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Coronary vasoconstriction induced by leukotrienes in the anaesthetized dog
European Journal of Pharmacology, 86 ( 1983) 125-128 Elsevier Biomedical Press
125
Short communication CORONARY VASOCONSTRICTION DOG
I N D U C E D BY L E U K O T R I E N E S
IN T H E A N A E S T H E T I Z E D
OWEN L. WOODMAN * and GREGORY J. DUSTING Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, 3084 Australia
Received 21 September 1982, accepted 2 November 1982
O.L. WOODMAN and G.J. DUSTING, Coronary vasoconstriction induced I)v leukotrienes in the anaesthetized dog, European J. Pharmacol. 86 (1983) 125-128. In the anaesthetized dog LTC 4, LTD 4 (0.3-10 #g, injected into the coronary artery) and the thromboxane-mimetic U46619 (5-10 ~g) decreased coronary blood flow. LTE 4 (1-10/~g), however, did not affect coronary blood flow. The vasoconstrictor responses to LTC 4, LTD 4 or U46619 were not altered by the cyclo-oxygenase inhibitor indomethacin (5 m g / k g i.v.). LTC 4 and LTD 4 did not stimulate the release of any prostaglandin-like substance into the pericardial fluid. It is concluded that LTC 4 and LTD 4 are able to produce coronary vasoconstriction in vivo independent of the production of any cyclo-oxygenase metabolites of arachidonic acid. Coronary vasoconstriction
Indomethacin
Leukotrienes
1. Introduction Three of the active c o n s t i t u e n t s of slow-reacting s u b s t a n c e of a n a p h y l a x i s which have recently been identified, are the leukotrienes LTC4, L T D 4 and L T E 4 (for review S a m u e l s s o n , 1982). T h e leukotrienes have been shown to cause c o n t r a c t i o n of isolated p u l m o n a r y arteries ( H a n d et al., 1981) a n d to decrease c o n t r a c t i l i t y a n d increase c o r o n a r y p e r f u s i o n pressure in isolated, perfused hearts ( T e r a s h i t a et al., 1981; Burke et al., 1982; Letts a n d Piper, 1982). These findings suggest that the leukotrienes m a y be involved in the c a r d i a c dysfunction occuring in a n a p h y l a c t i c reactions. The p u r p o s e of this investigation was to e x a m i n e the actions of L T C 4, L T D 4 a n d L T E 4 on c o r o n a r y b l o o d flow in vivo in the anaesthetized dog.
2. Materials and methods T h i r t e e n dogs (11 g r e y h o u n d s a n d 2 mongrels) o f either sex weighing 25-32 kg were a n a e s t h e t i z e d * To whom all correspondence should be addressed. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
U46619
with a - c h l o r a l o s e (70 m g / k g i.v.) following induction with t h i o p e n t o n e s o d i u m (25 m g / k g i.v.). The dogs were artificially ventilated at a steady rate a n d with a d d i t i o n a l oxygen if necessary to maintain b l o o d gases a n d p H within the following limits: PO 2, 100-170 m m H g ; P C O 2, 29-40 m m H g ; p H 7.3-7.4. Systemic arterial b l o o d pressure was m e a s u r e d from a c a n n u l a in the right femoral artery. H e a r t rate was m e a s u r e d from the E C G or the pulse interval using a c a r d i o t a c h o m e t e r coup l e r to p r o v i d e a c o n t i n u o u s record. A left t h o r a c o t o m y was p e r f o r m e d at the fourth intercostal space; the p e r i c a r d i u m was o p e n e d and a p e r i c a r d i a l sling constructed. A short segment of the left circumflex artery was dissected free of the s u r r o u n d i n g connective tissue a n d b l o o d flow was m e a s u r e d using a cuff-type e l e c t r o m a g n e t i c flow p r o b e (Statham). Local injections of drugs (0.3 ml) were m a d e into the circumflex artery through a p o l y t h e n e c a n n u l a with a 23 gauge needle tip inserted through the arterial wall, a n d washed in 0.2 ml saline. In two dogs the left ventricular e p i c a r d i u m a n d p e r i c a r d i u m was irrigated at 3 m l / m i n with w a r m e d (37°C), o x y g e n a t e d K r e b s solution as pre-
126
viously described by Dusting and Nolan (1981). The irrigation fluid was continuously withdrawn from the pericardial sling beneath the heart and used to superfuse a cascade of bioassay tissues (bovine coronary artery, rat stomach strip and rat colon). These tissues were continuously treated with a mixture of antagonists and indomethacin (1 /xg/ml) to increase the sensitivity and specificity of the tissues for detecting prostanoids (Dusting and Nolan, 1981). The following substances were used: hyoscine hydrobromide (Boehringer-lngelheim); indomethacin (Sigma): leukotriene (LT) C 4, LTD 4, LTE 4 (gifts from J. Rokach, Merck Frosst); mepyramine maleate (May and Baker); methysergide bimaleate (Sandoz); p h e n o x y b e n z a m i n e h y d r o c h l o r i d e (Smith, Kline and French); (_+)-propranolol hydrochloride (Sigma); prostacyclin sodium salt (gift from J. Pike, Upjohn): U46619 (15S-hydroxyllc~:9c~-(epoxymethano) prosta-5Z, 13E-dienoic acid, Upjohn).
