Hemodynamic effects of centrally administered norcocaine in the rat

Life Sciences, Vol. Printed in the USA

51, pp. 1269-1276

Pergamon Press

HEMODYNAMIC EFFECTS OF CENTRALLY ADMINISTERED NORCOCAINE IN THE RAT D. A. Barber and R. L. Tackett Cardiovascular Pharmacodynamics Laboratory College of Pharmacy University of Georgia Athens, GA 30602 (Received in final form August ii, 1992) Summary Norcocaine is the N-demethylated metabolite of cocaine. It is present in the CNS and is reported to be p h a r m a c o l o g i c a l l y active. The present study was designed to evaluate the cardiovascular actions of norcocaine following central administration. Wistar Kyoto (WKY) rats were anesthetized with pentobarbital and instrumented for measurement of blood pressure and renal and hindlimb blood flow (via Doppler flowprobes). A cerebroventricular cannula was placed in the lateral ventricle for drug administration. Cocaine or norcocaine was administered centrally in a dose range of 0.025 to 4.0 mg/kg. Under the above experimental conditions, 4.0 mg/kg of norcocaine decreased blood pressure without a significant change in either hind limb or renal blood flow. Central administration of cocaine also produced a similar depressor response. In conscious, unrestrained rats, cocaine produced a pressor response while norcocaine did not significantly alter blood pressure. The depressor response to both cocaine and norcocaine in the anesthetized animal is speculated to be due to the local anesthetic properties of the drugs. Modern society has recently witnessed a nearly worldwide surge in illicit cocaine abuse, particularly via inhalation of the volatilized free base form (i3). Subsequent increases in cocaine related morbidity and mortality have ensued (3-6). Although cocaine lethality is often secondary to cardiovascular complications including arrhythmias (7-10), strokes (ii), and myocardial infarcts (12,13), the mechanisms by which cocaine precipitates cardiovascular complications remains largely undetermined. Furthermore, even less is known about the actions of the pharmacologically active metabolites of cocaine. Norcocaine, the N-demethylated metabolite of cocaine, demonstrates inhibition of catecholamine uptake, similar to that of cocaine in rat brain synaptosomes (14). Peripherally administered cocaine has been shown to concentrate in the brain as much as six times that of plasma levels (15). Oxidative m e t a b o l i s m studies have demonstrated that cocaine is converted to norcocaine both peripherally (16) and centrally (17). Thus, norcocaine appears in significant concentrations in the brain regardless of the route of administration. To date, few studies have evaluated the pharmacological properties of norcocaine (18,19) and, to our knowledge, no studies have been conducted on the cardiovascular effects of centrally administered norcocaine. Previous work in our laboratory has evaluated the effects of centrally administered cocaine on cardiovascular functions (20,21). The present study 0024-3205/92 $5.00 + .O0 Copyright © 1992 Pergamon Press Ltd All rights reserved.

1270

Hemodynamic

Effects

of N o r c o c a i n e

Vol.

51, No.

16, 1992

e x a m i n e s the role of c e n t r a l l y a d m i n i s t e r e d n o r c o c a i n e on c a r d i o v a s c u l a r f u n c t i o n in b o t h the p e n t o b a r b i t a l - a n e s t h e t i z e d and c o n s c i o u s W i s t a r K y o t o (WKY) rat. Methods Experimental

