean values. Stroke volume was calculated by dividing cardiac index by heart rate. Systemic vascular resistance was calculated by dividing cardiac index into the difference between mean aortic and mean right atrial pressure. Pulmonary vascular resistance was obtained by dividing the difference between the mean main pulmonary artery and left atrial pressure by the cardiac index. Both are expressed as U/kg. All animal experimental procedures were approved by the Animal Care Committee of the University of Alberta. The results are expressed as mean t s.e.m. and analysed by two-way analysis of variance without replication. Significance is taken as a P value of less than 0.05. When a significant F value was obtained, means were compared using Duncan’s multiple range test.
Drug preparation Denopamine hydrochloride (Organic Chemistry Research Laboratory, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan) was dissolved in 0.9% NaCl and infused at doses of 2, 4 and 8 @kg per min cumulatively for 10 min at each dose in the right atrium.
Results Aortic pressure increased with the doses of 2 and 4pg/kg per min, but fell to baseline level with 8 pg/kg per min. Pulmonary pressure rose significantly ( P 0.05; Fig. 1). Cardiac index increased significantly (P< 0.01) with all doses, but stroke index tended to decrease slightly for doses of 4 and 8 pdkg per min (P> 0.05; Fig. 2). Systemic vascular resistance fell significantly for doses of 4 and 8pg/kg per min, but there was no significant alteration in the pulmonary vascular resistance (Fig. 3). Both left ventricular dp/dt and heart rates increased dose-dependently (P< 0.01; Fig. 4), the per cent increase of left ventricular dp/dt was greater than that of heart rates (Fig. 4; Table 1).
-
1
No treatment
2
4
8
Denopamine infusion (pQ/kg per min)
Discussion From animal experimental or clinical data, denopamine, a selectivep, partial agonist [ 1-51, has a potent inotropic action in the adult. It also has a chronotropic action that is far less pronounced than its inotropic action [6-1 I]. Although there are some studies on age-related differences in
Vol. 34 No. 4 August 1992
Fig. 3: Circulatory responses to denopamine infusion (pg/kg per min) in newborn piglets. 0,systemic vascular resistance; 0,pulmonary vascular resistance; *P< 0.01 (n = 5 ) .
the cardiovascular response to p-agonists [ 13, 141, the cardiovascular effects of denopamine in the neonatal period has not been investigated.
396 ( 12) Tomita et al.
400
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comitant preload reduction may add to the decrease in stroke volume. There is a paucity of adult data on the full hemodynamic effects of denopamine. Denopamine is reported to lower the systemic vascular resistance in relatively lower doses (< 1 pg/kg per min) [6, 8, 91. In newborn piglets, denopamine lowers the systemic vascular resistance at higher doses (> 4pg/kg per rnin), which may reflect the prematurity of vascular P-receptors in newborn piglets [ 131. Although denopamine appears to possess a beneficial inotropic property in the healthy newborn piglet. its vasodilatory property may be limited by its chronotropic action. It may be worthy of evaluation in the failing heart in the pediatric clinical setting.
0
Denopamine inlusion ( p g i k g per min)
Fig. 4. Neonatal circulatory responses to denopamine infusion. A, heart rate; ‘ left ventricular dp/dt; * P < 0.01 (n = 5).
.
In newborn piglets, 2&kg per min denopamine has a potent inotropic action, although heart rates increase significantly. The dosedependent increase in left ventricular dp/dt is probably greater than expected from the increase in heart rate alone. Reported changes of cardiac output by denopamine is controversial in adult studies. In an adult human study, a similar dose of denopamine produced a potent inotropic and preload-reducing action (i.e. a significant increase in left ventricular dp/dt and a decrease in Ieft ventricular end diastolic pressure without a significant increase in heart rate) (1 11. In some animal studies using dogs or pigs, denopamine increased cardiac output dose-dependently in both the healthy and failing heart [6-91, while no significant change in cardiac output due to significant preload reduction is documented in human clinical studies [lo, 111. There may be some species differences in the vascular effect of denopamine, especially in terms of venous dilatation. In newborn piglets, cardiac output increased dose-dependently with an increase in heart rate. The fall in atrial pressures and con-
Acknowledgements The authors are grateful for the invaluable help of Jonathan Timinsky. Denopamine was generously donated by Mr Katsuaki Kitayama, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan.
