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Vasoactive Effects of Ketamine on Isolated Rabbit Pulmonary Arteries
Vasoactive Effects of Ketamine on Isolated Rabbit Pulmonary Arteries* Tai-Shion Lee, MD, FCCP; and Xiuhua Hou, MD
Ketamine has been used in patients with congenital heart disease and pulmonary hypertension with hypothetical controversy. Its direct effect on pulmonary arteries has not yet been clearly characterized. This in vitro study was performed to determine the direct vasoactive effects of ketamine on isolated rabbit pulmonary arteries. Responses of pulmonary artery rings from New Zealand white rabbits were assessed in the presence and absence of intact endothelium and with or without precontraction by norepinephrine (NE, 3X 10- 6 M) or potassium chloride (KCl, 3Xl0-2 M). Using a preparatory tissue bath, cumulative concentration response curves of ketamine were obtained at different concentrations (0.03, 0.1, 0.3, 1, 3 mM) after a period of stabilization. Ketamine caused a dose-related vasodilation on KCl-precontracted pulmonary arteries. It elicited almost 100% relaxation at a concentration of 3 mM.
Jn vivo, the use of ketamine usually is associated
with increases in blood pressure, heart rate , and cardiac output, while changes in stroke volume and systemic vascular resistance are variable.1·2 The mechanisms of this cardiovascular stimulation are complex and seem to be predominated by the central activation of the sympathetic nervous system associated with increased plasma levels of epinephrine and norepinephrine (NE). 3 Whereas ketamine reportedly increases both pulmonary and systemic vascular resistances, some studies suggest that physiologic changes associated with ketamine are more pronounced on pulmonary than on systemic circulation, and on the right side rather than on the left side of the heart. 4-6 In the literature, ketamine has been suggested to be either a direct vasoconstrictor or vasodilator of pulmonary arteries, and the exact character has not yet been clearly defined. 7-9 Clinically, ketamine has been considered by some to be the anesthetic of choice for cardiac catheterization 8•10•11 as well as the induction technique of choice in patients with congenital heart disease , including cyanotic or potentially cyanotic groups.l 2- 14 It is considered that *From the Department of Anesthesiology, Harbor-UCLA Medical Center, Torrance, Calif. Manuscript received January 18, 1994; revision accepted August 4. Reprint requests: Dr. Lee, Department of Anesthesiology, Harbor-UCLA Medical Center, 1000 W . Carson Street, Torrance, CA 90509-2910 1152
Ketamine also induced a dose-related vasodilation on NE-precontracted pulmonary arteries at a lesser degree. All of the effects were endothelium independent. In conclusion, ketamine has strong endothelium-independent, direct vasodilatory effects on isolated rabbit pulmonary arteries. Ketamine may act through Ca ++channel-blocking effect as well as inhibition of Ca ++ release from sarcoplasmic reticulum. (Chest 1995; 107:1152-55)
KCI=potassium chloride; NE=norepinephrine
Key words: ketamine; pulmonary artery; vasodilation , Ca ++ channel; endothelium
ketamine can prevent the increase of right-to-left shunting in cyanotic congenital heart disease as a result of its tendency to increase systemic vascular resistance.l5·16 Nevertheless, conflicting data have raised a hypothetical concern about using ketamine in patients with pulmonary hypertension ,3.6 limited right ventricle reserve, 3 .l 7 or cyanotic congenital heart disease.8 Avoidance of ketamine has been recommended under these situations even though no notable problems have been encountered from clinical experience. 3 ·6 This study was designed to investigate the direct effect of ketamine on isolated rabbit pulmonary arteries (1) with or without intact endothelium, and (2) with potassium chloride (KCl) orNE precontraction. METHODS
Approval from the Institutional Animal Research Committee was obtained. Six New Zealand white rabbits, weighing 2 to 2.5 kg, were used for the experiment. The rabbits were anesthetized with pentobarbital sodium 40 mg / kg. A segment of main pulmonary artery just distal to the bifurcation was removed immediately following respiratory arrest through midsternotomy. Precaution was exercised to avoid damage of the intimal surface. The vessels were freed from the connective tissue and cut into 3-mm-wide rings. Each ring of pulmonary artery was immersed in a 10-mL tissue-organ bath containing a continuously oxygenated (95% 0 2, 5% C02 ) Krebs solution at 37° C and a pH of 7.4. The solution consisted of 118 mmol of NaCl, 0.8 mmol of KCl, 2.5 mmol CaC1 2 , 25 mmol of NaHC03, 1.18 mmol of KHzP04, 1.19 mmol of MqSD 4, and ll mmol of glucose. The ring was suspended Vasoactive Effects of Ketamine on Isolated Rabbit PAs (Lee, Hou)
