Effects of prostacyclin (PGI2) on vulnerability to ventricular fibrillation in the normal and ischemic canine heart

European Journal of Pharmacology, 80 (1982) 83-91

83

Elsevier Biomedical Press

E F F E C T S O F P R O S T A C Y C L I N ( P G I 2) O N V U L N E R A B I L I T Y T O V E N T R I C U L A R F I B R I L L A T I O N IN THE NORMAL AND ISCHEMIC CANINE HEART PETER R. KOWEY *, RICHARD L. VERRIER and BERNARD LOWN Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health, and the Cardiovascular Division, Department of Medicine of the Brigham and Women's Hospital Harvard Medical School Boston, MA, U.S.A.

Received 22 January 1982, accepted 1 February 1982

P.R. KOWEY, R.L. VERRIER and B. LOWN, Effects of prostacyclin (PGI2) on vulnerability to ventricular fibrillation in the normal and ischemic canine heart, European J. Pharmacol. 80 (1982) 83-91. Prostacyclin (PGI2) has been shown to have a number of beneficial effects on the cardiovascular system. However, its effects on ventricular electrical properties remain unexplored. We studied the effects of this naturally occuring humoral agent on ventricular vulnerability in the normal heart and in two models of myocardial ischemia: coronary artery occlusion and release and ergonovine-induced coronary vasoconstriction. Prostacyclin lowered the vulnerable period threshold in the normal animal. PGI 2 had no effect on ventricular vulnerability when the blood pressure was controlled with phenylephrine and was not protective during either occlusion or release. However, when blood pressure was controlled, PGI 2 did reverse the vasoconstrictor and profibrillatory effects of ergonovine. Ventricular fibrillation

Ergonovine

Myocardial ischemia

1. Introduction Prostacyclin ( P G I 2) exerts diverse effects on the c a r d i o v a s c u l a r system. It has a v a s o d i l a t o r action in the systemic ( K a d o w i t z et al., 1978; F i t z p a t r i c k et al., 1978; A r m s t o n g et al., 1977) as well as in the c o r o n a r y arterial circulation ( D u s t i n g et al., 1978; N e e d l e m a n a n d Kaley, 1977; H y m a n et al., 1978). P G I 2 also has b e e n f o u n d to limit infarct size d u r i n g e x p e r i m e n t a l c o r o n a r y occlusion (Jugdutt et al., 1979; Lefer et al., 1978; R i b e i r o et al., 1979) and, together with o t h e r p r o s t a g l a n d i n c o m p o u n d s such as P G E I, to reduce the incidence of ventricular a r r h y t h m i a (Mest a n d Foster, 1975; S o m b e r g et al., 1977; Mest et al., 1977a,b; T a n z et al., 1977; K e l l i h e r a n d G l e n n , 1973; Dix et al., 1978). How-

* Dr. Kowey is the recipient of a National Research Service Award from the National Institutes of Health, Bethesda, MD, U.S.A. To whom all correspondence should be addressed: Assistant Professor of Medicine, Cardiology Division, The Medical College of Pennsylvania, 3300 Henry Avenue, Philadelphia, Pennsylvania 19129, U.S.A. 0014-2999/82/0000-0000/$02.75

© 1982 Elsevier Biomedical Press

Reperfusion

Mean arterial blood pressure

ever, p r o s t a c y c l i n ' s effect on ventricular electrical p r o p e r t i e s r e m a i n s unexplored. T h e aim of the p r e s e n t investigation was to d e l i n e a t e the effects of P G I 2 on ventricular v u l n e r a b i l i t y in the n o r m a l c a n i n e heart. W e also e x a m i n e d the effects of p r o s t a c y c l i n on the e n h a n c e d v u l n e r a b i l i t y caused b y c o r o n a r y artery occlusion a n d release a n d b y e r g o n o v i n e - i n d u c e d c o r o n a r y vasoconstriction.