References 1. Naito K, Nagao T. Otsuka M et al. Studies on the
2.
3.
4.
5.
6.
7.
affinity and selectivity of denopamine (TA-064), a new cardiotonic agent, for beta-adrenergic receptors. Jpn J Pharmacol 1985; 38: 235-241. Naito K, Nagao T, Ono Y et al. Effect of GTP on the affinity of denopamine, a new cardiotonic agent, for 0-adrenergic receptors of turkey erythrocytes and rat reticulocyte membranes. Jpn J Pharmacol 1985; 39: 541-549. Inamasu M,TotsukaT, IkeoTet al.p,-Adrenergic selectivityof the new cardiotonic agent denopamine in its stiniulating effects on adenylate cyclase. Biochem Pharmacol 1987; 36: 1947-1954. Yokoyama H, Yanagisawa T, Taira N. Details of mode and mechanism of action of denopamine, a new orally active cardiotonic agent with affinity for /3,-receptors. J Cardiovasc Pharmacol 1988: 12: 323-331. Akahane K, Furukawa Y, Karasawa Y et al. Pharmacological analysis of positive chrono- and inotropic responses to denopamine (TA-064) in dog crosscirculated atrial and ventricular preparations. Jpn J Pharmacol 1990; 52: 69-79. Ikeo T, Nagao T. Effects of denopamine (TA064), a new positive inotropic agent, on myocardial oxygen consumption and left ventricular dimension in anesthetized dogs. Jpn J Pharmacol 1985; 39: 179-189. Nunoki K, GOIDT, Satoh K et al. Improvement by denopamine (TA-064) of pentobarbital-induced
Acta Paediatr Jprt
Circulatory efects of denopamine (1 3 ) 397 cardiac failure in the dog heart-lung preparation. Heart Vessels 1985; 1: 216-219. 8. Ikeo T, Nagao T, Suzuki T et al. Cardiovascular effects and plasma levels of denopamine (TA064), a new positive inotropic agent, in chronically instrumented dogs. Jpn J Pharmacol 1985; 39: 191-199. 9. Ikeo T, Nagao T, Murata S et al. Cardiovascular effects of the new positive inotropic agent denopamine with special reference to species difference and the effect on failing heart. Arzneimittelforschung 1986; 36: 1063-1068. 10. Kino M, Hirota Y, Yamamoto S et al. Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts. Am J Cardiol 1983; 51: 802-810.
Vol. 34 No. 4 August 1992
11. Kino M, Hirota Y , Saitho T et al. Cardiovascular effects of a new inotropic agent, Denopamine (TA-064), with reference to its effects on cardiac hemodynarnics and metabolism. Jpn Circ J 1986; 50: 644-65 1. 12. Perreault T, Coe JY, Olley PM et al. Pulmonary vascular effects of prostaglandin D2 in newborn pig. Am J Physiol 1990; 258: H1292-1299. 13. Buckley NM, Gootrnan PM, Yellin EL et al. Age-related cardiovascular effects of catecholamines in anesthetized piglets. Circ Res 1979: 45: 282-292. 14. Fiser DH, Fewell JE, Hill DE et al. Cardiovascular and renal effects of dopamine and dobutarnine in healthy, conscious piglets. Crit Care Med 1988; 16: 340-345.