between a fixed hook and an isometric transducer (Grass FT03). The contractions were recorded on a polygraph (Beckman R612 ). The resting tension of each ring was adjusted to 3.75 g based on the prior search of the optimal resting tension (Lmax) in rabbit pulmonary arteries. At least 1 h was allowed for equilibration and stabilization. Two groups of vessels were prepared, one with and one without intact endothelium. Both were tested under the same conditions for comparison. The de-endothelialization was performed by gently rubbing the intimal surface with forceps and confirmed pharmacologically by standard test with NE (3X 10- 7M) and acetylcholine (10- 6M). Two (one intact and one denuded) pulmonary arterial rings were obtained from each animal. Six rings were prepared for each set of the experiment; totally 12 rings were used.
Protocol Step 1: Following stabilization, the submaximal precontraction
of the vessels was randomly induced by either KCI (3Xl0-2 M) or NE (3X10- 6 M). When contractile responses reached a plateau, cumulative concentration-response curves of ketamine were constructed by adding increasing concentrations of ketamine in logarithmic increments (0.03 to 3 mM). Step 2: The rings were washed after step l until complete recovery of the resting tension was reached. Another hour was allowed for equilibration. Then the submaximal precontraction of the pulmonary arteries was again elicited by KCI (3Xl0- 2 M) or NE (3Xl0- 6 M) alternately, using the drug opposite to the one used in step l. When the plateau of contraction was reached, cumulative concentration-response curves of ketamine were determined in the same manner as in step l. After each assay, each pulmonary artery ring was removed from the tissue-organ bath, blotted dry, and weighed. All results were measured as a percentage of the control contractions and expressed as the mean value ± SEM. The difference between mean values was analyzed by analysis of variance and Student's t test. The difference was considered statistically significant at p<0.05. RESULTS
Ketamine caused vasodilatation in the KCl- (30 mM) precontracted isolated rabbit pulmonary arteries in a dose-dependent manner. At a concentration of 3 mM, it elicited almost 100% relaxation of the control (Fig 1). This vasodilatory response was endothelium independent. Ketamine also induced a dose-related vasodilata0
-20
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·~
5
-120
n::: -80
~
-100
-E(+) CJE(-)
-120~--------------------------------~
0.03
0 ..3
0.1
3
E :Endothelium
KETAMINE ( mM )
FIGUHE 2. Cumulative concentration responses of ketamine in isolated NE-precontracted rabbit pulmonary arteries with (+) or without (-) endothelium (E).
tion in NE-precontracted isolated rabbit pulmonary arteries (Fig 2). The magnitude of relaxation was significantly less than that on KCl-precontracted pulmonary arteries at the same doses of ketamine (Fig 3). At 3 mM, it produced about 60% relaxation of the control. There was no difference between groups with or without intact endothelium. DISCUSSIO'II
Theoretically, ketamine is expected to cause vasoconstriction through central sympathomimetic stimulation ,3 •17 inhibition of neuronal reuptake of NE, 17 •18 activation of the pituitary-adrenal axis, 19 and subsequent increase in circulating catecholamines. 20•21 However, ketamine has been reported to have dual effect on the peripheral vasculature. 22 The central pressor effect may be counterbalanced by the direct vasodilating property of ketamine, with variable net results. Our studies on isolated rabbit pulmonary arteries showed that ketamine caused a significant dose-related vasodilatation on KCl-precontracted as
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E : Endothelium KETAMINE ( mM ) of ketamine in responses FIGliHE l. Cumulative concentration isolated KCI-precontracted rabbit pulmonary arteries with (+)or without (- ) endothelium (E).