2. Materials and methods 2.1. General procedures

T w e n t y - t w o h e a l t h y m o n g r e l dogs of either sex, weighing 9 - 2 0 kg were used in this study. T h e a n i m a l s were anesthetized with i.v. a - c h l o r a l o s e 100 m g / k g (Sigma C h e m i c a l 10% weight p e r vol). A d d i t i o n a l a-chloralose, 50 m g / k g was given to m a i n t a i n the level of anesthesia d u r i n g the course o f the experiments. T h e a n i m a l s were ventilated with a m i x t u r e o f r o o m air a n d 100% oxygen given t h r o u g h a cuffed e n d o t r a c h e a l tube using a H a r v a r d respirator. T h e m i x t u r e was adjusted, to-

84 gether with respiratory rate, to maintain arterial oxygen tension between 80 and 100 mmHg, arterial carbon dioxide tension between 35-45 mmHg, and arterial p H between 7.35 and 7.45. A polyethylene catheter was inserted into a femoral artery for sampling arterial blood and monitoring systemic blood pressure. Mean systemic arterial pressures were obtained by electrically integrating the pulsatile output of the transducer. A femoral vein was cannulated for drug administration. Experimental studies were begun no less than 30 min after anesthetic administration.

Testing stimuli of 10 ms duration were employed using electrically isolated Grass $44 and $88 square wave pulse generators. A Kepco operational power supply (type OPS-100) provided constant current stimuli (2% accuracy). The current output was directly verified by means of a Tektronix P6021 alternating current probe attached to a Tektronix P6120N oscilloscope. Timing of stimuli was controlled using a BRS digital timer with a crystal controlled time base (-+0.01 accuracy) and was synchronized from either the pacing stimulus or the peak of the QRS complex. The pulse generator was equipped with appropriate circuitry to shut off the pacemaker output for up to 3 s after delivery of the test stimuli. Ventricular fibrillation thresholds were determined using the single stimulus method. Heart rate was controlled during cardiac electrical testing by ventricular pacing at a rate of 200 beats per min. This rate was selected to provide for consistent overdrive ventricular pacing for cardiac testing during drug administration.

pacing catheter by silk ligatures and terminated 30 m m proximal to the tip of the pacing catheter. This catheter was used to record the intracavitary electrocardiogram. Heart rate was controlled using a variable rate pacemaker that delivered constant current rectangular stimuli with a duration of 2 ms. The current of the pacemaker was set at twice the diastolic threshold. The distal pole of the pacemaker catheter was made cathodal. The duration of the test stimulus was set at 10 ms and the initial current at 4 m A . Electrical diastole was then scanned in 10 ms intervals beginning at the boundary of the effective refractory period and terminating beyond the T wave. The current was then increased in 2 mA steps and scanning continued. The lowest stimulus intensity that elicited ventricular fibrillation was taken as the ventricular fibrillation threshold (VFT). The lowest stimulus causing more than one response was taken as the repetitive extrasystole threshold (RET). Defibrillation was usually accomplished within 5 s utilizing a direct current capacitor discharge from a Lown direct current cardioverter. In closed-chest animals, a 100-200 W-s discharge was delivered through a pair of copper plates (150 cm 2) previously fastened on either side of the thorax. In open-chest dogs, a 10-20 W-s shock was delivered by means of two 6 cm 2 electrode paddles applied directly to the heart. Coronary blood flow measurements were performed using a Gould Statham Blood Flowmeter (Model SP 2202). A 1.5 m m or 2.0 m m electromagnetic flow probe was placed around the left anterior descending coronary artery about 1 cm below its origin. Pulsatile and mean coronary artery blood flow was recorded, together with aortic blood pressure, on a multi-channel recorder.

2.3. Single stimulus method

2.4. Prostaglandin infusion

Two bipolar catheters were employed. The first (Medtronic No. 5818 platinum electrodes with an interelectrode distance of 1.5 cm and a pole width of 3 mm) was placed in the right ventricular apex by way of a jugular vein. This catheter served both to control heart rate and to deliver test stimuli. The second catheter (U.S. Catheter Corporation, semifloating No. 003992 4F) was bound to the

One to 5 mg of prostacyclin (PGI2) powder provided as the sodium salt was dissolved in 1-5 ml of absolute ethanol to yield a stock solution concentration of I m g / m l . Stock solution was then diluted in a c a r b o n a t e / b i c a r b o n a t e buffer (0.02 M/0.02 M), with p H I0.0, made isotonic by the addition of sodium chloride. Concentrations of the prostacyclin were adjusted so that infusion

2.2. Cardiac testing

85 volumes ranged from 0.2 to 1.2 ml per rain. Solutions were maintained at temperatures of less than 4°C before and during infusion using a temperature-controUed crushed ice bath. Conduit tubing from syringe to animal measured less than 10 cm to prevent warming of the solution. Prostacyclin was administered using a femoral vein catheter and a constant delivery Harvard infusion pump.