3. Results L T C 4, L T D 4 and L T E 4 w e r e injected into the circumflex coronary artery in the dose range 0.3-l0
p.g. LTC 4 caused a dose dependent decrease in coronary blood flow of up to 42% at the highest dose (table 1). The blood flow returned to control levels within 3 rain of leukotriene injection. There was no change in systemic blood pressure, pulmonary artery pressure or heart rate (fig. 11. LTD 4 caused a dose-dependent decrease in coronary blood flow of a similar magnitude (table 11 and duration (fig. 11 to that produced by LTC 4. There was no change in any of the other cardiovascular parameters measured (fig. 11. LTE 4 had no effect on coronary blood flow, systemic blood pressure, pulmonary artery pressure or heart rate. In two experiments in which the pericardium and epicardial surface of the heart was superfused with Krebs solution the intracoronary injection of L T C 4 and LTD 4 did not cause detectable release of prostaglandin-like substances. Increases of prostaglandin-like substances were also not detected in the epicardial irrigation fluid when L T ( " 4 or LTD 4 (0.1 /xg/ml) were applied topically to the epicardial surface by inclusion in the Krebs" superfusate. The thromboxane A2-mimetic, U46619 (5-10 /zg), decreased coronary blood flow (table 1). and reduced pulmonary artery pulse pressure (fig. 1),
TABLE 1 Effect of leukotrienes and U46619 on coronary blood flow. Values are m e a n + S . E . M . The n u m b e r of e x p e r i m e n t s are indicated in parentheses. Control
lndomethacin 5 mg/kg
Resting (ml/min)
Change (%)
Resting (ml/min)
Change (q-)
85+24 106_+ 15 100+ 15 104+37
(4)
LT(_) (lag) 0.3
100± 19
(4)
10+3
1
111 + 13
(6)
21 + 3
3 10
104_+ 10 103_+22
(6) (3)
-25+6 -42+9
0.3
100+ 10
(4)
- 11 ± 6
1
101±
8
(7)
-10±3
103± 7 105_+ 14
(6) (3)
115+ 17 120+ 16
(7) (7)
11 + 1
16)
- 19 ± 4
(6) 131
18±4 36+7
15±4 -40+_9
7 9 + 20 9 5 + 13 98_+15 92+25
(4) 171 (6) (3)
- 9+ 6 -10+3 18+6 31 .+_2
24_+8 -26_+7
104+ 19 110+28
17) (7)
21 + 4 29+2
LTD4 (la,g)
3 10
U46619 (lag) 5 10
127
2o0[
I
BP
II
sec
t
J 2
min
mmHg
50 mBp'70[ mmHgl2 0 HR 180 I b/min 60 L CBFI60 m
ml/min
oL .m~mmmhm...,L
mmHcj IoL
t
LTC 4 pg (i.a.)