0.1
0.3
E :Endothelium KETAMINE ( mM ) PRECONTRACTED: 0 + BY NE \1 ._ BY KCI
FIGCHE 3. Comparison of cumulative concentration-response curves of ketamine in isolated KCl- or NE-precontracted rabbit pulmonary arteries with (+) or without (-) endothelium (E). CHEST /107 I 41 APRIL, 1995
1153
well as NE-precontracted vessels. Tweed et al 23 reported that in vivo ketamine increased pulmonary arterial pressure (44%) and cardiac output. Gassner et al8 and Morray et al 4 also demonstrated a statistically significant but clinically minor increase in pulmonary artery pressure and pulmonary vascular resistance. Clinically , it has been shown by Takahashi et aF that ketamine is a direct pulmonary vasoconstrictor. Spotoft et aF 7 also found that ketamine increased pulmonary vascular resistance, thereby increasing the work of the right ventricle. The results from clinical studies may be confusing because of uncontrolled factors such as different levels of autonomic tone , various disease states, difference in reflex reaction , or other factors . Arecent report speculated that some of the increase in pulmonary vascular resistance, as seen in previous studies, might be secondary to hypoxemia and hypercapnia due to hypoventilation.5·23 However , some studies showed that ketamine decreased pulmonary vascular resistance in both young lambs and adult sheep and also caused slight vasodilation in an isolated vascular bed .10 · 23 -25 Our results, in agreement with Rich et al ,26 confirm the latter and show that ketamine is indeed a strong vasodilator in isolated rabbit pulmonary arteries. At 3 mM concentration, it produced almost 100% relaxation on KCl-precontracted vessels and 60% on NE-precontracted ones. Since KCl causes contraction of the vascular smooth muscle by increasing Ca ++ influx via ca++ channels, which open after the membrane has depolarized , ketamine may have Ca++ channel-blocking effect. 27 This vasodilatory effect is dose related. However , NE induces contraction mainly by increasing the amount of ca++ released from sarcoplasmic reticulum as well as some increase in Ca++ influx. Relaxation caused by ketamine may indicate that ketamine can directly inhibit the release of Ca ++ from sarcoplasmic reticulum,27 or indirectly do so by decreasing ca++ influx through its ca++ channel-blocking effect , which in turn attenuates the Ca ++-induced Ca ++ release. Kanmura et al 9 report that ketamine-induced relaxation may be in part caused by inhibiting NEinduced synthesis of inositol 1,4,5-trisphosphate in the vascular smooth muscles and thus interfering with the release of Ca ++from intracellular store sites. Since there was no difference in the degree of relaxation between two groups with or without intact endothelium, we concluded that ketamine caused vasodilation on isolated rabbit pulmonary arteries without involvement of endothelial-derived relaxing factor. Similar to its well-known dose-related, direct myocardial depressant effect, 13·28 the direct vasoactive effect of ketamine causes relaxation of the pulmonary arteries. We ecognize r that the results ob1154
tained from this study should not be carelessly extrapolated to clinical practice. Nevertheless, they may, in part, explain the conflicting clinical data. The balance between central sympathomimetic responses and direct peripheral depressant will determine the outcome of the vascular tone. When the sympathetic nervous system is depressed, attenuated, blocked, or exhausted with depleted catecholamine stores, ketamine may cause paradoxical cardiovascular collapse by myocardial depression and peripheral vasodilatation .13·28 However, even though ketamine is generally believed to be the drug of choice for induction of anesthesia in cyanotic patients , the theoretical possibility of precipitation of a h ypercyanotic episode in patients with tetralogy of Fallot must be kept in mind.13 In summary, ketamine is not only a known bronchodilator ,29 but it is also a powerful vasodilator for isolated rabbit pulmonary arteries, more in those precontracted with KCl than with NE. R EFERE.!\CES
2 3 4
5
6
7
8
9
10 11 12
13
14