2.5. Measurements and calculations Coronary vascular resistance (CVR) was calculated as: C V R = m e a n diastolic arterial pressure/mean coronary arterial blood flow. These values were determined between 10-15 min after the administration of prostacyclin. All measurements were made twice during the control period. Statistical analysis of the data was performed using the Student's t-test for paired data; differences were considered significant when P < 0.05. All values are expressed as m e a n - standard error of the mean. A linear regression analysis was employed to analyze scatter diagrams. Displayed in those diagrams are values for the equation y = a + b~ as well as the regression coefficient (r) and a standard error of the estimate (SEE).

2.6. Experimental groups 2.6.1. Vehicle infusion In three closed chest chloralose anesthetized dogs, control values were obtained for mean arterial blood pressure (MABP) and heart rate (HR). Control determinations were made of effective refractory period (ERP), repetitive extrasystole threshold (RET) and ventricular fibrillation threshold (VFT). After a 15 min recovery period, a solution consisting of 1 ml of ethanol in 15 ml of carbonate/bicarbonate buffer was infused over a 15 min period (infusion rate: 1 ml/min). Determinations of arterial blood gases, BP and H R were made and cardiac electrical testing was repeated. 2.6.2. Prostacyclin infusion in normal hearts In six open-chest, chloralose anesthetized animals, control values of ERP, RET and VFT were obtained together with determinations of coronary artery blood flow (CBF), mean arterial

blood pressure and heart rate. After a recovery period of 15 min, PGI 2 was infused in doses of 10, 20, 50, 75 and 100 n g / k g per min. Doses were increased until MABP fell to 60 mmHg or the 100 n g / k g per min dose was reached. When MABP had reached its lowest level and cardiac testing had been performed, phenylephrine was administered to restore MABP to control levels. Phenylephrine was used for this purpose as an i.v. bolus every 3min in a dose of 35-90 /~g/kg. Once MABP was stabilized, electrical testing and determinations of CBF and heart rate were repeated.

2.6. 3. Occlusion and release Five animals underwent a thoracotomy through the left fourth intercostal space under chloralose anesthesia. The heart was exposed and an occlusive balloon catheter (Brunswick Corp., Quincy, MA) was placed around the left anterior descending coronary artery at the level of the left atrial appendage. The patency of the balloon was tested by inflation at the time of operation. The catheter was exteriorized through a subcutaneous tunnel at the nape of the neck and the chest closed. Following a 60 min recovery period, a coronary occlusion/release sequence was carried out. The balloon was first rapidly inflated and ventricular fibrillation threshold (VFT) determined every 2 min for a 10 min period. The balloon was then promptly deflated (deflation period was less than 2 s) and a VFT measurement was accomplished immediately upon coronary release. After a 1 h recovery period, prostacyclin (PGI2) was infused in doses of 20-50 n g / k g per min (mean 38 n g / k g per min) adjusted to reduce mean arterial blood pressure by 15-20 mmHg. Once this had been achieved, phenylephrine was administered as an intravenous bolus injection every 3 rain in a dose (35-65 # g / k g , mean 45 /~g/kg) sufficient to restore the mean blood pressure to control levels. When blood pressure had been stabilized, and within 10 min of the inception of prostacyclin infusion, a second occlusion-release sequence was performed with VFT determinations accomplished during balloon inflation and after abrupt release. 2.6. 4. Ergonovine administration In 8 closed chest, chloralose-anesthetized dogs,

86

control values of V F T and coronary blood flow (CBF) were ascertained. After a recovery period of 15 min, ergonovine maleate (0.1 mg) was administered as an i.v. bolus and values for V F T and CBF as well as heart rate and blood pressure were determined at 5 min. Prostacyclin was then administered as an i.v. infusion in a manner identical to that used in the occlusion-release sequence. Phenylephrine was again used to maintain mean arterial blood pressure at control levels. Within 5 - 1 0 min of the institution of PGI 2, repeat measurements of V F T and CBF were carried out.

A.

+10' PERCENT

CHANGES IN CBF

0

. . . . .

r i r

. . . . . . .