3
t
t
t
LT D4
U46619
PGI2
3
5
I
Fig. 1. Experimental record showing the effects of LTC 4, LTD 4, U46619 and prostacyclin (PGI2) on systemic blood pressure (BP), heart rate (HR), coronary blood flow (CBF) and pulmonary artery pressure (PAP). All substances were injected directly into the circumflex coronary artery.
with little or no effect on systemic blood pressure or heart rate. Prostacyclin (PGI 2, 1 fig) increased coronary blood flow and caused a slight reduction in systemic blood pressure without affecting heart rate or pulmonary artery pressure (fig.). The intravenous injection of the cyclo-oxygenase inhibitor, indomethacin (5 m g / k g ) generally caused a small, insignificant reduction in coronary blood flow (resting coronary blood flow before indomethacin 112 _+ 10 m l / m i n , n = 13; after indomethacin 102 + 9 m l / m i n , n = 13). In previous experiments this dose of indomethacin has been shown to abolish arachidonate-induced coronary vasodilatation and release of prostacyclin into
pericardial fluid (Dusting and Nolan, 1981). Indomethacin, however, had no significant effect (P > 0.05, Student's t-test for paired data) upon the vasoconstrictor responses to LTC 4, LTD 4 or U46619 (table 1).
4. Discussion
The leukotrienes LTC4, L T D 4 and LTE 4 have previously been reported to contract isolated vascular strips from guinea-pigs and rabbits (Hand et al., 1981; Kito et al., 1981) and to increase coronary perfusion pressure in guinea-pig isolated hearts (Terashita et al., 1981; Burke et al., 1982; Letts
128 a n d P i p e r , 1982). I n a d d i t i o n L T D 4 h a s b e e n s h o w n to cause coronary vasoconstriction in t h e a n a e s t h e t i z e d s h e e p ( M i c h e l a s s i et al., 1982). I n the present study we have shown that LTC 4 and L T D 4 r e d u c e c o r o n a r y b l o o d f l o w u p o n l o c a l in-
Australia. Dr. Dusting is a Senior Research Fellow of the National Heart Foundation. We are grateful to Tracey Drysdate and Michael Visentin for skilfut technical assistance.
j e c t i o n in t h e a n a e s t h e t i z e d d o g . L T C 4 a n d L T D 4 were active over the same dose range and each p r o d u c e d a r e d u c t i o n i n b l o o d f l o w o f u p to 40% a t t h e d o s e s u s e d . I n c o n t r a s t L T E 4, o v e r a s i m i l a r d o s e r a n g e d i d n o t a f f e c t c o r o n a r y b l o o d flow. Investigations using isolated, perfused hearts of t h e g u i n e a - p i g ( B u r k e et al., 1982) o r r a t ( W o o d m a n et al., 1982) a l s o s u g g e s t e d t h a t L T E 4 is a less potent coronary vasoconstrictor than either LTC 4
References
o r L T D 4. Some studies have suggested that the cardiovascular actions of the leukotrienes may be partly m e d i a t e d b y p r o s t a n o i d r e l e a s e ( O m i n i et al., 1981; L e t t s a n d P i p e r , 1982). I n o u r e x p e r i m e n t s , h o w ever, t h e c y c l o - o x y g e n a s e i n h i b i t o r i n d o m e t h a c i n f a i l e d to i n f l u e n c e t h e c o r o n a r y v a s o c o n s t r i c t i o n p r o d u c e d b y L T C 4 o r L T D 4. I n a d d i t i o n t h e r e w a s no evidence of production of prostaglandin-like substances by the pericardial membranes after topical or intra-coronary administration of LTC 4 o r L T D 4, w h e r e a s a r a c h i d o n i c a c i d a n d f a c t o r s increasing cardiac workload released large amounts of PGI 2 from these tissues (Dusting and Nolan, 1981). I n c o n c l u s i o n b o t h L T C 4 a n d L T D 4 a r e a b l e to cause coronary vasoconstriction in vivo independent of any cyclo-oxygenase metabolites of a r a c h i d o n i c acid. T h e l e u k o t r i e n e s m i g h t c o n t r i b ute to cardiac dysfunction in anaphylaxis.