procedures

A n e s t h e t i z e d A n i m a l s - Age m a t c h e d male W K Y rats (Charles River, Raleigh, NC) w e r e a n e s t h e t i z e d w i t h p e n t o b a r b i t a l (65 m g / k g ip). H e p a r i n i z e d p o l y e t h y l e n e 50 (PE-50) c a n n u l a s w e r e p l a c e d in b o t h the f e m o r a l a r t e r y and vein. The a r t e r i a l c a n n u l a was c o n n e c t e d to a S t a t h a m p r e s s u r e t r a n s d u c e r c o n n e c t e d to a Grass 7B p o l y g r a p h for the m e a s u r e m e n t of m e a n a r t e r i a l b l o o d p r e s s u r e (MAP). Heart rate (HR) was d e t e r m i n e d f r o m the b l o o d p r e s s u r e recording. The v e n o u s c a n n u l a was m a i n t a i n e d for s u p p l e m e n t a l anesthesia. To a s s e s s renal b l o o d flow, the left r e n a l a r t e r y was i s o l a t e d and i n s t r u m e n t e d w i t h a p u l s e d - D o p p l e r f l o w probe e m b e d d e d in a s i l i c o n cuff (22 ga ID). For h i n d l i m b b l o o d f l o w a s s e s s m e n t , a p r o b e (18 ga ID) was s i m i l a r l y p l a c e d on the d e s c e n d i n g a o r t a just a n t e r i o r to the f e m o r a l b i f u r c a t i o n . Probes were s u t u r e d c l o s e d w i t h 6-0 silk and c o n n e c t e d to a d i r e c t i o n a l pulsed Doppler flowmeter (Model 545C-4 Bioengineering, U n i v e r s i t y of Iowa) w h i c h was c o n n e c t e d to a Grass 7B p o l y g r a p h . A guide c a n n u l a was s t e r e o t a x i c a l l y p l a c e d in the lateral v e n t r i c l e at the f o l l o w i n g coordinates: -0.8 m m (A/P), +1.4 m m (M/L), and -4.4 m m (D/V). Conscious Animals In a s e p a r a t e group, age m a t c h e d m a l e W K Y rats were anesthetized with pentobarbital (65 mg/kg, ip) and the f e m o r a l a r t e r y was c a n n u l a t e d w i t h PE-50 t u b i n g w h i c h was e x t e r i o r i z e d on the d o r s a l side of the neck. A guide cannula was then stereotaxically placed using the above coordinates in the lateral v e n t r i c l e and a t t a c h e d to the skull w i t h dental acrylic. The a n i m a l s w e r e a l l o w e d to r e c o v e r at least 24 h o u r s at w h i c h time the a r t e r i a l c a n n u l a was c o n n e c t e d to a S t a t h a m p r e s s u r e t r a n s d u c e r c o n n e c t e d to a Grass 7B p o l y g r a p h for the m e a s u r e m e n t of M A P and HR. P r o t o c o l s - N o r c o c a i n e , cocaine, or diluent (50% n o r m a l s a l i n e / 5 0 % m e t h a n o l ) , was a d m i n i s t e r e d in a r a n d o m order at 0.025 mg/kg, 0.i mg/kg, 0.5 mg/kg, or 4.0 m g / k g icy in a c o n s t a n t volume of" 2 ~I. All drugs were d i s s o l v e d in diluent i m m e d i a t e l y p r i o r to a d m i n i s t r a t i o n and a m i n i m u m of f i f t e e n m i n u t e s was a l l o t t e d b e t w e e n doses. In all groups, p a r a m e t e r s were a s s e s s e d at one m i n u t e intervals for i0 minutes. At the c o n c l u s i o n of each e x p e r i m e n t c o r r e c t c a n n u l a p l a c e m e n t was v e r i f i e d by i n j e c t i o n of 5 #i of 1% m e t h y l e n e blue and gross h i s t o l o g i c v e r i f i c a t i o n of dye d i s p e r s i o n t h r o u g h o u t the c e r e b r o v e n t r i c u l a r system. Drugs - N o r c o c a i n e was o b t a i n e d from NIDA. o b t a i n e d f r o m Sigma C h e m i c a l Company.