- 397)
Original Article
Circulatory Effects of Denopamine in Newborn Piglets Hideshi Tomita, M.D.1,2,James Y. Coe, M.D. and Peter M. Olley, M.D. 'Department of Pediatrics, University of Alberta, Edmonton, Canada and 'Department of Pediatrics, Sapporo Medical College, Sapporo, Japan
Denopamine is an orally active agonist whose cardiovascular action in the newborn is unknown. We evaluated its circulatory effects during normoxia in newborn piglets less than 7 days of age. The piglets were acutely instrumented under general anesthesia with an electromagnetic flow probe around the main pulmonary artery and catheters in the main pulmonary artery, aorta, left ventricle, and the right and left atria. A Millar high-fidelity catheter was used to measure left ventricular dp/dt. The ductus arteriosus was ligated. Denopamine was administered in the right atrium as a continuous infusion of 2, 4, and 8pg/kg per min for 10 min each. Although cardiac index, heart rate and left ventricular dp/dt increased dose-dependently by 46.0 f 18.2%, 87.1 f 34.9% and 159.9 f 42.4%, respectively, stroke index was not significantly altered. Unlike pulmonary artery pressure (which increased dose-dependently), aortic pressure increased with 2 and 4 pglkg per rnin denopamine, respectively, it fell with 8 pg/kg per rnin denopamine. Similarly, the systemic vascular resistance decreased with the high dose (8pg/kg per min). There was no significant change in pulmonary vascular resistance. Denopamine is potently inotropic in the adult. However, its circulatory effect in the neonate is dependent on its chronotropic action. Furthermore, denopamine is a systemic vasodilator at high doses in the neonatal circulation. Key Words Denopamine, Newborn piglets
Introduction Intravenous infusion of catecholamines such as isoproterenol, dopamine and dobutamine have been used to improve the pump function of the heart, especially when associated with congesReceived November 7, 1991 Revised December 16. 199 1 Accepted February 7, 1992 Correspondence address: Hideshi Tomita, Department of Pediatrics, Sapporo Medical College, South- 1 West-16, Chuo-ku, Sapporo 060, Japan.
tive heart failure. Recently, several new orally active inotropic agents have been developed. Denopamine (TA-064), ( - )-(R)-l-Cp-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl) amino] ethanol is one such orally active inotropic agent that exerts its action via p , agonism [l-51. Although there are several reports regarding its potent inotropic action in adult animals 16-91 and on clinical efficacy in human adults [ 10, 1 11, the cardiovascular effect of denopamine in the newborn is unknown. This study therefore evaluates the cardiovascular effects of denopamine in acutely instrumented anesthetized piglets.
394 ( 1 0 ) Tomita et al.
Materials and Methods Five newborn piglets, 1-6 days old (mean 2 days). weighing 1.5-2.0 kg (mean 1.8 kg) were acutely instrumented as described previously under general anesthesia, nitrous oxide (5 I/min) and halothane (0.5Oh) in oxygen (5 I/min) [12]. Briefly, through a left thoracotomy, an electromagnetic flow probe (C and C Instruments, Culver City, CA, USA) was placed around the main pulmonary artery. Fine polyethylene catheters (PE90, OD = 1.27 mm and ID = 0.80 mm) were introduced into the main pulmonary artery and the left atrium by direct puncture and secured with purse string sutures. The ductus arteriosus was ligated. Similar PE90 catheters were placed in a right carotid artery and bilateral external jugular veins to measure the aortic and right atrial pressures, and to infuse denopamine in the right atrium continuously. A Millar highfidelity catheter was placed in the left ventricle via the contralateral carotid artery. The fluid-filled catheters were connected to Statham P23dB strain gauge transducers, the flow probes to a Gould/Statham SP2202 flowmeter (Gould/Statham, OH, USA), and the Millar high-fidelity catheter to a Millar Transducer Control Unit (model TC510; Millar Investment Inc., TX, USA). All signals (main pulmonary arterial flow; pulmonary, aortic, right atrial, left atrial and left ventricular pressures: and left ventricular dp/dt) were continuously monitored and recorded on a Gould ES2000 physiological recorder for the duration of the denopamine infusion. Arterial blood gases were monitored periodically through each study with a Nova Stat Profile 5 Blood Gas Analyzer
(Nova Biomedical, MA, USA) to maintain normocapneic normoxia. All hernodynamic parameters are expressed as mean values. Stroke volume was calculated by dividing cardiac index by heart rate. Systemic vascular resistance was calculated by dividing cardiac index into the difference between mean aortic and mean right atrial pressure. Pulmonary vascular resistance was obtained by dividing the difference between the mean main pulmonary artery and left atrial pressure by the cardiac index. Both are expressed as U/kg. All animal experimental procedures were approved by the Animal Care Committee of the University of Alberta. The results are expressed as mean t s.e.m. and analysed by two-way analysis of variance without replication. Significance is taken as a P value of less than 0.05. When a significant F value was obtained, means were compared using Duncan’s multiple range test.