Acknowledgements This work was supported by the National Health and Medical Research Council and National Heart Foundation of
Burke, J.A., R. Levi, Z.-G. Guo and E.J. Corey, 1982, Leukotrienes C4, D 4 and E4: effects on human and guineapig cardiac preparations in vitro, J. Pharmacol. Exp. Ther. 221, 235. Dusting, G.J. and R.D. Nolan, 1981, Stimulation of prostacyclin release from the epicardium of anaesthetized dogs, Br. J. Pharmacol. 74, 553. Hand, J.M., J.A. Will and C.K. Buckner, 1981, Effects of leukotrienes on isolated guinea-pig pulmonary arteries, European J. Pharmacol. 76, 439. Kito, G., H. Okuda, S. Ohkawa, S. Terao and K. Kibuchi, 1981, Contractile activities of leukotrienes C4 and D 4 on vascular strips from rabbits, Life Sci. 29, 1325. Letts, L.G. and P.J. Piper, 1982, The actions of leukotrienes ('4 and D 4 on guinea-pig isolated hearts, Br. J. Pharmacol. 76, 169. Michelassi, F., L. Landa, R.D. Hill, E, Lowenstein, W.D. Watkins, A.J. Petkau and W.M. Zapol, 1982, Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction, Science 217, 841. Omini, C., G.C. Folco, T. Vigano, G. Rossoni, G. Brunelli and F. Berti, 1981, Leukotriene C4 induces generation of PGI 2 and TXA 2 in guinea-pig in vivo, Pharmacol. Res. Commun. 13, 633. Samuelsson, B., 1982, The leukotrienes: an introduction, Adv. Prost. Thromb. Leuk. Res. 9, 1. Terashita, Z.-I., H. Fukui, M. Hirata, S. Terao, S. Ohkawa, K. Nishikawa and S. Kikuchi, 1981, Coronary vasoconstriction and PGI 2 release by leukotrienes in isolated guinea-pig hearts, European J. Pharmacol. 73. 357. Woodman, O.L., W.J. Hum and G.J. Dusting, 1982, Leukotriene-induced coronary vasoconstriction, Proc. Aust. Physiol. Pharmacol. Soc. 13, 160P.
125
Short communication CORONARY VASOCONSTRICTION DOG
I N D U C E D BY L E U K O T R I E N E S
IN T H E A N A E S T H E T I Z E D
OWEN L. WOODMAN * and GREGORY J. DUSTING Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, 3084 Australia
Received 21 September 1982, accepted 2 November 1982
O.L. WOODMAN and G.J. DUSTING, Coronary vasoconstriction induced I)v leukotrienes in the anaesthetized dog, European J. Pharmacol. 86 (1983) 125-128. In the anaesthetized dog LTC 4, LTD 4 (0.3-10 #g, injected into the coronary artery) and the thromboxane-mimetic U46619 (5-10 ~g) decreased coronary blood flow. LTE 4 (1-10/~g), however, did not affect coronary blood flow. The vasoconstrictor responses to LTC 4, LTD 4 or U46619 were not altered by the cyclo-oxygenase inhibitor indomethacin (5 m g / k g i.v.). LTC 4 and LTD 4 did not stimulate the release of any prostaglandin-like substance into the pericardial fluid. It is concluded that LTC 4 and LTD 4 are able to produce coronary vasoconstriction in vivo independent of the production of any cyclo-oxygenase metabolites of arachidonic acid. Coronary vasoconstriction
Indomethacin
Leukotrienes
1. Introduction Three of the active c o n s t i t u e n t s of slow-reacting s u b s t a n c e of a n a p h y l a x i s which have recently been identified, are the leukotrienes LTC4, L T D 4 and L T E 4 (for review S a m u e l s s o n , 1982). T h e leukotrienes have been shown to cause c o n t r a c t i o n of isolated p u l m o n a r y arteries ( H a n d et al., 1981) a n d to decrease c o n t r a c t i l i t y a n d increase c o r o n a r y p e r f u s i o n pressure in isolated, perfused hearts ( T e r a s h i t a et al., 1981; Burke et al., 1982; Letts a n d Piper, 1982). These findings suggest that the leukotrienes m a y be involved in the c a r d i a c dysfunction occuring in a n a p h y l a c t i c reactions. The p u r p o s e of this investigation was to e x a m i n e the actions of L T C 4, L T D 4 a n d L T E 4 on c o r o n a r y b l o o d flow in vivo in the anaesthetized dog.
