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Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats
European Journal of Pharmacology, 87 (1983) 349-352
349
Elsevier Biomedical Press
Short communication E F F E C T S O F A D E N O S I N E O N [ 3 H ] N O R E P I N E P H R I N E RELEASE F R O M P E R F U S E D M E S E N T E R I C A R T E R I E S OF S H R A N D RENAL H Y P E R T E N S I V E RATS T A K A O KUBO
*
and CHE SU **
Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 3926, Springfield, Illinois 62708, U.S.A. Received 23 November 1982, accepted 20 December 1982
T. KUBO and C. SU, Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats, European J. Pharmacol. 87 (1983) 349-352. Adenosine (10-30 #M) inhibited the 3H-efflux evoked by sympathetic nerve stimulation in the perfused rat mesenteric arteries preincubated with [3H]norepinephrine. The inhibition was smaller in the prehypertensive (5 weeks old) as well as hypertensive (15-18 weeks) SHR (spontaneously hypertensive rats), compared with age-matched normotensive Wistar Kyoto rats. However, it was not diminished in Wistar rats rendered hypertensive by left renal artery occlusion. Thus, a diminished adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically inherent in SHR. Adenosine
Spontaneously hypertensive rats
Renal hypertensive rats
1. Introduction The release of norepinephrine from noradrenergic neurons can be influenced via receptor systems on the nerve ending. It is conceivable that alterations of such receptor systems are associated with hypertensive states. Our recent findings on adult S H R and W K Y (Wistar Kyoto rats) in fact support this notion. Constrictor responses of mesenteric arteries to sympathetic nerve stimulation were markedly depressed by adenosine in concentrations which only slightly affected responses to exogenously applied norepinephrine. Since the arteries from S H R were less sensitive to adenosine, it was postulated that inhibition of vascular noradrenergic neurotransmission mediated by the presynaptic adenosine receptor is decreased in S H R compared to W K Y (Kamikawa et al., 1980). Conversely, facilitation of the transmission mediated by the presynaptic angiotensin re* Present address: Department of Pharmacology, Yokohama City University School of Medicine, Yohohama, Japan. ** To whom all correspondence should be addressed. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
Hypertension
ceptor and fl-adrenoceptor is enhanced in these genetically hypertensive rats (Kawasaki, 1982a,b). The sensitivity of several receptor systems has been shown to change under various clinical and experimental conditions (Snyder, 1979). The observed alterations in S H R could, therefore, be the consequence rather than cause of elevated blood pressure. This possibility was examined in the present study of adenosine by determining its effect on [3H]norepinephrine release in vasculature from prehypertensive and hypertensive SHR and renal hypertensive rats.
2. Materials and methods Male S H R (5- and 15-18-week-old) and agematched male W K Y were used in this study. Additionally, for the induction of renal hypertension, 5-week-old male Wistar rats were anesthetized by pentobarbital and subjected to occlusion of the left renal artery by silver clip with 0.2 m m slit (the two-kidney Goldblatt model). They were used when 10-11 weeks old for experiments and com-