White PF. Comparative evaluation of intravenous agents for rapid seq uence induction-thiopental, ketam ine, and midazolam. Anesthesiology 1982; 57:279-84 Puu G, Koch M, Artursson E. Ketamine enantiomers and acetylcholinesterase. Biochem Pharmacal 1991 ; 41:2043-45 White PF, Way WL, Trevor AJ. Ketamin e-its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119-36 Morray JP, Lynn AM, Stamm SJ, et al. H emodynamic effects of ketam ine in children with congenital heart disease. Anesth Analg 1984; 63:895-99 Hickey PR, H ansen DD, Cramolini GM, et al. Pulmonary and systemic hemodynamic responses to ketamine in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1985; 62:287-93 Gooding JM , Dimick AR, Tavakoli M, et al. A physiologic analysis of cardiopulmonary responses to ketam ine anesthesia in noncardiac patients. Anesth Analg 1977; 56:813-16 Takahashi K, Shuna I, Koga Y. The effects of ketamine on the pulmonary hemodynamics in dogs. Jpn J Anaesth 1971 ; 20:842-46 Gassner S, Cohen M, Aygen M, et al. The effect of ketamine on pulmonary artery pressure: an experimental and clinical study. Anaesthesia 1974; 29:141-46 Kanmura Y, Kajikuri J, Iteh T, et l.a Effects of ketamine on contraction and synthesis of inositol1 ,4,5- trisphosphate in the smooth muscles of the rabbit mesenteric artery. Anesthesiology 1993; 79:571-79 Faithful! NS, Haider R. Ketamine for cardiac ca theterisation. Anaesthesia 1971; 26:318-23 Cappel DL, Dundee JW. Ketamine anaesthesia for cardiac catheterization. Anaesthesia 1972; 27:25-31 H ackel A. Anesthetic management of the pediatric patient. In: Ream AK, Fogdall RP, eds. Acute cardiovascular managem ent : anesthesia and intensive care. Philadelphia: JB Lippincott, 1982; 606-34 Bland JW, Williams WH. Anesthesia for treatment of congenital heart defects. In : Kaplan AL, ed. Cardiac anesthesia. New York: Grune & Stratton, 1979; 294 Hickey PR , Hansen DD, Norwood WI, et al. Anesthetic complications in surgery forcongenital heart disease. Anesth Analg Vasoactive Effects of Ketamine on Isolated Rabbit PAs (Lee, Hou)
1984; 63:657-64 15 Dowdy EG. Studies of the mechanism of cardiovascular response to CI-5. Anesthesiology 1968; 29:931-43 16 Taber DL, Wilson RD, Priano II. The effects of beta-adrenergic blockade on cardiopulmonary response to ketamine. Anesth Analg 1970; 49:604-13 17 Spotoft H , Korshin JD, Bredgaard Sorensen M, et al. The cardiovascular effects of ketamine used for induction of anaesthesia in patients with valvular heart disease. Can Anaesth Soc J 1979; 26:463-67 18 Byrne AJ, Tomlinson DR, Healy TEJ. Ketamine and sympathetic mechanisms in cardiac and smooth muscle. Acta Anaesthesiol Scand 1982; 26:479-84 19 Oyama T, Matsumoto F, Kudo !. Effects of ketamine on adrenocortical function in man. Anesth Analg 1970; 49:697-700 20 Newsome LR, Moldenhauer CC, Hug CC, et al. Hemodynamic interactions of moderate doses of fentanyl with etomidate and ketamine. Anesth Analg 1985; 64:260 21 Lundy PM, Colhoun EH, Gowdey CW. Pressor responses of ketamine and circulating biogenic amines. Nature 1974; 241:80-2 22 Liao JC, Koehn top DE, Buckley JJ. Dual effect of ketamine on
peripheral vasculature. Anesthesiology 1979; 51 :Sll6 23 Tweed WA, Minuck M, Mymin D. Circulatory responses to ketamine anesthesia. Anesthesiology 1972; 37:613-19 24 Hanowell ST, Zwischen berger JB, Siwek LG, et al. The effect of ketamine in the lamb with left to right shunt. Anesthesiology 1981; 55:A15 25 Bodai BI, Harms BA, Nottingham PB, et al. The effect of ketamine on endotoxin-induced lung injury. Anesth Analg 1983; 62:398-403 26 Rich GF, Roos CM, Anderson SM, et al. Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung. Anesth Analg 1994; 78:961-66 27 Yamazaki M, Ito Y, Kuze S, et al. Effects of ketamine on voltage-dependent Ca2+ currents in single smooth muscle cells from rabbit portal vein. Pharmacology 1992; 45:162-69 28 Stowe DF, Bosnjak ZJ, Kampine JP. Comparison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts. Anesth Analg 1992; 74:547-58 29 Park GR, Manara AR, Mendel L, et al. Ketamine infusion: its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia 1987; 42:980-83
CHEST /107/4/ APRIL, 1995
1155