2. Materials and methods T h i r t e e n dogs (11 g r e y h o u n d s a n d 2 mongrels) o f either sex weighing 25-32 kg were a n a e s t h e t i z e d * To whom all correspondence should be addressed. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
U46619
with a - c h l o r a l o s e (70 m g / k g i.v.) following induction with t h i o p e n t o n e s o d i u m (25 m g / k g i.v.). The dogs were artificially ventilated at a steady rate a n d with a d d i t i o n a l oxygen if necessary to maintain b l o o d gases a n d p H within the following limits: PO 2, 100-170 m m H g ; P C O 2, 29-40 m m H g ; p H 7.3-7.4. Systemic arterial b l o o d pressure was m e a s u r e d from a c a n n u l a in the right femoral artery. H e a r t rate was m e a s u r e d from the E C G or the pulse interval using a c a r d i o t a c h o m e t e r coup l e r to p r o v i d e a c o n t i n u o u s record. A left t h o r a c o t o m y was p e r f o r m e d at the fourth intercostal space; the p e r i c a r d i u m was o p e n e d and a p e r i c a r d i a l sling constructed. A short segment of the left circumflex artery was dissected free of the s u r r o u n d i n g connective tissue a n d b l o o d flow was m e a s u r e d using a cuff-type e l e c t r o m a g n e t i c flow p r o b e (Statham). Local injections of drugs (0.3 ml) were m a d e into the circumflex artery through a p o l y t h e n e c a n n u l a with a 23 gauge needle tip inserted through the arterial wall, a n d washed in 0.2 ml saline. In two dogs the left ventricular e p i c a r d i u m a n d p e r i c a r d i u m was irrigated at 3 m l / m i n with w a r m e d (37°C), o x y g e n a t e d K r e b s solution as pre-
126
viously described by Dusting and Nolan (1981). The irrigation fluid was continuously withdrawn from the pericardial sling beneath the heart and used to superfuse a cascade of bioassay tissues (bovine coronary artery, rat stomach strip and rat colon). These tissues were continuously treated with a mixture of antagonists and indomethacin (1 /xg/ml) to increase the sensitivity and specificity of the tissues for detecting prostanoids (Dusting and Nolan, 1981). The following substances were used: hyoscine hydrobromide (Boehringer-lngelheim); indomethacin (Sigma): leukotriene (LT) C 4, LTD 4, LTE 4 (gifts from J. Rokach, Merck Frosst); mepyramine maleate (May and Baker); methysergide bimaleate (Sandoz); p h e n o x y b e n z a m i n e h y d r o c h l o r i d e (Smith, Kline and French); (_+)-propranolol hydrochloride (Sigma); prostacyclin sodium salt (gift from J. Pike, Upjohn): U46619 (15S-hydroxyllc~:9c~-(epoxymethano) prosta-5Z, 13E-dienoic acid, Upjohn).