. . . .

-20" - 50"

2.0~ B. CVR

(mmHg/ ml/min) 20

3. Results

. . . . . . .

- 10"

50

50

+

Phenylephrine

DOSE PGI2 (ng/Kg/min)

3.1. Effect of vehicle infusion Ethanol-buffer infusion did not alter VFT, MABP, H R or CBF. Likewise, arterial blood gases and arterial p H remained unchanged.

3.2. Effect of prostacyclin on blood pressure, heart rate and coronary blood flow PGI produced a decrease in mean arterial blood pressure from 5 to 45% which was maximal at a 50PERCENT 40REDUCTION 50VF THRESHOLD 20. 10 H

•

•

: ~

! 81

:

r - 0.88

SEE,6.9

1

22.8 - 6.9 ÷ 0.27(58.9) r • 0.74 SEE • 8 . 8

,50"

PERCENT 40. REDUCTION MEAN 50" ARTERIAL BLOOD 20PRESSURE 10-

. ~ .

lb z'0

~.-"-""

5'o

dose of 50-100 n g / k g per min (fig. 1). In addition, there was an increase in heart rate from a control of 121 ± 9 to a maximum of 1 7 8 ± 8 (P<0.001). CBF decreased by 20-30% of the control values (fig. 2A). The maximal effect on CBF was observed following infusion of 100 n g / k g per min of P G I 2 and was reproducible when animals were re-challenged with the 100 n g / k g per min dose (note multiple points at this dose level). Increases in infusion rates above these values produced no further reduction in CBF. Coronary vascular resistance remained unchanged during PGI 2 infusion and during BP manipulation with phenylephrine (fig. 2B).

3.3. Effect of prostacyclin on ventricular vulnerability

:

• .

Fig. 2. Percent changes in coronary blood flow (CBF) and coronary vascular resistance (CVR) with increasing doses of PGI 2 before and after addition of phenylephrine, n = 6 dogs. * P<0.01 compared with control.

: :

r'5

t60

DOSE PGI2 (ng/gg/min) Fig. 1. Percent reduction of ventricular fibrillation (VF) threshold and mean arterial blood pressure as a function of dose of PGI 2. Equation represents the values for ~ = a+h(~). S E E = s t a n d a r d error of the estimate, n = 6 dogs.

Coincident with its effects on MABP, PGI 2 resulted in a marked reduction in ventricular fibrillation threshold (VFT) (fig. 1). That these phenomena are related is suggested by the similarity of the slopes of the dose-response curves for MABP and VFT. The lowering in V F T was accompanied by a reduction in the repetitive extrasystole threshold as well as by a shortening of the effective refractory

87

TABLE 1 Effects of prostacyclin and prostacyclin plus phenylephrine on effective refractory period (ERP), repetitive extrasystole threshold (RET), and ventricular fibrillation threshold (VFT) in the normal heart, n = 6 dogs.

25"

VF THRESHOLD (mo)

20'

Control PGI 2 (50 t~g/kg per min) PGI 2 (50 #g/kg per rain) + phenylephrine (0.45 ~,g/kg)

ERP (ms at 6 mA)

RET (mA)

VFT (mA)

15"

133-+3

23-+---3

31-+4

10'

4

124_--.5 a

15___3 a

137-+5

-

19-+2a

27-+2

a P
p e r i o d m e a s u r e d at a stimulus intensity of 6 m A ( t a b l e 1). R e s t o r a t i o n of b l o o d pressure with pheny l e p h r i n e r e t u r n e d V F T to c o n t r o l values.

3. 4. Influence of PGI 2 during coronary occlusion and release T h e effects of occlusion a n d release on h e a r t rate a n d b l o o d pressure are shown in t a b l e 2 . C o r o n a r y occlusion was a c c o m p a n i e d b y a fall in b l o o d pressure of a p p r o x i m a t e l y 8% a n d b y an a c c o m p a n y i n g increase in heart rate of 18%. All a n i m a l s h a d ST segment changes c o m p a t i b l e with

TABLE 2 Mean arterial blood pressure (MABP) and heart rate responses during sequence of coronary artery occlusion and release before and during treatment with prostacyclin and phenylephrine. n = 5 dogs.