Cocaine

and s o d i u m p e n t o b a r b i t a l

were

Statistics The data were a n a l y z e d u s i n g t w o - w a y a n a l y s i s of v a r i a n c e to establish direction of significance. A post hoc test u t i l i z i n g the least s i g n i f i c a n t d i f f e r e n c e o p t i o n of o n e - w a y A N O V A was p e r f o r m e d on data means to d e t e r m i n e w h e r e the s i g n i f i c a n t d i f f e r e n c e s o c c u r r e d b e t w e e n drug and c o n t r o l pairs. A l l data are p r e s e n t e d as means ± s t a n d a r d error of the m e a n (SEM) and o n l y those differences w i t h a p v a l u e of less t h a n 0.05 w e r e c o n s i d e r e d s t a t i s t i c a l l y significant.

Results Anesthetized: B a s e l i n e H R and p r e s e n t e d in Table i.

M A P v a l u e s for the p e n t o b a r b i t a l - a n e s t h e t i z e d rat are C e n t r a l l y a d m i n i s t e r e d n o r c o c a i n e did n o t s i g n i f i c a n t l y

Vol. 51, No. 16, 1992

Hemodynamic Effects of Norcocaine

1271

affect MAP at doses of 0.025 - 0.5 mg/kg. However, at 4.0 mg/kg, a significant decrease in MAP was observed with a maximal decrease of 14 ± 4 m m Hg, which occurred at 3 min following administration of norcocaine (Fig. IA). This effect was sustained and remained significant throughout the i0 min assessment period and returned to pre-injection baseline values in approximately 15 min. Cocaine produced a similar depressor response at 4.0 mg/kg beginning at 4 min with a maximal decrease in MAP of 22 ± 5 nun Hg occurring at i0 min (Fig. IB). The depressor responses of norcocaine and cocaine were not statistically different except at 3 and 4 min. Norcocaine did not significantly affect HR at doses of 0.025 - 0.5 mg/kg. However, at 4.0 mg/kg norcocaine elicited an immediate tachycardia with a maximal increase of 12 ± 7 beats/min with a duration of less than 5 min (Fig. 3A). Cocaine produced a mild tachycardia of ii ± 4 beats/min at the 0.5 mg/kg dose (Fig. 3B). In contrast to norcocaine, cocaine produced a sustained bradycardia at 4.0 mg/kg with a maximal decrease in HR of 17 ± 8 beats/min occurring at i0 min after administration (Fig. 3B). Pre-injection baseline HR values returned within 15 min. Centrally administered norcocaine caused insignificant changes in renal and hind limb blood flow at all doses administered. At the 4.0 mg/kg dose, renal and hind limb vascular resistances significantly decreased compared to control (Fig. 2). At all other doses, changes in resistance were insignificant.

Table i - Baseline mean arterial blood pressures and heart rates for p e n t o b a r b i t a l - a n e s t h e t i z e d and conscious WKY rats expressed as mean ± SEM Mean Arterial Pressure (mmHg)

Anesthetized

(n=8)

Unanesthetized

(n=5)

Heart Rate (beats/min)

139 ± 3

381 ± 8

136 ± 6

398 ± 9

Unanesthetized: Baseline values for HR and MAP are presented in Table i. In the u n a n e s t h e t i z e d WKY rat, centrally administered norcocaine did not alter MAP at any of these doses administered (Fig. IC). However, cocaine elicited a significant increase in MAP at all doses except the lowest, 0.025 mg/kg (Fig. ID). This effect was short lived with a duration of less than 5 min. Maximal increases in MAP occurred at 2 min with a change of 9 ± 3 mm Hg at 0.i mg/kg, 8 ± 5 nun Hg at 0.5 mg/kg, and 12 ± 2 nun Hg at 4.0 mg/kg (Fig. ID). Norcocaine evoked a significant tachycardiac response at a dose of 0.5 mg/kg. This effect was short lived with a duration of less than 5 min and a maximal increase of 50 ± 27 beats/min occurring at 3 min after administration (Fig. 3C). Cocaine elicited a dose dependent increase in HR. The tachycardia was transient and lasted less than 5 min. Maximal increases in HR were 27 ± 4 beats/min at 0.i mg/kg, 42 ± 13 beats/min at 0.5 mg/kg, and 52 ± 17 beats/min at 4.0 mg/kg (Fig. 3D).