350 p a r e d with a g e - m a t c h e d u n o p e r a t e d control W i s t a r rats. The systolic b l o o d pressure of all rats was d e t e r m i n e d in the conscious state b y the tail-cuff method. T h e isolated mesenteric arteries were p r e p a r e d for perfusion as d e s c r i b e d previously ( K a m i k a w a et al., 1980). In p r e p a r a t i o n s from the a d u l t rats, o n l y four m a i n arterial b r a n c h e s from the s u p e r i o r mesenteric artery t r u n k r u n n i n g to the terminal i l e u m were perfused. In those from the 5-week-old S H R a n d W K Y all the b r a n c h e s were perfused. T h e y were i n c u b a t e d for 60 min with m o d i f i e d K r e b s b i c a r b o n a t e solution c o n t a i n i n g 0.1 # M [7,8- 3 H ] l _ n o r e p i n e p h r i n e ([3 H ] N E ; specific activity, 8 C i / m m o l , N e w E n g l a n d Nuclear, Boston, Mass.) in a 10 ml organ b a t h at 37°C. This was followed b y p e r f u s i o n with fresh K r e b s solution at a c o n s t a n t flow rate (5 m l / m i n ) . The solution h a d the following c o m p o s i t i o n (in m M ) : NaC1 122; KC1 5.2; CaC12. 2 H 2 0 2.4; M g S O 4- 7 H 2 0 1.2; N a H C O 3 25.6; E D T A . 2 N A 0.03 a n d dextrose 11. A f t e r 60 min the p e r f u s a t e was collected every 2 min for liquid scintillation spectrometry. Postganglionic s y m p a t h e t i c nerve fibers were stimulated via a p a i r of p l a t i n u m electrodes p l a c e d a r o u n d the p r o x i m a l end of the s u p e r i o r mesenteric artery. T w o - m i n trains of nerve s t i m u l a t i o n (NS), 2 ms square wave pulses of s u p r a m a x i m a l voltage at 2 Hz, were a p p l i e d five times ( S t - S s ) at 16 min intervals. This frequency was p r e f e r r e d to the previously used 16 H z ( K a m i k a w a et al., 1980) since low frequencies are suited for the d e m o n s t r a t i o n of p r e s y n a p t i c receptors (Starke, 1977). F r o m the
3H-activity of the fraction collected d u r i n g the 2 - m i n s t i m u l a t i o n and 2 subsequent fractions, the 3H-level of the p r e s t i m u l a t i o n fraction was subt r a c t e d a n d the sum of the differences was taken as the net 3H-efflux i n d u c e d b y a p a r t i c u l a r NS. T h e net efflux expected with the fifth N S ($5) was g r a p h i c a l l y e x t r a p o l a t e d from the net effluxes associated with S t through S4 in each p r e p a r a t i o n . T h e o b s e r v e d S5 efflux in the presence or absence o f a d e n o s i n e was expressed as a percentage of the e x p e c t e d S5 efflux. The S t u d e n t ' s t-test was used for statistical inferences.
3. Results T h e five-week-old S H R and W K Y d i d n o t significantly differ in the m e a n systolic b l o o d pressure. C o n s i d e r a b l y higher b l o o d pressure develo p e d in the W i s t a r rats after arterial occlusion and the a d u l t S H R (table 1). The net 3H-effluxes i n d u c e d b y r e p e a t e d N S were highly consistent. A d e n o s i n e 30 ~ M a d d e d to the p e r f u s a t e 10 min before and through S5 signific a n t l y decreased the N S - i n d u c e d 3H-efflux (fig. 1). As s u m m a r i z e d in table 1, the i n h i b i t o r y effect of a d e n o s i n e 30 # M was clearly smaller in the 5week-old S H R as well as 1 5 - 1 8 - w e e k - o l d S H R , t h a n in the respectively a g e - m a t c h e d W K Y . A lower c o n c e n t r a t i o n of a d e n o s i n e (10 # M ) signific a n t l y d i m i n i s h e d the efflux in the a d u l t W K Y but not SHR. In contrast, a d e n o s i n e 30 ~ M exerted an i n h i b i t i o n in the renal hypertensive rats not signifi-
TABLE 1 Systolic blood pressure and nerve stimulation-induced 3H-efflux from [3H]norepinephrine-treated mesenteric arteries. Rat (weeks old)
Pressure, mmHg
Expected S5 efflux b (#M adenosine in perfusate) 0
10
WKY (5) SHR (5)
127+2 (7) ~ 130 + 2 (7)
102.2_+ 1.1 (3) 101.9 -+4.6 (3)
WKY ( 15-18) SHR ( 15-18)
129 + 2 (12) 190 + 2 (12) a
98.4 -+2.2 (4) 99.3 _+2.4 (4)
Normal Wistar (10-11) Renal hypertensive ( 10-11 )
125 + 2 (7) 202 -+8 (7) d
100.8 _+3.9 (3) 102.0 -+4.0 (3)
30 61.8_+4.0 (4) f 91.6 _+3.6 (4) d
83.1 _+3.5 (4) e 94.3 _+3.4 (4)
51.6 _+3.2 (4) f 81.9 + 3.7 (4) mf 55.1 + 4.8 (4) r 61.5 + 4.3 (4) f
Values are mean _+S.E.M. (n). b Net efflux during fith period of stimulation, % of expected. ~P < 0.05, d p < 0.01 compared to normotensive rats. ~ P < 0.05, f P < 0.01 compared to 0 #M adenosine.
351
lOmin i 4.
A
!