Control Occlusion-release preceded by treatment with PGI 2 (20-50 mg/kg per rain) plus phenylephrine a P<0.05 compared with control.

MABP (mmHg)

Heart rate (beats/min)

93 ---5 85 -+5 a 94-+7

119 -+ 10 140-+ 9 138-+-- 5 a

5'

Control

Occlusion Releose

Fig. 3. Changes in the ventricular fibrillation (VF) threshold during coronary artery occlusion and release before the drug intervention and after treatment with prostacyclin (PGI2) and phenylephrine, n=5 dogs. * P<0.006 compared with control. [] No drug; • PGI 2 +phenylephrine.

ischemia d u r i n g occlusion which persisted to the p o i n t of release. A characteristic p a t t e r n of changes in V F T was o b s e r v e d d u r i n g the occlusion-release sequence in the c o n t r o l setting. T w o min after o b s t r u c t i o n of the c o r o n a r y vessel, there was a decrease in the fibrillation t h r e s h o l d f r o m 2 3 - 3 to 17---2 m A (P < 0.006) which r e m a i n e d d e p r e s s e d for 5---1 min. U p o n reperfusion, the V F T again precipitously declined for a p e r i o d of less t h a n 30 s b e f o r e r e t u r n i n g to c o n t r o l values. A d m i n i s t r a t i o n of P G I 2 d i d n o t alter the changes in v u l n e r a b i l i t y o b s e r v e d either d u r i n g occlusion or release. Fig. 3 d e m o n s t r a t e s the changes in V F T b e f o r e a n d after t r e a t m e n t with P G I 2.

3.5. Effect of ergonovine on coronary flow and VFT I n 5 of 8 dogs receiving ergonovine, the V F T d e c r e a s e d b y 30% which c o r r e s p o n d e d with a 32% decrease in C B F a n d a d o u b l i n g of c o r o n a r y vasc u l a r resistance (fig. 4). T h e r e was a rise in m e a n as well as diastolic b l o o d pressure in these a n i m a l s (table 3). T h r e e of the five dogs showed m a r k e d ST segment elevation as r e c o r d e d b y an i n t r a c a r d i a c E C G lead. O n e a n i m a l d e v e l o p e d s p o n t a n e o u s V F after ergonovine injection which r e c u r r e d r a p i d l y

88

3.6. Influence of PGI 2 on ergonovine-induced changes in VFT and CBF THRESHOLD

(ma)

The 5 dogs which manifested a response to e r g o n o v i n e were treated with P G I 2 a n d repeat d e t e r m i n a t i o n s of CBF, C V R a n d V F T were carried out. As shown in fig. 4, t r e a t m e n t with P G I 2 alone in a n i m a l s which received ergonovine did n o t correct the C B F or the V F T although C V R r e t u r n e d to control values. W h e n p h e n y l e p h r i n e was used to restore blood pressure (table 3), there was a reversion of the V F T a n d C B F to baseline values.

20

10

CBF 5it (ml/min) CVR 4"0 5.0t

(mmHg/ml/min)2.O1 1.0~

CON+ROL

I"

EROO'NOVlNE"~ + + PGI2

PGI2

+

Phenylephrine

Fig. 4. Changes in the ventricular fibrillation (VF) threshold, coronary blood flow (CBF) and coronary vascular resistance (CVR) with ergonovine before and after prostacyclin and prostacyclin with phenylephrine, n=5 dogs. * P<0.01 compared with control.

after each defibrillation. Defibrillation was successful only after P G I 2 i n f u s i o n was initiated. T h r e e of the 8 a n i m a l s in this series of experiments failed to show a n y response to ergonovine despite the a d m i n i s t r a t i o n of a n a d d i t i o n a l 0.1 mg of the drug.

4. Discussion 4.1. Effects of prostacyclin on the normal heart Prostacyclin is a n arterial vasodilator drug a n d therefore induces a dose d e p e n d e n t decrease in systemic blood pressure a n d reflex tachycardia. W h e n a d m i n i s t e r e d as a bolus injection, prostacyclin causes b r a d y c a r d i a which suggests reflex vagal activation ( H i n t z e et al., 1979). Because of rapid uptake a n d metabolism, c o n s t a n t infusions were used in our experiments. The dogs did not develop b r a d y c a r d i a in our experiments. D u r i n g prostacyclin infusion, c o r o n a r y blood flow decreased while c o r o n a r y vascular resistance did not change. W h e n the b l o o d pressure was s u p p o r t e d with p h e n y l e p h r i n e , c o r o n a r y flow was

TABLE 3 Mean arterial blood pressure (MABP) and heart rate response to ergonovine administration, in those animals which showed a response, before and during treatment with prostacyclin and phenylephrine, n = 5 dogs.