1272

Hemodynamic

-

Norcocaine

E f f e c t s of N o r c o c a i n e

Vol.

Anesthetized

51, No.

16, 1992

Cocaine - Anesthetized

A

B

o

'°[

t

.

,

T

T

8

9

10

8

g

10

E

g

X

~-20

-

I

2

3

~rn

Norcocaine

5 S e (Minutes)

8

g

2 1

/

j

c"

l ~" 0~

"--" 0.5mg/kg

r

o

10

Unonesthetized o--o Control I .--* O.025mg/kgJ ~--~,O.ImgLkg I

z0

-

7

1

2

3

Cocaine -

Unanesthetized

1

'~,

i

-20

o

7

D

T-~ -lO [

f

4 5 8 ~me (Minutes)

1

i

i

2

3

i

i

i

,) S 5 l i m e (Minutes)

i

i

i

i

7

8

9

1o

-lO o

1

2

~

4

5

8

7

lime (Minutes)

Fig.

i

E f f e c t s of c e n t r a l l y a d m i n i s t e r e d n o r c o c a i n e and c o c a i n e in the unanesthetized and p e n t o b a r b i t a l - a n e s t h e t i z e d WKY rat on m e a n a r t e r i a l p r e s s u r e (MAP). S i g n i f i c a n t d i f f e r e n c e s f r o m c o n t r o l are i n d i c a t e d by *. All v a l u e s r e p r e s e n t m e a n ± SEM. Panel A - Effect of n o r c o c a i n e on M A P in the a n e s t h e t i z e d rat. Panel B - E f f e c t of c o c a i n e on M A P in the a n e s t h e t i z e d rat. Panel C E f f e c t of n o r c o c a i n e on M A P in the u n a n e s t h e t i z e d rat. P a n e l D - E f f e c t of c o c a i n e on M A P in the u n a n e s t h e t i z e d rat.

Discussion P r e v i o u s s t u d i e s h a v e c l e a r l y e s t a b l i s h e d the a b i l i t y of c o c a i n e to r a p i d l y i n c r e a s e HR a n d M A P in the rat (20-22), dog (23) and m a n (24-26). C o c a i n e is r a p i d l y m e t a b o l i z e d into n u m e r o u s m e t a b o l i t e s (27,28), at least one of which, n o r c o c a i n e , has b e e n s h o w n to be p h a r m a c o l o g i c a l l y a c t i v e (14). H o w e v e r , to o u r k n o w l e d g e the c e n t r a l l y m e d i a t e d c a r d i o v a s c u l a r a c t i o n s of n o r c o c a i n e h a v e n o t b e e n evaluated. The r e s u l t s of the p r e s e n t s t u d y d e m o n s t r a t e that n o r c o c a i n e shares a s i m i l a r but not identical, h e m o d y n a m i c p r o f i l e w i t h c o c a i n e and thus, c o u l d c o n t r i b u t e to the c o m p l e x c a r d i o v a s c u l a r r e s p o n s e s of cocaine. In the a n e s t h e t i z e d animal, the h i g h e s t dose of n o r c o c a i n e and c o c a i n e e l i c i t e d d e p r e s s o r r e s p o n s e s w h i c h w e r e s i g n i f i c a n t l y d i f f e r e n t f r o m one a n o t h e r e x c e p t at three min. H o w e v e r , in the c o n s c i o u s rat, n o r c o c a i n e a d m i n i s t r a t i o n did not e l i c i t any c h a n g e in b l o o d p r e s s u r e . In c o n t r a s t ,