~3
,,=,
u
L.J
u
$I
$2
$3
$4
4
Ss
J
Adenoslne 3 0 j u M
Fig. 1. Effect of adenosine on NS-induced 3H-efflux from mesenteric arteries of 16-week-old WKY. Mesenteric arteries were pretreated with [3H]norepinephrine (10 -7 M) for 1 h and rinsed for 1 b before stimulation. Two-rain trains of periarterial NS (2 Hz, 2 ms) were applied 5 times (S]-$5) at 16 min intervals. Adenosine perfusion was started 10 min before S5 and ended immediately after.
cantly smaller than in the normotensive control rats.
tory effect of adenosine in SHR results secondarily from elevated blood pressure. The results suggest that the presynaptic adenosine receptor changes occur genetically in SHR. A body of evidence indicates that an increase in sympathetic nerve function plays an important role in development and maintenance of hypertension in SHR. The latter has been considered to be a useful model for the study of human essential hypertension. There is also evidence that purine compounds may participate in feedback regulation of adrenergic neurotransmission in blood vessels (Hedqvist and Fredholm, 1976; Su, 1978): endogenous purine compounds are locally released by nerve impulses to N E inhibit the subsequent release of NE. This hypothesis has gained substantial support since prevention of adenosine uptake or metabolism suppress noradrenergic transmission, and blockade of adenosine receptor facilitates it in vitro or in vivo (Enero and Saidman, 1977; Moylan and Westfall, 1979; Horn and Lokhandwala, 1981). Should such purinergic feedback inhibition occur, its attenuation could contribute to the enhanced sympathetic nerve function at the developmental and maintenance stages of hypertension in SHR.
4. Discussion Acknowledgements In the present study adenosine inhibited the NS-induced 3H-efflux from rat mesenteric arteries labeled with [3 H]NE confirming findings on other tissues (Hedqvist and Fredholm, 1976) including blood vessels (Enero and Saidman, 1977; Verhaeghe et al., 1977; Su, 1978). The inhibitory action of adenosine on the NS-induced 3H-efflux was smaller in the adult SHR than in the agematched WKY. This provides direct support for our previous suggestion that presynaptic inhibition of vascular adrenergic neurotransmission by purine compounds is reduced in SHR (Kamikawa et al., 1980). Notably, the inhibitory action of adenosine was just as much reduced in the prehypertensive 5-week-old SHR compared to the age-matched WKY. By contrast, there was no significant difference between normotensive and renal hypertensive rats in the inhibitory action of adenosine. It seems unlikely that the reduced presynaptic inhibi-
This work was supported by Public Health grant HL24683 and an SIU School of Medicine C R C grant.
References Enero, M.A. and B.Q. Saidman, 1977, Possible feedback inhibition of noradrenaline release by purine compounds, Naunyn-Schmiedeb. Arch. Pharmacol. 297, 39. Hedqvist, P. and B.B. Fredholm, 1976, Effects of adenosine on adrenergic transmission; prejunctional inhibition and postj u n c t i o n a l e n h a n c e m e n t , N a u n y n - S c h m i e d e b . Arch. Pharmacol. 293, 217. Hom, G.J. and M.F. Lokhandwala, 1981, Effect of dipyridamole on sympathetic nerve function: role of adenosine and presynaptic purinergic receptors, J. Cardiovasc. Pharmacol. 3, 391. Kamikawa, Y., W.H. Cline, Jr. and C. Su, 1980, Diminished purinergic modulation of the vascular adrenergic neurotransmission in spontaneously hypertensive rats, European J. Pharmacol. 66, 347.
352 Kawasaki, H., W.H. Cline, Jr. and C. Su, 1982a, Enhanced angiotensin-mediated facilitation of adrenergic neurotransmission in spontaneously hypertensive rats, J. Pharmacol. Exp. Ther. 221, 112. Kawasaki, H., W.H. Cline, Jr. and C. Su, 1982b, Enhanced beta-adrenoceptor-mediated modulation of vascular adrenergic neurotransmission in spontaneously hypertensive rats, Fed. Proc. 41, 1682. Moylan, R.D. and T.C. Westfall, 1979, Effect of adenosine on adrenergic neurotransmission in the superfused rat portal vein, Blood Vessels 16, 302.
Snyder, S.H., 1979, Receptors, neurotransmitters and drug responses, New Eng. J. Med. 300, 465. Starke, K., 1977, Regulation of noradrenaline release by presynaptic receptor systems, Rev. Physiol. Pharmacol. 77, 1. Su, C., 1978, Purinergic inhibition of adrenergic transmission in rabbit blood vessels, J. Pharmacol. Exp. Ther. 204, 351. Verhaeghe, R.H., P.M. Vanhoutte and J.T. Shepherd, 1977, Inhibition of sympathetic neurotransmission in canine blood vessels by adenosine and adenine nucleotides, Circ. Res. 40, 208.
