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Endogenous prostaglandins do not modulate the hindquarters vascular responses to adrenergic stimulation in rats
Prostaglandins Leukotrienes and Medicine I0: 65-72, 1985
E N D O G E N O U S P R O S T A G L A N D I N S DO NOT M O D U L A T E THE H I N D Q U A R T E R S V A S C U L A R R E S P O N S E S TO A D R E N E R G I C S T I M U L A T I O N IN RATS T s u t o m u Imaizumi, A k i r a Takeshita, T o s h i a k i A s h i h a r a and Motoomi Nakamura R e s e a r c h I n s t i t u t e of A n g i o c a r d i o l o g y and C a r d i o v a s c u l a r Clinic, K y u s h u U n i v e r s i t y M e d i c a l School, 3-1-1 Maidashi, H i g a s h i - k u , F u k u o k a 812, Japan (Reprint r e q u e s t s to AT). ABSTRACT The p u r p o s e of this study was to e x a m i n e w h e t h e r endogenous prostaglandins (PGs) m o d u l a t e v a s c u l a r r e s p o n s i v e ness to a d r e n e r g i c stimuli in the h i n d q u a r t e r s of s t r o k e prone S p o n t a n e o u s l y H y p e r t e n s i v e Rats (SHR-sp) and W i s t a r Kyoto rats (WKY). P r e v i o u s l y we have shown t h a t s y n t h e s i s of e n d o g e n o u s PGs in blood v e s s e l s in the rat h i n d q u a r t e r s was g r e a t e r in S H R - s p than in WKY and that high salt diet i n c r e a s e d the level of e n d o g e n o u s PGs in S H R - s p but not in WKY. V a s c u l a r r e s p o n s e s to n o r e p i n e p h r i n e (NE) and s y m p a t h e t i c nerve s t i m u l a t i o n (SNS) w e r e e x a m i n e d b e f o r e and after i n d o m e t h a c i n (IND), 2 mg/kg, a d m i n i s t e r e d intravenously. NE was a d m i n i s t e r e d i n t r a a r t e r i a l l y into the autoperfused hindquarters. Hindquarters vascular responses to these v a s o c o n s t r i c t o r stimuli were not a l t e r e d by IND in S H R - s p and WKY at the d i f f e r e n t level of e n d o g e n o u s PGs. These r e s u l t s i n d i c a t e that h i n d q u a r t e r s v a s o c o n s t r i c t i o n in r e s p o n s e to a d r e n e r g i c s t i m u l i w e r e not a l t e r e d by IND even w h e n v a s c u l a r s y n t h e s i s of e n d o g e n o u s PGs was augmented. The r e s u l t s suggest that e n d o g e n o u s PGs do not m o d u l a t e the h i n d q u a r t e r s r e s p o n s e s to a d r e n e r g i c stimulation in rats.
65
INTRODUCTION P r o s t a g l a n d i n s (PGs) participate in control of vascular resistance through its direct action on the blood vessels as well as by modulating vascular responses to v a s o c o n s t r i c t o r stimuli (1-6). Experimental evidence indicates that exogenously administered p r o s t a g l a n d i n s modulate vascular responses to n o r e p i n e p h r i n e (NE), SNS and angiotensin (7,8). However several studies suggested that endogenous PGs might not m o d u l a t e vascular responses to v a s o c o n strictor stimuli (9). Lonigro et al. reported that indomethacin, a p r o s t a g l a n d i n synthesis inhibitor, failed to potentiate v a s o c o n s t r i c t o r action of angiotensin in the h i n d l i m b of dogs. They attributed failure of indomethacin to alter the responses to a n g i o t e n s i n to the low p r o s t a g l a n d i n biosynthetic capacity of the limb of the dog in the resting state (9). However, it may be possible that endogenous PGs may have little or no m o d u l a t i n g effects on v a s o c o n s t r i c t o r stimuli. Similarly, D u v o c o v i c h and Langer studied the effect of IND on the nerve t r a n s m i s s i o n in the perfused cat spleen and concluded that endogenous PGs did not regulate neurotransmission (10). M i c a l i z z i and Pals studied chronotropic responses to c a r d i o a c c e r a t o r nerve s t i m u l a t i o n in dogs. They did not observe alteration of this response by IND (Ii). We have r e c e n t l y shown that synthesis of endogenous PGs was greater in SHR-sp than in WKY and that high NaCI diet increased endogenous PGs in SHR-sp (12). Therefore the purpose of this study was to examine w h e t h e r endogenous PGs m o d u l a t e d adrenergic v a s o c o n s t r i c t i o n in vessels of the rat hindquarters at the three d i f f e r e n t levels of endogenous PGs. METHODS SHR-sp and WKY used in the study were bred in our laboratory. The rats were fed regular chow c o n t a i n i n g 0.3 % NaCI from w e a n i n g until about 2 months old. The rats were then fed either normal (0.3 % NaCI) or high (8 % NaCl) salt diets for 5 weeks. P o t a s s i u m chloride content was 0.8 % for both diets. Water was p r o v i d e d for d r i n k i n g ad lib.