Ketamine has been used in patients with congenital heart disease and pulmonary hypertension with hypothetical controversy. Its direct effect on pulmonary arteries has not yet been clearly characterized. This in vitro study was performed to determine the direct vasoactive effects of ketamine on isolated rabbit pulmonary arteries. Responses of pulmonary artery rings from New Zealand white rabbits were assessed in the presence and absence of intact endothelium and with or without precontraction by norepinephrine (NE, 3X 10- 6 M) or potassium chloride (KCl, 3Xl0-2 M). Using a preparatory tissue bath, cumulative concentration response curves of ketamine were obtained at different concentrations (0.03, 0.1, 0.3, 1, 3 mM) after a period of stabilization. Ketamine caused a dose-related vasodilation on KCl-precontracted pulmonary arteries. It elicited almost 100% relaxation at a concentration of 3 mM.
Jn vivo, the use of ketamine usually is associated
with increases in blood pressure, heart rate , and cardiac output, while changes in stroke volume and systemic vascular resistance are variable.1·2 The mechanisms of this cardiovascular stimulation are complex and seem to be predominated by the central activation of the sympathetic nervous system associated with increased plasma levels of epinephrine and norepinephrine (NE). 3 Whereas ketamine reportedly increases both pulmonary and systemic vascular resistances, some studies suggest that physiologic changes associated with ketamine are more pronounced on pulmonary than on systemic circulation, and on the right side rather than on the left side of the heart. 4-6 In the literature, ketamine has been suggested to be either a direct vasoconstrictor or vasodilator of pulmonary arteries, and the exact character has not yet been clearly defined. 7-9 Clinically, ketamine has been considered by some to be the anesthetic of choice for cardiac catheterization 8•10•11 as well as the induction technique of choice in patients with congenital heart disease , including cyanotic or potentially cyanotic groups.l 2- 14 It is considered that *From the Department of Anesthesiology, Harbor-UCLA Medical Center, Torrance, Calif. Manuscript received January 18, 1994; revision accepted August 4. Reprint requests: Dr. Lee, Department of Anesthesiology, Harbor-UCLA Medical Center, 1000 W . Carson Street, Torrance, CA 90509-2910 1152
Ketamine also induced a dose-related vasodilation on NE-precontracted pulmonary arteries at a lesser degree. All of the effects were endothelium independent. In conclusion, ketamine has strong endothelium-independent, direct vasodilatory effects on isolated rabbit pulmonary arteries. Ketamine may act through Ca ++channel-blocking effect as well as inhibition of Ca ++ release from sarcoplasmic reticulum. (Chest 1995; 107:1152-55)
KCI=potassium chloride; NE=norepinephrine
Key words: ketamine; pulmonary artery; vasodilation , Ca ++ channel; endothelium
ketamine can prevent the increase of right-to-left shunting in cyanotic congenital heart disease as a result of its tendency to increase systemic vascular resistance.l5·16 Nevertheless, conflicting data have raised a hypothetical concern about using ketamine in patients with pulmonary hypertension ,3.6 limited right ventricle reserve, 3 .l 7 or cyanotic congenital heart disease.8 Avoidance of ketamine has been recommended under these situations even though no notable problems have been encountered from clinical experience. 3 ·6 This study was designed to investigate the direct effect of ketamine on isolated rabbit pulmonary arteries (1) with or without intact endothelium, and (2) with potassium chloride (KCl) orNE precontraction. METHODS
Approval from the Institutional Animal Research Committee was obtained. Six New Zealand white rabbits, weighing 2 to 2.5 kg, were used for the experiment. The rabbits were anesthetized with pentobarbital sodium 40 mg / kg. A segment of main pulmonary artery just distal to the bifurcation was removed immediately following respiratory arrest through midsternotomy. Precaution was exercised to avoid damage of the intimal surface. The vessels were freed from the connective tissue and cut into 3-mm-wide rings. Each ring of pulmonary artery was immersed in a 10-mL tissue-organ bath containing a continuously oxygenated (95% 0 2, 5% C02 ) Krebs solution at 37° C and a pH of 7.4. The solution consisted of 118 mmol of NaCl, 0.8 mmol of KCl, 2.5 mmol CaC1 2 , 25 mmol of NaHC03, 1.18 mmol of KHzP04, 1.19 mmol of MqSD 4, and ll mmol of glucose. The ring was suspended Vasoactive Effects of Ketamine on Isolated Rabbit PAs (Lee, Hou)