349
Elsevier Biomedical Press
Short communication E F F E C T S O F A D E N O S I N E O N [ 3 H ] N O R E P I N E P H R I N E RELEASE F R O M P E R F U S E D M E S E N T E R I C A R T E R I E S OF S H R A N D RENAL H Y P E R T E N S I V E RATS T A K A O KUBO
*
and CHE SU **
Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 3926, Springfield, Illinois 62708, U.S.A. Received 23 November 1982, accepted 20 December 1982
T. KUBO and C. SU, Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats, European J. Pharmacol. 87 (1983) 349-352. Adenosine (10-30 #M) inhibited the 3H-efflux evoked by sympathetic nerve stimulation in the perfused rat mesenteric arteries preincubated with [3H]norepinephrine. The inhibition was smaller in the prehypertensive (5 weeks old) as well as hypertensive (15-18 weeks) SHR (spontaneously hypertensive rats), compared with age-matched normotensive Wistar Kyoto rats. However, it was not diminished in Wistar rats rendered hypertensive by left renal artery occlusion. Thus, a diminished adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically inherent in SHR. Adenosine
Spontaneously hypertensive rats
Renal hypertensive rats
1. Introduction The release of norepinephrine from noradrenergic neurons can be influenced via receptor systems on the nerve ending. It is conceivable that alterations of such receptor systems are associated with hypertensive states. Our recent findings on adult S H R and W K Y (Wistar Kyoto rats) in fact support this notion. Constrictor responses of mesenteric arteries to sympathetic nerve stimulation were markedly depressed by adenosine in concentrations which only slightly affected responses to exogenously applied norepinephrine. Since the arteries from S H R were less sensitive to adenosine, it was postulated that inhibition of vascular noradrenergic neurotransmission mediated by the presynaptic adenosine receptor is decreased in S H R compared to W K Y (Kamikawa et al., 1980). Conversely, facilitation of the transmission mediated by the presynaptic angiotensin re* Present address: Department of Pharmacology, Yokohama City University School of Medicine, Yohohama, Japan. ** To whom all correspondence should be addressed. 0014-2999/83/0000-0000/$03.00 © 1983 Elsevier Biomedical Press
Hypertension
ceptor and fl-adrenoceptor is enhanced in these genetically hypertensive rats (Kawasaki, 1982a,b). The sensitivity of several receptor systems has been shown to change under various clinical and experimental conditions (Snyder, 1979). The observed alterations in S H R could, therefore, be the consequence rather than cause of elevated blood pressure. This possibility was examined in the present study of adenosine by determining its effect on [3H]norepinephrine release in vasculature from prehypertensive and hypertensive SHR and renal hypertensive rats.
2. Materials and methods Male S H R (5- and 15-18-week-old) and agematched male W K Y were used in this study. Additionally, for the induction of renal hypertension, 5-week-old male Wistar rats were anesthetized by pentobarbital and subjected to occlusion of the left renal artery by silver clip with 0.2 m m slit (the two-kidney Goldblatt model). They were used when 10-11 weeks old for experiments and com-
350 p a r e d with a g e - m a t c h e d u n o p e r a t e d control W i s t a r rats. The systolic b l o o d pressure of all rats was d e t e r m i n e d in the conscious state b y the tail-cuff method. T h e isolated mesenteric arteries were p r e p a r e d for perfusion as d e s c r i b e d previously ( K a m i k a w a et al., 1980). In p r e p a r a t i o n s from the a d u l t rats, o n l y four m a i n arterial b r a n c h e s from the s u p e r i o r mesenteric artery t r u n k r u n n i n g to the terminal i l e u m were perfused. In those from the 5-week-old S H R a n d W K Y all the b r a n c h e s were perfused. T h e y were i n c u b a t e d for 60 min with m o d i f i e d K r e b s b i c a r b o n a t e solution c o n t a i n i n g 0.1 # M [7,8- 3 H ] l _ n o r e p i n e p h r i n e ([3 H ] N E ; specific activity, 8 C i / m m o l , N e w E n g l a n d Nuclear, Boston, Mass.) in a 10 ml organ b a t h at 37°C. This was followed b y p e r f u s i o n with fresh K r e b s solution at a c o n s t a n t flow rate (5 m l / m i n ) . The solution h a d the following c o m p o s i t i o n (in m M ) : NaC1 122; KC1 5.2; CaC12. 