Vol. 51, No. 16, 1992

Hemodynamic Effects of Norcocaine

1273

A £

g

-tO

c -20 0--0 0--4,

Control n=8 4,0mg/kg n=6

i

,

L

i

,

J

,

~

i

1

2

3

4

5

6

7

8

9

i__ 10

40

o~

2o

o

c o £~

D -•--A

-20

D Renol

Hind Limb

-50

-40

I

I

I

I

I

I

I

I

I

I

t

2

3

4

5

6

7

8

9

10

0

10

C OI

-~

-10

0 ~E

-20

c 0

-30

g

D--

D Renol

• --

• Hind Limb

-40

-50 O

)

i

i

1

2

3

L

=

=

i

i

=

i

4

5

6

7

8

9

10

Time (Minutes)

Fig. 2 Comparative effects of 4.0 mg/kg centrally administered norcocaine in the p e n t o b a r b i t a l - a n e s t h e t i z e d WKY rat on MAP, b l o o d flow, and vascular resistance. A significant difference from control is indicated by *. All values represent the mean i SEM. Panel A - The effect of norcocaine on mean arterial pressure (MAP). Panel B - The effect of norcocaine on renal and hindlimb blood flows expressed as a percentage of p r e i n j e c t i o n flows. Panel C The effect of norcocaine on renal and hindlimb vascular resistances.

cocaine administration to conscious animals elicited pressor responses. Differential hemodynamic responses to cocaine have been previously noted between anesthetized and conscious animals and both preparations have clinical relevance (29,30). The depressor responses observed in the anesthetized animals could be explained by an interaction of the local anesthetic properties (34) of cocaine or norcocaine with the barbiturate anesthetic. In

1274

Hemodynamic

Effects of Norcocaine

Vol.

Norcocoine - Anesthetized

Cocoine -- Anesthetized

A -

51, No. 16, 1992

B

T

20 °

~-10

~0 o

l!Sli

-20

1 -

l

O

1 1

1 2

~ 3

, 4

, , 5 8 ~me (Minutes)

l

l

7

l

B

l

9

-30

lO

o

1

2

Norcocaine - Unanesthetized C

T ~° / * m

o

, * T T ! / "~'~I

//

4m

5 ! e (Minutes)

7

8

R

10

g

10

70

.--. 4.0mg/kg

"\ \

/=

3

Cocoine - Unanesthetized

o--oControl .--. O.025mg/k~ a--z,O.lmg/kg •--• 0.Smg/kg

T

!

n=5-8

\T

I

I

-

"

-2o

~" 2o ~ m

c~

0 -lo

-8o -ec

1

2

3

4

~irne

5

6

(Minutes)

7

E

9

2

~0

Fig.

3

4 5 8 ]3me ( M i n u t e s )

7

8

3

Effects of centrally administered norcocaine and cocaine in the u n a n e s t h e t i z e d and p e n t o b a r b i t a l - a n e s t h e t i z e d WKY rat on heart rate (HR). Significant differences from control are indicated by *. All values represent mean ± SEM. Panel A - Effect of norcocaine on HR in the a n e s t h e t i z e d rat. Panel B - Effect of cocaine on HR in the a n e s t h e t i z e d rat. Panel C - Effect of norcocaine on HR in the unanesthetized rat. Panel D Effect of cocaine on I|R in the u n a n e s t h e t i z e d rat.

this context, Pitts et al. (22) observed a pressor component following cocaine a d m i n i s t r a t i o n in conscious, pentobarbital-anesthetized, and urethanea n e s t h e t i z e d rats. However, a secondary depressor response was noted only in pentobarbital anesthetized rats. Similar responses were observed with procaine, a local anesthetic which lacks the ability to inhibit catecholamine re-uptake. The interaction of the pentobarbital anesthesia and the local anesthetic properties of cocaine or norcocaine could also explain the differential responses of MAP observed in the anesthetized vs. conscious animals. Alternatively, Raczkowski et al. (31) have postulated that a depressor response to cocaine could be the result of an interaction of cocaine in the h i n d b r a i n independent of its local anesthetic actions. Cocaine (and norcocaine) could lower mean arterial pressure by inhibiting norepinephrine re-uptake. Increased norepinephrine levels would then activate central a- 2 receptors to decrease central sympathetic outflow. This hypothesis is further supported by a recent study by Gantenberg and Hageman (32). This m e c h a n i s m was also shown to be sensitive to anesthesia and could explain the differential effects of cocaine and norcocaine in the a n e s t h e t i z e d and conscious state.