Control Ergonovine 0. Img Ergonovine and PGI 2 20-50 ng/kg per min Ergonovine and PGI 2 20-50 ng/kg per min and phenylephrine P<0.003, b P<0.05, compared with controls.

MABP (mm Hg)

Diastolic BP (mm Hg)

Heart rate (beats/min)

I 11_+3 132± 6 a 80-+ 8 h 113 ± 5

77+5 90_+4 b 50_+4 b 74±4

II0± 9 I10_+ 13 131_+ 17 118_+ 9

89

restored while coronary resistance was unaltered. PGI 2 has been generally found to be a coronary vasodilator in previous studies (Dusting et al., 1978; Needleman et al., 1977; Hyman et al., 1978; Hintze and Kaley, 1977; Dusting et al., 1977). Our results indicate that the moderate effect which PGI 2 has on coronary flow in the normal heart may be obscured by its more potent effects on the systemic, and ultimately, coronary perfusion pressure. Coincident with its hypotensive effects, PGI 2 caused a dose-related decrement in the ventricular fibrillation threshold and repetitive extrasystole threshold and a shortening of the effective refractory period. When the blood pressure was maintained with phenylephrine, baroreceptor-mediated sympathetic stimulation presumably was suppressed (Verrier et al., 1974a,b). In this fashion, the changes in ventricular vulnerability were abolished. This phenomenon of indirectly induced alteration in ventricular vulnerability by hypotension is a property also observed with other vasodilator agents such as nitroglycerin and nifedipine (Stockman et al., 1979; Margolis et al., 1980). 4.2. Coronary artery occlusion and release Coronary artery occlusion and release consistently increases ventricular vulnerability to fibrillation. This effect is mediated in part by myocardial ischemia as well as by increases in sympathetic tone. Coronary reperfusion is also accompanied by a fall in the VFT, attributed to washout products of ischemia or reperfusion (Corbalan et al., 1976; Surawicz, 1971; Hearse, 1977). The lack of protection of various prostaglandin compounds, including PGI 2 has been previously reported (Harvie et al., 1978; Lawrence et al., 1978). The reason for failure to protect is not clear but may be due partly to the lack of substantial effect of the prostaglandin on coronary flow during acute ischemia (Hintze and Kaley, 1977; Needleman and Kaley, 1978). Nevertheless, the possibility that prostacyclin has a stabilizing influence on cell membranes cannot be excluded and may serve to explain the antiarrhythmic effectiveness of this agent in ventricular arrhythmia not provoked by myocardial ischemia (Mest and

Forster, 1975; Somberg et al., 1977; Mest et al., 1977a,b; Tanz et al., 1977; Kelliher et al., 1973). However, any non-vascular effects of the drug on ventricular vulnerability appear to be overcome by the potent influences of total coronary occlusion and the release of arrhythmogenic metabolites which accompany myocardial reperfusion. 4.3. Ergonovine-induced coronary vasoconstriction Ergonovine maleate infusion resulted in a decrease in coronary blood flow and an increase in coronary vascular resistance in 5 of the 8 animals tested. We have no ready explanation for this inter-animal variability in the ability to provoke coronary vasoconstriction, although a difference in receptor sensitivity to adrenergic stimulation may be a factor. The changes in coronary resistance were accompanied by a reduction in the current necessary to induce VF. A significant relationship between these findings is indicated both by the identity of the changes (only animals with reduced CBF had an alteration in the VFT) as well as by the similarity in magnitude of change in each. This association is consistent with clinical reports of the precipitation of malignant ventricular arrhythmia during episodes of coronary vasospasm occurring either spontaneously or after ergonovine administration (Heiyler, 1980). Prostacyclin protected against the vulnerability changes induced by ergonovine by reducing coronary vascular resistance. However, the doses of PGI 2 which were required to obtain this effect also caused peripheral vasodilation thereby reducing coronary blood flow and preventing correction of the VFT. When coronary perfusion was restored by means of phenylephrine, the ergonovine-induced changes in VFT were prevented. The mechanism by which PGI 2 prevents ergonovine-mediated vasoconstriction is not clear. However, since PGI 2 does cause an increase in intravascular cyclic AMP, it is possible that, under conditions of high vascular tone, PGI 2 causes a direct relaxation of smooth muscle as produced by other agents which modulate intracellular nucleotide activation (Anderson, 1973). Prostacyclin is also a potent antiplatelet agent (Moncada et al., 1976). It is therefore conceivable that the protection it affords