66
After the d i e t a r y periods, we studied the control hindquarters vascular resistance. Rats were anesthetized w i t h sodium pentobarbital, 50 mg/kg intraperitoneally. A tracheal cannula was inserted to facilitate spontaneous respiration. A jugular vein was cannulated for intravenous injection of drugs. The abdominal aorta was exposed through a midline incision. The aorta was ligated distal to the renal arteries and two cannula were inserted. Blood from the proximal aorta was pumped at a constant flow into the distal aorta p e r f u s i n g the vascularly isolated hindquarters, using a peristaltic pump (Watson M a r l o w Model MHRE i00). Hindquarters p e r f u s i o n pressure was measured via the side arm in the p e r f u s i o n tubing d o w n s t r e a m from the pump. Hindquarters p e r f u s i o n pressure at a constant flow indicated hindquarters vascular resistance. In tabulating perfusion pressure at a given flow, we subtracted the pressure resulting from the resistance of the p e r f u s i o n tubing. Resistance of the tubing was determined at the end of each study. We examined v a s o c o n s t r i c t o r responses to norepinephrine (NE) and sympathetic nerve stimulation (SNS) before and after a d m i n i s t r a t i o n of indomethacin. Indomethacin was dissolved in Na2CO3 and injected at the dose of 2 mg/kg through the jugular vein. The change of h i n d q u a r t e r s perfusion pressure was recorded 30 minutes after a drug administration when hindquarters p e r f u s i o n pressure became stable. Vehicle itself did not produce significant changes. NE (30, i00 and 300 ng base) were injected into the p e r f u s i o n tubing u p s t r e a m from the pump in 0.01 ml of 5 % xylitol in water. Injection of vehicle alone did not alter hindquarters perfusion pressure. Injection of each dose was separated by 2-3 minutes at which time p e r f u s i o n pressure had returned to the base line. The lumbar sympathetic chains, which run side by side, were exposed and placed on a bipolar p l a t i n u m electrode at L3. The chains were stimulated electrically at supramaximal voltage (i0 V) at 3 msec duration and 3, i0 and 30 Hz for i0 seconds each. Each period of stimulation was
67
s e p a r a t e d by 1-2 m i n u t e s by w h i c h time p e r f u s i o n p r e s s u r e had r e t u r n e d to the b a s e line. R e s p o n s e s to SNS a n d NE were o b t a i n e d at the flow of 3 m l / m i n . Statistical analysis were performed using Student's t test and a n a l y s i s of v a r i a n c e . V a l u e s of p < 0 . 0 5 were r e g a r d e d as s t a t i s t i c a l l y s i g n i f i c a n t . All v a l u e s w e r e e x p r e s s e d as m e a n + SEM. RESULTS F i g u r e 1 d e m o n s t r a t e d c h a n g e s in h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by i n d o m e t h a c i n (IND). IND i n c r e a s e d h i n d q u a r t e r s V R in S H R - s p but not in WKY. The i n c r e a s e in h i n d q u a r t e r s V R by IND was g r e a t e r in high salt fed S H R - s p t h a n in n o r m a l salt fed S H R - s p (p < 0 . 0 1 ) . H i n d q u a r t e r s v a s c u l a r r e s p o n s e s to s y m p a t h e t i c nerve s t i m u l a t i o n and n o r e p i n e p h r i n e (NE) b e f o r e and a f t e r IND are s u m m a r i z e d in T a b l e i. Hindquarters v a s c u l a r r e s p o n s e s to SNS or NE w e r e not d i f f e r e n t b e f o r e and a f t e r IND in S H R - s p t r e a t e d w i t h e i t h e r high or n o r m a l salt as w e l l as in e i t h e r g r o u p of WKY. DISCUSSION The r e s u l t s of this study i n d i c a t e that v a s o c o n s t r i c t o r r e s p o n s e s to i n t r a a r t e r i a l l y a d m i n i s t e r e d nore p i n e p h r i n e (NE) or to SNS w e r e not a l t e r e d by indom e t h a c i n (IND) in the h i n d q u a r t e r s vessels. These r e s u l t s s u g g e s t that e n d o g e n o u s PGs do not m o d u l a t e r e s p o n s e s to a d r e n e r g i c v a s o c o n s t r i c t o r s t i m u l i in the h i n d q u a r t e r s r e s i s t a n c e v e s s e l s in rats. R e p o r t e d e v i d e n c e i n d i c a t e that e x o g e n o u s l y a d m i n i s tered PGs m o d u l a t e v a s c u l a r r e s p o n s e s to a d r e n e r g i c s t i m u l i in the d i f f e r e n t v a s c u l a r beds (1,7,8). Effects of PGs m a y d i f f e r in v a s c u l a r beds and in s p e c i e s , but m o d u l a t i o n of v a s c u l a r r e s p o n s e s to a d r e n e r g i c s t i m u l i by e x o g e n o u s l y a d m i n i s t e r e d PGs is shown in the v a s c u l a r beds of the s k e l t a l m u s c l e of rats (i). M a l i k et al. r e p o r t e d that in the m e s e n t e r i c a r t e r y of rats, IND i n h i b i t e d the r e s p o n s e s to a d r e n e r g i c s t i m u l i and that e x o g e n o u s l y a d m i n i s t e r e d PGEI and PGE 2 p o t e n t i a t e d the v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c s t i m u l i (i).