2 H 2 0 2.4; M g S O 4- 7 H 2 0 1.2; N a H C O 3 25.6; E D T A . 2 N A 0.03 a n d dextrose 11. A f t e r 60 min the p e r f u s a t e was collected every 2 min for liquid scintillation spectrometry. Postganglionic s y m p a t h e t i c nerve fibers were stimulated via a p a i r of p l a t i n u m electrodes p l a c e d a r o u n d the p r o x i m a l end of the s u p e r i o r mesenteric artery. T w o - m i n trains of nerve s t i m u l a t i o n (NS), 2 ms square wave pulses of s u p r a m a x i m a l voltage at 2 Hz, were a p p l i e d five times ( S t - S s ) at 16 min intervals. This frequency was p r e f e r r e d to the previously used 16 H z ( K a m i k a w a et al., 1980) since low frequencies are suited for the d e m o n s t r a t i o n of p r e s y n a p t i c receptors (Starke, 1977). F r o m the
3H-activity of the fraction collected d u r i n g the 2 - m i n s t i m u l a t i o n and 2 subsequent fractions, the 3H-level of the p r e s t i m u l a t i o n fraction was subt r a c t e d a n d the sum of the differences was taken as the net 3H-efflux i n d u c e d b y a p a r t i c u l a r NS. T h e net efflux expected with the fifth N S ($5) was g r a p h i c a l l y e x t r a p o l a t e d from the net effluxes associated with S t through S4 in each p r e p a r a t i o n . T h e o b s e r v e d S5 efflux in the presence or absence o f a d e n o s i n e was expressed as a percentage of the e x p e c t e d S5 efflux. The S t u d e n t ' s t-test was used for statistical inferences.
3. Results T h e five-week-old S H R and W K Y d i d n o t significantly differ in the m e a n systolic b l o o d pressure. C o n s i d e r a b l y higher b l o o d pressure develo p e d in the W i s t a r rats after arterial occlusion and the a d u l t S H R (table 1). The net 3H-effluxes i n d u c e d b y r e p e a t e d N S were highly consistent. A d e n o s i n e 30 ~ M a d d e d to the p e r f u s a t e 10 min before and through S5 signific a n t l y decreased the N S - i n d u c e d 3H-efflux (fig. 1). As s u m m a r i z e d in table 1, the i n h i b i t o r y effect of a d e n o s i n e 30 # M was clearly smaller in the 5week-old S H R as well as 1 5 - 1 8 - w e e k - o l d S H R , t h a n in the respectively a g e - m a t c h e d W K Y . A lower c o n c e n t r a t i o n of a d e n o s i n e (10 # M ) signific a n t l y d i m i n i s h e d the efflux in the a d u l t W K Y but not SHR. In contrast, a d e n o s i n e 30 ~ M exerted an i n h i b i t i o n in the renal hypertensive rats not signifi-
TABLE 1 Systolic blood pressure and nerve stimulation-induced 3H-efflux from [3H]norepinephrine-treated mesenteric arteries. Rat (weeks old)
Pressure, mmHg
Expected S5 efflux b (#M adenosine in perfusate) 0
10
WKY (5) SHR (5)
127+2 (7) ~ 130 + 2 (7)
102.2_+ 1.1 (3) 101.9 -+4.6 (3)
WKY ( 15-18) SHR ( 15-18)
129 + 2 (12) 190 + 2 (12) a
98.4 -+2.2 (4) 99.3 _+2.4 (4)
Normal Wistar (10-11) Renal hypertensive ( 10-11 )
125 + 2 (7) 202 -+8 (7) d
100.8 _+3.9 (3) 102.0 -+4.0 (3)
30 61.8_+4.0 (4) f 91.6 _+3.6 (4) d
83.1 _+3.5 (4) e 94.3 _+3.4 (4)
51.6 _+3.2 (4) f 81.9 + 3.7 (4) mf 55.1 + 4.8 (4) r 61.5 + 4.3 (4) f
Values are mean _+S.E.M. (n). b Net efflux during fith period of stimulation, % of expected. ~P < 0.05, d p < 0.01 compared to normotensive rats. ~ P < 0.05, f P < 0.01 compared to 0 #M adenosine.
351
lOmin i 4.
A
!