between a fixed hook and an isometric transducer (Grass FT03). The contractions were recorded on a polygraph (Beckman R612 ). The resting tension of each ring was adjusted to 3.75 g based on the prior search of the optimal resting tension (Lmax) in rabbit pulmonary arteries. At least 1 h was allowed for equilibration and stabilization. Two groups of vessels were prepared, one with and one without intact endothelium. Both were tested under the same conditions for comparison. The de-endothelialization was performed by gently rubbing the intimal surface with forceps and confirmed pharmacologically by standard test with NE (3X 10- 7M) and acetylcholine (10- 6M). Two (one intact and one denuded) pulmonary arterial rings were obtained from each animal. Six rings were prepared for each set of the experiment; totally 12 rings were used.
Protocol Step 1: Following stabilization, the submaximal precontraction
of the vessels was randomly induced by either KCI (3Xl0-2 M) or NE (3X10- 6 M). When contractile responses reached a plateau, cumulative concentration-response curves of ketamine were constructed by adding increasing concentrations of ketamine in logarithmic increments (0.03 to 3 mM). Step 2: The rings were washed after step l until complete recovery of the resting tension was reached. Another hour was allowed for equilibration. Then the submaximal precontraction of the pulmonary arteries was again elicited by KCI (3Xl0- 2 M) or NE (3Xl0- 6 M) alternately, using the drug opposite to the one used in step l. When the plateau of contraction was reached, cumulative concentration-response curves of ketamine were determined in the same manner as in step l. After each assay, each pulmonary artery ring was removed from the tissue-organ bath, blotted dry, and weighed. All results were measured as a percentage of the control contractions and expressed as the mean value ± SEM. The difference between mean values was analyzed by analysis of variance and Student's t test. The difference was considered statistically significant at p<0.05. RESULTS
Ketamine caused vasodilatation in the KCl- (30 mM) precontracted isolated rabbit pulmonary arteries in a dose-dependent manner. At a concentration of 3 mM, it elicited almost 100% relaxation of the control (Fig 1). This vasodilatory response was endothelium independent. Ketamine also induced a dose-related vasodilata0
-20
z
·~
5
-120
n::: -80
~
-100
-E(+) CJE(-)
-120~--------------------------------~
0.03
0 ..3
0.1
3
E :Endothelium
KETAMINE ( mM )
FIGUHE 2. Cumulative concentration responses of ketamine in isolated NE-precontracted rabbit pulmonary arteries with (+) or without (-) endothelium (E).
tion in NE-precontracted isolated rabbit pulmonary arteries (Fig 2). The magnitude of relaxation was significantly less than that on KCl-precontracted pulmonary arteries at the same doses of ketamine (Fig 3). At 3 mM, it produced about 60% relaxation of the control. There was no difference between groups with or without intact endothelium. DISCUSSIO'II
Theoretically, ketamine is expected to cause vasoconstriction through central sympathomimetic stimulation ,3 •17 inhibition of neuronal reuptake of NE, 17 •18 activation of the pituitary-adrenal axis, 19 and subsequent increase in circulating catecholamines. 20•21 However, ketamine has been reported to have dual effect on the peripheral vasculature. 22 The central pressor effect may be counterbalanced by the direct vasodilating property of ketamine, with variable net results. Our studies on isolated rabbit pulmonary arteries showed that ketamine caused a significant dose-related vasodilatation on KCl-precontracted as
-20
0 ~ -40
::; -60
~
w n::: -80 -100
w
X
-60
~
-60
<(
_..1
z
0
X
-40
~
X
0
IW
~ -40
-20
z
0
w n::: -80 ~
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-100
lfJ
OPEN: E( +)
SOLID: E(-)
4J 0.03
0.1
0.3
3
E : Endothelium KETAMINE ( mM ) of ketamine in responses FIGliHE l. Cumulative concentration isolated KCI-precontracted rabbit pulmonary arteries with (+)or without (- ) endothelium (E).