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Figure. C h a n g e s in h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by i n d o m e t h a c i n . Note that i n d o m e t h a c i n i n c r e a s e d h i n d q u a r t e r s VR in SHR-sp but not in WKY. I n c r e a s e in h i n d q u a r t e r s VR by i n d o m e t h a c i n was g r e a t e r in SHR-sphigh salt than in S H R - s p - n o r m a l salt ( p < 0 . 0 1 ) (n=8-10). L o n i g r o et al. r e p o r t e d that IND did not p o t e n t i a t e the v a s o c o n s t r i c t o r e f f e c t of a n g i o t e n s i n in the hindlimb of the dog (9). H o w e v e r they c o n s i d e r e d that the f a i l u r e of a u g m e n t a t i o n of r e s p o n s e s to a n g i o t e n s i n by IND was due to the low level of e n d o g e n o u s PGs s y n t h e s i s in the r e s t i n g h i n d l i m b of the dog. In this study, the i n c r e a s e in the h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by IND w e r e d i f f e r e n t in S H R - s p on h i g h salt, SHR-sp on n o r m a l salt and WKY on e i t h e r h i g h or n o r m a l salt, w h i c h s u g g e s t e d that s y n t h e s i s of e n d o g e n o u s PGs w e r e d i f f e r e n t b e t w e e n three g r o u p s of rats. Thus we e x a m i n e d v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c s t i m u l i at the three d i f f e r e n t levels of e n d o g e n o u s PGs. Our r e s u l t s indicate that v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c stimuli w e r e not a l t e r e d by IND in any of these g r o u p s of rats. These r e s u l t s s u g g e s t that an a b s e n c e of m o d u l a t i o n of v a s o c o n s t r i c t o r r e s p o n s e s by IND was not due to the low level of e n d o g e n o u s PGs. 69
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It is not clear why inhibition of endogenous PGs did not augment responses to adrenergic stimuli, whereas exogenously a d m i n i s t e r e d PGs alters v a s c u l a r responses to adrenergic v a s o c o n s t r i c t i o n (7,8). However, the difference in the m o d u l a t i n g effects of adrenergic stimuli between endogenous PGs and exogenously a d m i n i s t e r e d PGs might be accounted for by the difference in PGs. It is suggested that major endogenous PG in the blood vessels is PGI 2 (13) and that PGI 2 may have little or no inhibitory effects on the n e u r o t r a n s m i t t e r release. For example, it is shown that PGI 2 had no inhibitory effects on the transmitter release in rabbit pulmonary artery strips (14) and that PGI2 did not inhibit n e u r o t r a n s m i t t e r release in the isolated p e r f u s e d rabbit kidney (15). In summary, our results indicate that inhibition of endogenous PGs by IND did not modulate v a s o c o n s t r i c t o r responses to adrenergic stimuli in the h i n d q u a r t e r s vessels in rats and that the lack of m o d u l a t i o n was not related to the level of endogenous PGs. ACKNOWLEDGEMENT We wish to acknowledge Tomoko Hirokawa.