Drug preparation Denopamine hydrochloride (Organic Chemistry Research Laboratory, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan) was dissolved in 0.9% NaCl and infused at doses of 2, 4 and 8 @kg per min cumulatively for 10 min at each dose in the right atrium.
Results Aortic pressure increased with the doses of 2 and 4pg/kg per min, but fell to baseline level with 8 pg/kg per min. Pulmonary pressure rose significantly ( P 0.05; Fig. 1). Cardiac index increased significantly (P< 0.01) with all doses, but stroke index tended to decrease slightly for doses of 4 and 8 pdkg per min (P> 0.05; Fig. 2). Systemic vascular resistance fell significantly for doses of 4 and 8pg/kg per min, but there was no significant alteration in the pulmonary vascular resistance (Fig. 3). Both left ventricular dp/dt and heart rates increased dose-dependently (P< 0.01; Fig. 4), the per cent increase of left ventricular dp/dt was greater than that of heart rates (Fig. 4; Table 1).
-
1
No treatment
2
4
8
Denopamine infusion (pQ/kg per min)
Discussion From animal experimental or clinical data, denopamine, a selectivep, partial agonist [ 1-51, has a potent inotropic action in the adult. It also has a chronotropic action that is far less pronounced than its inotropic action [6-1 I]. Although there are some studies on age-related differences in
Vol. 34 No. 4 August 1992
Fig. 3: Circulatory responses to denopamine infusion (pg/kg per min) in newborn piglets. 0,systemic vascular resistance; 0,pulmonary vascular resistance; *P< 0.01 (n = 5 ) .
the cardiovascular response to p-agonists [ 13, 141, the cardiovascular effects of denopamine in the neonatal period has not been investigated.
396 ( 12) Tomita et al.
400
3000
300
2000
I
c
. -
n
E
0
I
u1
a m
E
L
I I
a
-I
9 a
L
S
I m
200
1 oc
6
It
I
0
I
5
T
1000
v,,’ I‘i ’* N o treatment
I *
I
1
I
I
2
4
E
comitant preload reduction may add to the decrease in stroke volume. There is a paucity of adult data on the full hemodynamic effects of denopamine. Denopamine is reported to lower the systemic vascular resistance in relatively lower doses (< 1 pg/kg per min) [6, 8, 91. In newborn piglets, denopamine lowers the systemic vascular resistance at higher doses (> 4pg/kg per rnin), which may reflect the prematurity of vascular P-receptors in newborn piglets [ 131. Although denopamine appears to possess a beneficial inotropic property in the healthy newborn piglet. its vasodilatory property may be limited by its chronotropic action. It may be worthy of evaluation in the failing heart in the pediatric clinical setting.
0
Denopamine inlusion ( p g i k g per min)
Fig. 4. Neonatal circulatory responses to denopamine infusion. A, heart rate; ‘ left ventricular dp/dt; * P < 0.01 (n = 5).
.