Vol. 51, No. 16, 1992

Hemodynamic Effects of Norcocaine

1275

A peripheral site of action is possible due to leakage of the cocaine and the norcocaine from the CNS. However, several points argue against this possibility. First, previous studies in our laboratory (20,21,33) have demonstrated only pressor responses to peripherally administered cocaine. Secondly, to date, no studies have examined the peripheral actions of norcocaine. However, one preliminary study by Ghoski et al. (35) reported that norcocaine produced vasoconstriction. Thus if cocaine or norcoeaine were acting peripherally, a prominent pressor response would be anticipated. In the conscious WKY rat, norcocaine produces a tachycardia only at the 0.5 mg/kg dose which is not statistically different from the tachycardia produced by cocaine at the identical dose. Noreocaine failed to produce a tachycardia at other doses, unlike cocaine, which consistently produced a dose dependent tachycardia. Our lab has previously demonstrated a centrally mediated m e c h a n i s m in cocaine-induced tachycardia (20). The lack of tachyeardia response to nr,rcocaine at doses other than 0.5 mg/kg may be due to a combination of local a'.esthetic properties and direct stimulatory properties. In the anesthetized animal, norcocaine produced a mild but significant tachycardia at the highest dose administered. In contrast, cocaine produced a bradycardia at the highest dose and a tachycardia at a lower dose. These data suggest that the effect of norcocaine on HR does not coincide with cocaine in the unanesthetized animal but that in conscious animals the effect on HR is similar in action but weaker in potency in comparison to cocaine. Norcocaine had no effect on blood flows even when a depressor response was evident. Thus, the ability of the renal artery and lower descending aorta to decrease resistance and maintain a constant flow despite a MAP decrease is not impaired by centrally administered norcoeaine. Still, these observations do not rule out the possibility of peripheral sites of action for norcocaine.

References

i. 2. 3. 4. 5. 6. 7. 8. 9. i0. ii. 12. 13.

14. 15.

D.K. PITTS and J. MARWAH. Can. J. Pharmacol. 6/7 1168-1176 (1987). R.R. CLAYTON. Natl. Inst. Drug Abuse Res. Monogr. Ser. 6 1 8-33 (1985). R.K. SIEGEL. Natl. Inst. Drug Abuse Res. Monogr. Ser. 6 1 204-220 (1985). R.E. MITTLEMAN and C.V. WETLI. JAMA 252 1889-1893 (1984). L.L. CREGLER and H. MARK. New Eng. J. Med. 315 1495-1500 (1986). H.I. ABELSON and J.D. MILLER. Natl. Inst. Drug Abuse Res. Monogr. Ser. 6 1 35-49 (1985). A. BENCHIMOL, H. BARTALL, K.B. DESSER. Ann. Intern. Med. 88-4 519-520 (1978). G . E . BILLMAN. FASEB J . 4 2 4 6 9 - 2 4 7 5 ( 1 9 9 0 ) . A . A . NANJI a n d J . D . FILIPENKO. Chest 85-1 132-133 (1984). D. YOUNG and J.3. GLAUBER. Amer. Heart J. 34 272-279 (1946). S.R. LEVINE, J.M. WASHINGTON, M.F. JEFFERSON, S.N. KIERAN, M. MOEN, H. FEIT and K.M.A. WELCH. Neurology 37 1849-1853 (1987). E.K. ASCHER, J.-C.E. STAUFFER and W.H. GAASCH. Amer. J. Cardiol. 61 939-941 (1988). J.M. ISNER, M. ESTES III, P.D. THOMPSON, M.R. COSTANZO-NORDIN, R. SUBRAMANIAN, G. MILLER, G. KATSAS, K. SWEENEY and W.Q. STURNER. New Eng. J. Med. 315 1438-1443 (1986). R.L. HAWKS, I.J. KOPIN, R.W. COLBURN, and N.B. THOA. Life Sci. i_5521892195 (1974). P.K. NAYAK, A.L. MISRA, and S.J. MULE. J. Pharmacol. Exp. Ther. 196 556-569 (1976).