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Kadowitz PJ. Effect of prostaglandins El, E 2 and A2 on vascular resistance and responses to noreadrenaline, nerve stimulation and angiotensin in the dog hindlimb. Br J Pharmacol 46: 395-400, 1972
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Lonigro AJ, Terragno NA, Malik KV, McGiff JC. Differential inhibition by prostaglandins of the renal actions of pressor stimuli. Prostag!andins 3: 596-606, 1973
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Duvocovich ML, Langer SZ. Evidence against a physiological role of prostaglandins in the regulation of noradrenergic release in the cat spleen. J Physiol 251: 737, 1975
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Micalizz ER, Pals DT. Evidence against p r o s t a g l a n d i n m o d u l a t i o n of c a r d i o a c c e l e r a t i o n nerve activity in the anesthetized dog. Prostaglandins 20: 147-152, 1980
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Imaizumi T, Takeshita A, Ashihara T, Nakamura M. Augmented hindquarters vascular responses to p r o s t a g l a n d i n synthesis inhibitors during high salt intake in Spontaneously Hypertensive Rats. A m J Physiol, accepted.
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Bunting S, Gryglowski RJ, Moncada S, Vane JR. Arterial walls generate from p r o s t a g l a n d i n endoperoxide a substance (prostaglandin X) which relaxes strips of m e s e n t e r i c and coeliac arteries and inhibits platelet aggregation. Prostaglandins 12: 897-913, 1976
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Weitzell R, Stappler A, Starke K. Effects of Prostaglandin E2, p r o s t a g l a n d i n 12 and 6 - k e t o - p r o s t a g l a n d i n F I ~ on adrenergic n e u r o t r a n s m i s s i o n in the pulmonary artery of the rabbit. Eur J Pharmacol 52: 137-141, 1978
15.
Hedquist P. Actions of prostacyclin (PGI 2) on adrenergic n e u r o e f f e c t o r transmission in the rabbit kidney. Prostaglandins 17: 249-258, 1979
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E N D O G E N O U S P R O S T A G L A N D I N S DO NOT M O D U L A T E THE H I N D Q U A R T E R S V A S C U L A R R E S P O N S E S TO A D R E N E R G I C S T I M U L A T I O N IN RATS T s u t o m u Imaizumi, A k i r a Takeshita, T o s h i a k i A s h i h a r a and Motoomi Nakamura R e s e a r c h I n s t i t u t e of A n g i o c a r d i o l o g y and C a r d i o v a s c u l a r Clinic, K y u s h u U n i v e r s i t y M e d i c a l School, 3-1-1 Maidashi, H i g a s h i - k u , F u k u o k a 812, Japan (Reprint r e q u e s t s to AT). ABSTRACT The p u r p o s e of this study was to e x a m i n e w h e t h e r endogenous prostaglandins (PGs) m o d u l a t e v a s c u l a r r e s p o n s i v e ness to a d r e n e r g i c stimuli in the h i n d q u a r t e r s of s t r o k e prone S p o n t a n e o u s l y H y p e r t e n s i v e Rats (SHR-sp) and W i s t a r Kyoto rats (WKY). P r e v i o u s l y we have shown t h a t s y n t h e s i s of e n d o g e n o u s PGs in blood v e s s e l s in the rat h i n d q u a r t e r s was g r e a t e r in S H R - s p than in WKY and that high salt diet i n c r e a s e d the level of e n d o g e n o u s PGs in S H R - s p but not in WKY. V a s c u l a r r e s p o n s e s to n o r e p i n e p h r i n e (NE) and s y m p a t h e t i c nerve s t i m u l a t i o n (SNS) w e r e e x a m i n e d b e f o r e and after i n d o m e t h a c i n (IND), 2 mg/kg, a d m i n i s t e r e d intravenously. NE was a d m i n i s t e r e d i n t r a a r t e r i a l l y into the autoperfused hindquarters. Hindquarters vascular responses to these v a s o c o n s t r i c t o r stimuli were not a l t e r e d by IND in S H R - s p and WKY at the d i f f e r e n t level of e n d o g e n o u s PGs. These r e s u l t s i n d i c a t e that h i n d q u a r t e r s v a s o c o n s t r i c t i o n in r e s p o n s e to a d r e n e r g i c s t i m u l i w e r e not a l t e r e d by IND even w h e n v a s c u l a r s y n t h e s i s of e n d o g e n o u s PGs was augmented. The r e s u l t s suggest that e n d o g e n o u s PGs do not m o d u l a t e the h i n d q u a r t e r s r e s p o n s e s to a d r e n e r g i c stimulation in rats.