0.1
0.3
E :Endothelium KETAMINE ( mM ) PRECONTRACTED: 0 + BY NE \1 ._ BY KCI
FIGCHE 3. Comparison of cumulative concentration-response curves of ketamine in isolated KCl- or NE-precontracted rabbit pulmonary arteries with (+) or without (-) endothelium (E). CHEST /107 I 41 APRIL, 1995
1153
well as NE-precontracted vessels. Tweed et al 23 reported that in vivo ketamine increased pulmonary arterial pressure (44%) and cardiac output. Gassner et al8 and Morray et al 4 also demonstrated a statistically significant but clinically minor increase in pulmonary artery pressure and pulmonary vascular resistance. Clinically , it has been shown by Takahashi et aF that ketamine is a direct pulmonary vasoconstrictor. Spotoft et aF 7 also found that ketamine increased pulmonary vascular resistance, thereby increasing the work of the right ventricle. The results from clinical studies may be confusing because of uncontrolled factors such as different levels of autonomic tone , various disease states, difference in reflex reaction , or other factors . Arecent report speculated that some of the increase in pulmonary vascular resistance, as seen in previous studies, might be secondary to hypoxemia and hypercapnia due to hypoventilation.5·23 However , some studies showed that ketamine decreased pulmonary vascular resistance in both young lambs and adult sheep and also caused slight vasodilation in an isolated vascular bed .10 · 23 -25 Our results, in agreement with Rich et al ,26 confirm the latter and show that ketamine is indeed a strong vasodilator in isolated rabbit pulmonary arteries. At 3 mM concentration, it produced almost 100% relaxation on KCl-precontracted vessels and 60% on NE-precontracted ones. Since KCl causes contraction of the vascular smooth muscle by increasing Ca ++ influx via ca++ channels, which open after the membrane has depolarized , ketamine may have Ca++ channel-blocking effect. 27 This vasodilatory effect is dose related. However , NE induces contraction mainly by increasing the amount of ca++ released from sarcoplasmic reticulum as well as some increase in Ca++ influx. Relaxation caused by ketamine may indicate that ketamine can directly inhibit the release of Ca ++ from sarcoplasmic reticulum,27 or indirectly do so by decreasing ca++ influx through its ca++ channel-blocking effect , which in turn attenuates the Ca ++-induced Ca ++ release. Kanmura et al 9 report that ketamine-induced relaxation may be in part caused by inhibiting NEinduced synthesis of inositol 1,4,5-trisphosphate in the vascular smooth muscles and thus interfering with the release of Ca ++from intracellular store sites. Since there was no difference in the degree of relaxation between two groups with or without intact endothelium, we concluded that ketamine caused vasodilation on isolated rabbit pulmonary arteries without involvement of endothelial-derived relaxing factor. Similar to its well-known dose-related, direct myocardial depressant effect, 13·28 the direct vasoactive effect of ketamine causes relaxation of the pulmonary arteries. We ecognize r that the results ob1154
tained from this study should not be carelessly extrapolated to clinical practice. Nevertheless, they may, in part, explain the conflicting clinical data. The balance between central sympathomimetic responses and direct peripheral depressant will determine the outcome of the vascular tone. When the sympathetic nervous system is depressed, attenuated, blocked, or exhausted with depleted catecholamine stores, ketamine may cause paradoxical cardiovascular collapse by myocardial depression and peripheral vasodilatation .13·28 However, even though ketamine is generally believed to be the drug of choice for induction of anesthesia in cyanotic patients , the theoretical possibility of precipitation of a h ypercyanotic episode in patients with tetralogy of Fallot must be kept in mind.13 In summary, ketamine is not only a known bronchodilator ,29 but it is also a powerful vasodilator for isolated rabbit pulmonary arteries, more in those precontracted with KCl than with NE. R EFERE.!\CES