3. Results L T C 4, L T D 4 and L T E 4 w e r e injected into the circumflex coronary artery in the dose range 0.3-l0
p.g. LTC 4 caused a dose dependent decrease in coronary blood flow of up to 42% at the highest dose (table 1). The blood flow returned to control levels within 3 rain of leukotriene injection. There was no change in systemic blood pressure, pulmonary artery pressure or heart rate (fig. 11. LTD 4 caused a dose-dependent decrease in coronary blood flow of a similar magnitude (table 11 and duration (fig. 11 to that produced by LTC 4. There was no change in any of the other cardiovascular parameters measured (fig. 11. LTE 4 had no effect on coronary blood flow, systemic blood pressure, pulmonary artery pressure or heart rate. In two experiments in which the pericardium and epicardial surface of the heart was superfused with Krebs solution the intracoronary injection of L T C 4 and LTD 4 did not cause detectable release of prostaglandin-like substances. Increases of prostaglandin-like substances were also not detected in the epicardial irrigation fluid when L T ( " 4 or LTD 4 (0.1 /xg/ml) were applied topically to the epicardial surface by inclusion in the Krebs" superfusate. The thromboxane A2-mimetic, U46619 (5-10 /zg), decreased coronary blood flow (table 1). and reduced pulmonary artery pulse pressure (fig. 1),
TABLE 1 Effect of leukotrienes and U46619 on coronary blood flow. Values are m e a n + S . E . M . The n u m b e r of e x p e r i m e n t s are indicated in parentheses. Control
lndomethacin 5 mg/kg
Resting (ml/min)
Change (%)
Resting (ml/min)
Change (q-)
85+24 106_+ 15 100+ 15 104+37
(4)
LT(_) (lag) 0.3
100± 19
(4)
10+3
1
111 + 13
(6)
21 + 3
3 10
104_+ 10 103_+22
(6) (3)
-25+6 -42+9
0.3
100+ 10
(4)
- 11 ± 6
1
101±
8
(7)
-10±3
103± 7 105_+ 14
(6) (3)
115+ 17 120+ 16
(7) (7)
11 + 1
16)
- 19 ± 4
(6) 131
18±4 36+7
15±4 -40+_9
7 9 + 20 9 5 + 13 98_+15 92+25
(4) 171 (6) (3)
- 9+ 6 -10+3 18+6 31 .+_2
24_+8 -26_+7
104+ 19 110+28
17) (7)
21 + 4 29+2
LTD4 (la,g)
3 10
U46619 (lag) 5 10
127
2o0[
I
BP
II
sec
t
J 2
min
mmHg
50 mBp'70[ mmHgl2 0 HR 180 I b/min 60 L CBFI60 m
ml/min
oL .m~mmmhm...,L
mmHcj IoL
t
LTC 4 pg (i.a.)
3
t
t
t
LT D4
U46619
PGI2
3
5
I
Fig. 1. Experimental record showing the effects of LTC 4, LTD 4, U46619 and prostacyclin (PGI2) on systemic blood pressure (BP), heart rate (HR), coronary blood flow (CBF) and pulmonary artery pressure (PAP). All substances were injected directly into the circumflex coronary artery.
with little or no effect on systemic blood pressure or heart rate. Prostacyclin (PGI 2, 1 fig) increased coronary blood flow and caused a slight reduction in systemic blood pressure without affecting heart rate or pulmonary artery pressure (fig.). The intravenous injection of the cyclo-oxygenase inhibitor, indomethacin (5 m g / k g ) generally caused a small, insignificant reduction in coronary blood flow (resting coronary blood flow before indomethacin 112 _+ 10 m l / m i n , n = 13; after indomethacin 102 + 9 m l / m i n , n = 13). In previous experiments this dose of indomethacin has been shown to abolish arachidonate-induced coronary vasodilatation and release of prostacyclin into
pericardial fluid (Dusting and Nolan, 1981). Indomethacin, however, had no significant effect (P > 0.05, Student's t-test for paired data) upon the vasoconstrictor responses to LTC 4, LTD 4 or U46619 (table 1).
4. Discussion
The leukotrienes LTC4, L T D 4 and LTE 4 have previously been reported to contract isolated vascular strips from guinea-pigs and rabbits (Hand et al., 1981; Kito et al., 1981) and to increase coronary perfusion pressure in guinea-pig isolated hearts (Terashita et al., 1981; Burke et al., 1982; Letts
128 a n d P i p e r , 1982). I n a d d i t i o n L T D 4 h a s b e e n s h o w n to cause coronary vasoconstriction in t h e a n a e s t h e t i z e d s h e e p ( M i c h e l a s s i et al., 1982). I n the present study we have shown that LTC 4 and L T D 4 r e d u c e c o r o n a r y b l o o d f l o w u p o n l o c a l in-
Australia. Dr. Dusting is a Senior Research Fellow of the National Heart Foundation. We are grateful to Tracey Drysdate and Michael Visentin for skilfut technical assistance.