In newborn piglets, 2&kg per min denopamine has a potent inotropic action, although heart rates increase significantly. The dosedependent increase in left ventricular dp/dt is probably greater than expected from the increase in heart rate alone. Reported changes of cardiac output by denopamine is controversial in adult studies. In an adult human study, a similar dose of denopamine produced a potent inotropic and preload-reducing action (i.e. a significant increase in left ventricular dp/dt and a decrease in Ieft ventricular end diastolic pressure without a significant increase in heart rate) (1 11. In some animal studies using dogs or pigs, denopamine increased cardiac output dose-dependently in both the healthy and failing heart [6-91, while no significant change in cardiac output due to significant preload reduction is documented in human clinical studies [lo, 111. There may be some species differences in the vascular effect of denopamine, especially in terms of venous dilatation. In newborn piglets, cardiac output increased dose-dependently with an increase in heart rate. The fall in atrial pressures and con-
Acknowledgements The authors are grateful for the invaluable help of Jonathan Timinsky. Denopamine was generously donated by Mr Katsuaki Kitayama, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan.
References 1. Naito K, Nagao T. Otsuka M et al. Studies on the
2.
3.
4.
5.
6.
7.
affinity and selectivity of denopamine (TA-064), a new cardiotonic agent, for beta-adrenergic receptors. Jpn J Pharmacol 1985; 38: 235-241. Naito K, Nagao T, Ono Y et al. Effect of GTP on the affinity of denopamine, a new cardiotonic agent, for 0-adrenergic receptors of turkey erythrocytes and rat reticulocyte membranes. Jpn J Pharmacol 1985; 39: 541-549. Inamasu M,TotsukaT, IkeoTet al.p,-Adrenergic selectivityof the new cardiotonic agent denopamine in its stiniulating effects on adenylate cyclase. Biochem Pharmacol 1987; 36: 1947-1954. Yokoyama H, Yanagisawa T, Taira N. Details of mode and mechanism of action of denopamine, a new orally active cardiotonic agent with affinity for /3,-receptors. J Cardiovasc Pharmacol 1988: 12: 323-331. Akahane K, Furukawa Y, Karasawa Y et al. Pharmacological analysis of positive chrono- and inotropic responses to denopamine (TA-064) in dog crosscirculated atrial and ventricular preparations. Jpn J Pharmacol 1990; 52: 69-79. Ikeo T, Nagao T. Effects of denopamine (TA064), a new positive inotropic agent, on myocardial oxygen consumption and left ventricular dimension in anesthetized dogs. Jpn J Pharmacol 1985; 39: 179-189. Nunoki K, GOIDT, Satoh K et al. Improvement by denopamine (TA-064) of pentobarbital-induced
Acta Paediatr Jprt
Circulatory efects of denopamine (1 3 ) 397 cardiac failure in the dog heart-lung preparation. Heart Vessels 1985; 1: 216-219. 8. Ikeo T, Nagao T, Suzuki T et al. Cardiovascular effects and plasma levels of denopamine (TA064), a new positive inotropic agent, in chronically instrumented dogs. Jpn J Pharmacol 1985; 39: 191-199. 9. Ikeo T, Nagao T, Murata S et al. Cardiovascular effects of the new positive inotropic agent denopamine with special reference to species difference and the effect on failing heart. Arzneimittelforschung 1986; 36: 1063-1068. 10. Kino M, Hirota Y, Yamamoto S et al. Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts. Am J Cardiol 1983; 51: 802-810.
Vol. 34 No. 4 August 1992
11. Kino M, Hirota Y , Saitho T et al. Cardiovascular effects of a new inotropic agent, Denopamine (TA-064), with reference to its effects on cardiac hemodynarnics and metabolism. Jpn Circ J 1986; 50: 644-65 1. 12. Perreault T, Coe JY, Olley PM et al. Pulmonary vascular effects of prostaglandin D2 in newborn pig. Am J Physiol 1990; 258: H1292-1299. 13. Buckley NM, Gootrnan PM, Yellin EL et al. Age-related cardiovascular effects of catecholamines in anesthetized piglets. Circ Res 1979: 45: 282-292. 14. Fiser DH, Fewell JE, Hill DE et al. Cardiovascular and renal effects of dopamine and dobutarnine in healthy, conscious piglets. Crit Care Med 1988; 16: 340-345.