2 3 4
5
6
7
8
9
10 11 12
13
14
White PF. Comparative evaluation of intravenous agents for rapid seq uence induction-thiopental, ketam ine, and midazolam. Anesthesiology 1982; 57:279-84 Puu G, Koch M, Artursson E. Ketamine enantiomers and acetylcholinesterase. Biochem Pharmacal 1991 ; 41:2043-45 White PF, Way WL, Trevor AJ. Ketamin e-its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119-36 Morray JP, Lynn AM, Stamm SJ, et al. H emodynamic effects of ketam ine in children with congenital heart disease. Anesth Analg 1984; 63:895-99 Hickey PR, H ansen DD, Cramolini GM, et al. Pulmonary and systemic hemodynamic responses to ketamine in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1985; 62:287-93 Gooding JM , Dimick AR, Tavakoli M, et al. A physiologic analysis of cardiopulmonary responses to ketam ine anesthesia in noncardiac patients. Anesth Analg 1977; 56:813-16 Takahashi K, Shuna I, Koga Y. The effects of ketamine on the pulmonary hemodynamics in dogs. Jpn J Anaesth 1971 ; 20:842-46 Gassner S, Cohen M, Aygen M, et al. The effect of ketamine on pulmonary artery pressure: an experimental and clinical study. Anaesthesia 1974; 29:141-46 Kanmura Y, Kajikuri J, Iteh T, et l.a Effects of ketamine on contraction and synthesis of inositol1 ,4,5- trisphosphate in the smooth muscles of the rabbit mesenteric artery. Anesthesiology 1993; 79:571-79 Faithful! NS, Haider R. Ketamine for cardiac ca theterisation. Anaesthesia 1971; 26:318-23 Cappel DL, Dundee JW. Ketamine anaesthesia for cardiac catheterization. Anaesthesia 1972; 27:25-31 H ackel A. Anesthetic management of the pediatric patient. In: Ream AK, Fogdall RP, eds. Acute cardiovascular managem ent : anesthesia and intensive care. Philadelphia: JB Lippincott, 1982; 606-34 Bland JW, Williams WH. Anesthesia for treatment of congenital heart defects. In : Kaplan AL, ed. Cardiac anesthesia. New York: Grune & Stratton, 1979; 294 Hickey PR , Hansen DD, Norwood WI, et al. Anesthetic complications in surgery forcongenital heart disease. Anesth Analg Vasoactive Effects of Ketamine on Isolated Rabbit PAs (Lee, Hou)
1984; 63:657-64 15 Dowdy EG. Studies of the mechanism of cardiovascular response to CI-5. Anesthesiology 1968; 29:931-43 16 Taber DL, Wilson RD, Priano II. The effects of beta-adrenergic blockade on cardiopulmonary response to ketamine. Anesth Analg 1970; 49:604-13 17 Spotoft H , Korshin JD, Bredgaard Sorensen M, et al. The cardiovascular effects of ketamine used for induction of anaesthesia in patients with valvular heart disease. Can Anaesth Soc J 1979; 26:463-67 18 Byrne AJ, Tomlinson DR, Healy TEJ. Ketamine and sympathetic mechanisms in cardiac and smooth muscle. Acta Anaesthesiol Scand 1982; 26:479-84 19 Oyama T, Matsumoto F, Kudo !. Effects of ketamine on adrenocortical function in man. Anesth Analg 1970; 49:697-700 20 Newsome LR, Moldenhauer CC, Hug CC, et al. Hemodynamic interactions of moderate doses of fentanyl with etomidate and ketamine. Anesth Analg 1985; 64:260 21 Lundy PM, Colhoun EH, Gowdey CW. Pressor responses of ketamine and circulating biogenic amines. Nature 1974; 241:80-2 22 Liao JC, Koehn top DE, Buckley JJ. Dual effect of ketamine on
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