90

during ergonovine challenge is related, at least in part, .to the prevention of release of vasoconstrictor substances which are produced during intravascular platelet aggregation (Mehta and Mehta, 1981).

Acknowledgments We express our appreciation to Jean M. Young, Sally D. Carr and James P. Kiely for their capable technical assistance and to Ms. Nancy Ahonen, Mrs. Claudia Kenney, Ms. Mary Cashman and Mrs. Rachel Chatburn for preparation of the manuscript. This work was supported in part by Grant HL 06014 and Grant HL 07776 from the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Public Health Service, Bethesda, MD 20205, U.S.A. PGI 2 was kindly supplied by Dr. John Pike from the Upjohn Pharmaceutical Company, Kalamazoo, Michigan, U.S.A.

References Armstrong, J.M., D. Chapple, J. Dusting, R. Hughes, S. Moncada and J.R. Vane, 1977, Cardiovascular actions of prostacyclin (PGI z) in chloralose anesthetized dogs, Br. J. Pharmacol. 62, 136P. Anderson, R., 1973, Cyclic AMP as a mediator of the relaxing action of papaverine, nitroglycerin, diazoxide and hydralazine on intestinal and vascular smooth muscle, Acta Pharmacol. Toxicol. 32, 321. Corbalan, R., R.L. Verrier and B. Lown, 1976, Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release, Am. Heart J. 92, 233. Dix, R.K., G.J. Kelliher, N. Jurkiewicz and T. Lawrence, 1978, The influence of prostacyclin on coronary occhision induced arrhythmia in cats, Prostagland. Med. 3, 173. Dusting, G.J., D.J. Chapple, R. Hughes, S. Moncada and J.R. Vane, 1978, Prostacyclin (PGI 2) induces coronary vasodilatation in anesthetized dogs, Cardiovasc. Res. 12, 270. Dusting, G.J., S. Moncada and J.R. Vane, 1977, Prostacyclin (PGI2) causes a weak contraction of coronary arteries of the pig, European J. Pharmacol. 45, 301. Fitzpatrick, T.M., I. Aha, E.J. Corey, P.W. Ramwell, J.C. Rose and P.A. Kot, 1978, Cardiovascular responses to PGI 2 (prostaglandin) in the dog, Circ. Res. 42, 192. Harvie, C.J., G.A. Collins, R.T. Miyagashmia and M.J.A. Walker, 1978, The action of prostaglandin E 2 and F I on myocardial ischemia-infarction arrhythmias in the dog, Prostaglandins 16, 885. Hearse, D.J., 1977, Reperfusion of the ischemic myocardium, J. Mol. Cell Cardiol. 9, 607. Heiyler, F.A., 1980, Syndrome of symptomatic coronary arterial spasm with nearly normal coronary arteriograms, Am. J. Cardiol. 45, 873.