~3
,,=,
u
L.J
u
$I
$2
$3
$4
4
Ss
J
Adenoslne 3 0 j u M
Fig. 1. Effect of adenosine on NS-induced 3H-efflux from mesenteric arteries of 16-week-old WKY. Mesenteric arteries were pretreated with [3H]norepinephrine (10 -7 M) for 1 h and rinsed for 1 b before stimulation. Two-rain trains of periarterial NS (2 Hz, 2 ms) were applied 5 times (S]-$5) at 16 min intervals. Adenosine perfusion was started 10 min before S5 and ended immediately after.
cantly smaller than in the normotensive control rats.
tory effect of adenosine in SHR results secondarily from elevated blood pressure. The results suggest that the presynaptic adenosine receptor changes occur genetically in SHR. A body of evidence indicates that an increase in sympathetic nerve function plays an important role in development and maintenance of hypertension in SHR. The latter has been considered to be a useful model for the study of human essential hypertension. There is also evidence that purine compounds may participate in feedback regulation of adrenergic neurotransmission in blood vessels (Hedqvist and Fredholm, 1976; Su, 1978): endogenous purine compounds are locally released by nerve impulses to N E inhibit the subsequent release of NE. This hypothesis has gained substantial support since prevention of adenosine uptake or metabolism suppress noradrenergic transmission, and blockade of adenosine receptor facilitates it in vitro or in vivo (Enero and Saidman, 1977; Moylan and Westfall, 1979; Horn and Lokhandwala, 1981). Should such purinergic feedback inhibition occur, its attenuation could contribute to the enhanced sympathetic nerve function at the developmental and maintenance stages of hypertension in SHR.
4. Discussion Acknowledgements In the present study adenosine inhibited the NS-induced 3H-efflux from rat mesenteric arteries labeled with [3 H]NE confirming findings on other tissues (Hedqvist and Fredholm, 1976) including blood vessels (Enero and Saidman, 1977; Verhaeghe et al., 1977; Su, 1978). The inhibitory action of adenosine on the NS-induced 3H-efflux was smaller in the adult SHR than in the agematched WKY. This provides direct support for our previous suggestion that presynaptic inhibition of vascular adrenergic neurotransmission by purine compounds is reduced in SHR (Kamikawa et al., 1980). Notably, the inhibitory action of adenosine was just as much reduced in the prehypertensive 5-week-old SHR compared to the age-matched WKY. By contrast, there was no significant difference between normotensive and renal hypertensive rats in the inhibitory action of adenosine. It seems unlikely that the reduced presynaptic inhibi-
This work was supported by Public Health grant HL24683 and an SIU School of Medicine C R C grant.
References Enero, M.A. and B.Q. Saidman, 1977, Possible feedback inhibition of noradrenaline release by purine compounds, Naunyn-Schmiedeb. Arch. Pharmacol. 297, 39. Hedqvist, P. and B.B. Fredholm, 1976, Effects of adenosine on adrenergic transmission; prejunctional inhibition and postj u n c t i o n a l e n h a n c e m e n t , N a u n y n - S c h m i e d e b . Arch. Pharmacol. 293, 217. Hom, G.J. and M.F. Lokhandwala, 1981, Effect of dipyridamole on sympathetic nerve function: role of adenosine and presynaptic purinergic receptors, J. Cardiovasc. Pharmacol. 3, 391. Kamikawa, Y., W.H. Cline, Jr. and C. Su, 1980, Diminished purinergic modulation of the vascular adrenergic neurotransmission in spontaneously hypertensive rats, European J. Pharmacol. 66, 347.
352 Kawasaki, H., W.H. Cline, Jr. and C. Su, 1982a, Enhanced angiotensin-mediated facilitation of adrenergic neurotransmission in spontaneously hypertensive rats, J. Pharmacol. Exp. Ther. 221, 112. Kawasaki, H., W.H. Cline, Jr. and C. Su, 1982b, Enhanced beta-adrenoceptor-mediated modulation of vascular adrenergic neurotransmission in spontaneously hypertensive rats, Fed. Proc. 41, 1682. Moylan, R.D. and T.C. Westfall, 1979, Effect of adenosine on adrenergic neurotransmission in the superfused rat portal vein, Blood Vessels 16, 302.
Snyder, S.H., 1979, Receptors, neurotransmitters and drug responses, New Eng. J. Med. 300, 465. Starke, K., 1977, Regulation of noradrenaline release by presynaptic receptor systems, Rev. Physiol. Pharmacol. 77, 1. Su, C., 1978, Purinergic inhibition of adrenergic transmission in rabbit blood vessels, J. Pharmacol. Exp. Ther. 204, 351. Verhaeghe, R.H., P.M. Vanhoutte and J.T. Shepherd, 1977, Inhibition of sympathetic neurotransmission in canine blood vessels by adenosine and adenine nucleotides, Circ. Res. 40, 208.