j e c t i o n in t h e a n a e s t h e t i z e d d o g . L T C 4 a n d L T D 4 were active over the same dose range and each p r o d u c e d a r e d u c t i o n i n b l o o d f l o w o f u p to 40% a t t h e d o s e s u s e d . I n c o n t r a s t L T E 4, o v e r a s i m i l a r d o s e r a n g e d i d n o t a f f e c t c o r o n a r y b l o o d flow. Investigations using isolated, perfused hearts of t h e g u i n e a - p i g ( B u r k e et al., 1982) o r r a t ( W o o d m a n et al., 1982) a l s o s u g g e s t e d t h a t L T E 4 is a less potent coronary vasoconstrictor than either LTC 4
References
o r L T D 4. Some studies have suggested that the cardiovascular actions of the leukotrienes may be partly m e d i a t e d b y p r o s t a n o i d r e l e a s e ( O m i n i et al., 1981; L e t t s a n d P i p e r , 1982). I n o u r e x p e r i m e n t s , h o w ever, t h e c y c l o - o x y g e n a s e i n h i b i t o r i n d o m e t h a c i n f a i l e d to i n f l u e n c e t h e c o r o n a r y v a s o c o n s t r i c t i o n p r o d u c e d b y L T C 4 o r L T D 4. I n a d d i t i o n t h e r e w a s no evidence of production of prostaglandin-like substances by the pericardial membranes after topical or intra-coronary administration of LTC 4 o r L T D 4, w h e r e a s a r a c h i d o n i c a c i d a n d f a c t o r s increasing cardiac workload released large amounts of PGI 2 from these tissues (Dusting and Nolan, 1981). I n c o n c l u s i o n b o t h L T C 4 a n d L T D 4 a r e a b l e to cause coronary vasoconstriction in vivo independent of any cyclo-oxygenase metabolites of a r a c h i d o n i c acid. T h e l e u k o t r i e n e s m i g h t c o n t r i b ute to cardiac dysfunction in anaphylaxis.
Acknowledgements This work was supported by the National Health and Medical Research Council and National Heart Foundation of
Burke, J.A., R. Levi, Z.-G. Guo and E.J. Corey, 1982, Leukotrienes C4, D 4 and E4: effects on human and guineapig cardiac preparations in vitro, J. Pharmacol. Exp. Ther. 221, 235. Dusting, G.J. and R.D. Nolan, 1981, Stimulation of prostacyclin release from the epicardium of anaesthetized dogs, Br. J. Pharmacol. 74, 553. Hand, J.M., J.A. Will and C.K. Buckner, 1981, Effects of leukotrienes on isolated guinea-pig pulmonary arteries, European J. Pharmacol. 76, 439. Kito, G., H. Okuda, S. Ohkawa, S. Terao and K. Kibuchi, 1981, Contractile activities of leukotrienes C4 and D 4 on vascular strips from rabbits, Life Sci. 29, 1325. Letts, L.G. and P.J. Piper, 1982, The actions of leukotrienes ('4 and D 4 on guinea-pig isolated hearts, Br. J. Pharmacol. 76, 169. Michelassi, F., L. Landa, R.D. Hill, E, Lowenstein, W.D. Watkins, A.J. Petkau and W.M. Zapol, 1982, Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction, Science 217, 841. Omini, C., G.C. Folco, T. Vigano, G. Rossoni, G. Brunelli and F. Berti, 1981, Leukotriene C4 induces generation of PGI 2 and TXA 2 in guinea-pig in vivo, Pharmacol. Res. Commun. 13, 633. Samuelsson, B., 1982, The leukotrienes: an introduction, Adv. Prost. Thromb. Leuk. Res. 9, 1. Terashita, Z.-I., H. Fukui, M. Hirata, S. Terao, S. Ohkawa, K. Nishikawa and S. Kikuchi, 1981, Coronary vasoconstriction and PGI 2 release by leukotrienes in isolated guinea-pig hearts, European J. Pharmacol. 73. 357. Woodman, O.L., W.J. Hum and G.J. Dusting, 1982, Leukotriene-induced coronary vasoconstriction, Proc. Aust. Physiol. Pharmacol. Soc. 13, 160P.