Hintze, T.H. and G. Kaley, 1977, Prostaglandins and the control of blood flow in the canine myocardium, Circ. Res. 40, 313. Hintze, T.H., E.G. Martin, E.J. Messina and G. Kaley, 1979, Prostacyclin (PGI2) elicits reflex bradycardia in dogs: Evidence of vagal mediation, Proc. Soc. Exp. Biol. Med. 162, 96. Hyman, A.L., P.J. Kadowitz, W.E.M. Lands, E.G. Crawford, J. Fired and J. Barton, 1978, Coronary vasodilator activity of 13,14-dihydro-prostacyclin methyl ester: Comparison with prostacyclin and other prostanoids, Proc. Natl. Acad. Sci. U.S.A. 75, 3522. Jugdutt, B.I., G.M. Hutchins, B.H. Bulkley and L.C. Becker, 1979, Infarct size reduction by prostacyclin after coronary occlusion in conscious dogs, Clin. Res. 27, 177A. Kadowitz, P.J., B.M. Chapnick, L.P. Feigen, A.U Hyman, P.K. Nelson and E.W. Spannhake, 1978, Pulmonary and vasodilator effects of the newly discovered prostaglandin, PGI 2, J. Appl. Physiol. 45, 408. Kelliher, G.J. and T.M. Glenn, 1973, Effect of prostaglandin E I on ouabain-induced arrhythmias, European J. Pharmacol. 24, 410. Lawrence, T., G.J. Kelliher and N. Jurkiewicz, 1978, Effect of prostaglandins on ventricular arrhythmias following coronary occlusion in the cat, Fed. Proc. 37, 730. Lefer, A.M., M.L. Ogletree, J.B. Smith, M.J. Silver, K.C. Nicolaou, W.E Barnette and G.P. Gasie, 1978, Prostacyclin: a potentially valuable agent for preserving myocardial tissue in acute myocardial ischemia, Science 200, 52. Margolis, B., R.L. Verrier and B. Lown, 1980, Influence of ergonovine-induced coronary artery spasm on vulnerability to ventricular fibrillation, Am. J. Cardiol. 45, 455A. , Mehta, J. and P. Mehta, 1981, Role of blood platelets and prostaglandins in coronary_ artery" disease, Am. J. Cardiol. 48, 366. Mest, H.J., K.E. Blass and W. Forster, 1977a, The antiarrhythmic effects of prostaglandins A I, E I, A 2 , E 2 and F 2 in the cat strophanthidin model, Acta Biol. Med. Ger. 35, 63. Mest, H.J. and W. Forster, 1975, Comparison of the antiarrhythmic effects of PGA I. PGA 2, PGE 2 and PGF 2 on barium chloride arrhythmia model in unanesthetized rabbits, Arch. Int. Pharmacodyn. Ther. 217, 152. Mest, H.J., J. Winkler and W. Forster, 1977b, The antiarrhythmic effect of prostaglandin E 2 on catecholamineinduced arrhythmias, Acta Biol. Med. Ger. 36, 1193. Moncada, S., R, Gryglewski, S. Bunting and J.R. Vane, 1976, An enzyme isolated from arteries transforms prostaglandin endoperoxidases to an unstable substance that inhibits platelet aggregation, Nature 263, 663. Needleman, P. and G. Kaley, 1978, Cardiac and coronary prostaglandin synthesis and function, New Engl. J. Med. 298, 1122. Needleman, P., A. Raz, P.S. Kulkarni, A. Wyche and S.E. Dennis, 1977, Prostaglandin 12 synthesis and vascular effects in isolated coronary artery, in: Mechanisms of Vasodilatation, eds. P.M. Vanhoutte and I. Leusen (Karger, New York) p. 122.

91 Ribeiro, L.G.T., L.A. Reduto, T.A. Brandon, A.A. Taylor, D.G. Hopkins and R.R. Miller, 1979, Effects of prostacyclin on hemodynamics, regional myocardial blood flow, infarct size and mortality in experimental myocardial infarction, Clin. Res. 27, 199A. Somberg, J.E., H. Bounus, N. Cagin, C. Anagnostopoulos and B. Levitt, 1977, The influence of prostaglandins E I and E 2 on ouabain cardiotoxicity in the cat, J. Pharmacol. Exp. Ther. 203,480. Stockman, M.B., R.L. Verrier and B. Lown, 1979, Effect of nitroglycerin on vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion, Am. J. Cardiol. 43, 233.

Surawicz, B., 1971, Ventricular fibrillation, Am. J. Cardiol. 28, 268. Tanz, R.D., J.B. Robbins, B.N. Harwood and D. Rightmeier, 1977, Reversal of aconitine-induced tachycardia by prostaglandin in the Rabbit Langendorff preparation, Cardiovasc. Res. 11,446. Verrier, R.L., A. Calvert, B. Lown and P. Axelrod, 1974a, Effect of acute blood pressure elevation on the ventricular fibrillation threshold, Am. J. Physiol. 226, 893. Verrier, R.L., P.L. Thompson and B. Lown, 1974b, Ventricular vulnerability during sympathetic stimulation: role of heart rate and blood pressure, Cardiovasc. Res. 8, 602.