1276

16. 17. 18. 19. 20. 21. 22. 23

24

Hemodynamic Effects of Norcocaine

Vol. 51, No. 16, 1992

V.S. ESTEVEZ, B.T. HO, and L.F. ENGLERT. Res. Comm. Chem. Path. Pharmacol. 17-1 179-182 (1977). M. BENUCK, M.E.A. REITH, H. SERSHEIN, H.L. WIENER, and A. LAJTHA. Proc. Soc. Exp. Biol. Med. 190 7-13 (1989). M.C. WILSON, J.A. BEDFORD, A.H. KIBBE, and J.A. SAM. Pharmacol. Biochem. & Behav. 9 141-145 (1978). R.F. BORNE, J.A. BEDFORD, C.B. BUELKE, T.C. HARDIN, A.H. KIBBE, and M.C. WILSON. J. Pharmacol. Sei. 66-i 119-120 (1977). L.F. JONES and R.L. TACKETT. Life Sci. 46 723-728 (1990). L.F. JONES and R.L. TACKETT. Res. Comm. Subs. Abus. ll-l&2 1-9 (1990). D.K. PITTS, C.E. UDOM, and J. MARWAH. Life Sci. 40 i099-iiii (1987). S.J. KABAS, S.M. BLANCHARD, Y. MATSUYAMA, J.D. LONG, G.W. HOFFMAN, JR, E.H. ELLINWOOD, P.K. SMITH, and H.C. STRAUSS. J. Pharmaeol. Exp. Ther. 252-1 185-191 (1989) R.B. RESNICK, R.S. KESTENBAUM, and L.K. SCHWARTZ. Sci. 195 696-698

(1977). 25 26 27 28. 29 3O

R.W. FOLTIN, M.A. McENTEE, R.M. CAPRIOTTI, J.J. PEDROSO, and M.W. FISCHMAN. Pharmacol. Biochem. & Behav. 31 387-391 (1987). C. MUNTANER, K.M. KUMOR, C. NAGOSHI, and J.H. JAFFE. Pharmacol. Biochem. & Behav. 3_~4697-703 (1989) T. INABA. Can. J. Pharmacol. 67 1154-1157 (1989). M. BENUCK, A. LAJTHA, M.E.A. REITH. J. Pharmacol. Exp. Ther. 243-1 144149 (1987) D.R. WILKERSON. J. Pharmacol. Exp. Ther. 246-2 466-471 (1988). R.A. KLONER, S. HALE, K. ALKER, and S. REZKALLA. Circ. 85 407-419

(1992). 31

32 33 34 35.

V.F.C. RACZKOWSKI, Y.M. HERNANDEZ, H.K. ERZOUKI, T.P. ABRAHAMS, A.K. MANDAL, P. HAMOSH, E. FRIEDMAN, J.A. QUEST, K.L. DRETCHAN, and R.A. GILLIS. J. Pharmacol. Exp. Ther. 257 511-519 (1991). N.S. GANTENBERG and G.R. HAGEMAN. J. Cardiovasc. Pharmacol. 17 434-439 (1991). L.F. JONES and R.L. TACKETT. Pharmacol. Biochem. Behav, 38 601-603 (1991). W.W. JUST and J. HOYER. Experientia 33-1 70-71 (1977). S.K. CHOSKI, D. GAL, and J.M. ISNER. Circ. 80 Suppl II 11-132 (1989),