65
INTRODUCTION P r o s t a g l a n d i n s (PGs) participate in control of vascular resistance through its direct action on the blood vessels as well as by modulating vascular responses to v a s o c o n s t r i c t o r stimuli (1-6). Experimental evidence indicates that exogenously administered p r o s t a g l a n d i n s modulate vascular responses to n o r e p i n e p h r i n e (NE), SNS and angiotensin (7,8). However several studies suggested that endogenous PGs might not m o d u l a t e vascular responses to v a s o c o n strictor stimuli (9). Lonigro et al. reported that indomethacin, a p r o s t a g l a n d i n synthesis inhibitor, failed to potentiate v a s o c o n s t r i c t o r action of angiotensin in the h i n d l i m b of dogs. They attributed failure of indomethacin to alter the responses to a n g i o t e n s i n to the low p r o s t a g l a n d i n biosynthetic capacity of the limb of the dog in the resting state (9). However, it may be possible that endogenous PGs may have little or no m o d u l a t i n g effects on v a s o c o n s t r i c t o r stimuli. Similarly, D u v o c o v i c h and Langer studied the effect of IND on the nerve t r a n s m i s s i o n in the perfused cat spleen and concluded that endogenous PGs did not regulate neurotransmission (10). M i c a l i z z i and Pals studied chronotropic responses to c a r d i o a c c e r a t o r nerve s t i m u l a t i o n in dogs. They did not observe alteration of this response by IND (Ii). We have r e c e n t l y shown that synthesis of endogenous PGs was greater in SHR-sp than in WKY and that high NaCI diet increased endogenous PGs in SHR-sp (12). Therefore the purpose of this study was to examine w h e t h e r endogenous PGs m o d u l a t e d adrenergic v a s o c o n s t r i c t i o n in vessels of the rat hindquarters at the three d i f f e r e n t levels of endogenous PGs. METHODS SHR-sp and WKY used in the study were bred in our laboratory. The rats were fed regular chow c o n t a i n i n g 0.3 % NaCI from w e a n i n g until about 2 months old. The rats were then fed either normal (0.3 % NaCI) or high (8 % NaCl) salt diets for 5 weeks. P o t a s s i u m chloride content was 0.8 % for both diets. Water was p r o v i d e d for d r i n k i n g ad lib.
66
After the d i e t a r y periods, we studied the control hindquarters vascular resistance. Rats were anesthetized w i t h sodium pentobarbital, 50 mg/kg intraperitoneally. A tracheal cannula was inserted to facilitate spontaneous respiration. A jugular vein was cannulated for intravenous injection of drugs. The abdominal aorta was exposed through a midline incision. The aorta was ligated distal to the renal arteries and two cannula were inserted. Blood from the proximal aorta was pumped at a constant flow into the distal aorta p e r f u s i n g the vascularly isolated hindquarters, using a peristaltic pump (Watson M a r l o w Model MHRE i00). Hindquarters p e r f u s i o n pressure was measured via the side arm in the p e r f u s i o n tubing d o w n s t r e a m from the pump. Hindquarters p e r f u s i o n pressure at a constant flow indicated hindquarters vascular resistance. In tabulating perfusion pressure at a given flow, we subtracted the pressure resulting from the resistance of the p e r f u s i o n tubing. Resistance of the tubing was determined at the end of each study. We examined v a s o c o n s t r i c t o r responses to norepinephrine (NE) and sympathetic nerve stimulation (SNS) before and after a d m i n i s t r a t i o n of indomethacin. Indomethacin was dissolved in Na2CO3 and injected at the dose of 2 mg/kg through the jugular vein. The change of h i n d q u a r t e r s perfusion pressure was recorded 30 minutes after a drug administration when hindquarters p e r f u s i o n pressure became stable. Vehicle itself did not produce significant changes. NE (30, i00 and 300 ng base) were injected into the p e r f u s i o n tubing u p s t r e a m from the pump in 0.01 ml of 5 % xylitol in water. Injection of vehicle alone did not alter hindquarters perfusion pressure. Injection of each dose was separated by 2-3 minutes at which time p e r f u s i o n pressure had returned to the base line. The lumbar sympathetic chains, which run side by side, were exposed and placed on a bipolar p l a t i n u m electrode at L3. The chains were stimulated electrically at supramaximal voltage (i0 V) at 3 msec duration and 3, i0 and 30 Hz for i0 seconds each. Each period of stimulation was
67
s e p a r a t e d by 1-2 m i n u t e s by w h i c h time p e r f u s i o n p r e s s u r e had r e t u r n e d to the b a s e line. R e s p o n s e s to SNS a n d NE were o b t a i n e d at the flow of 3 m l / m i n . Statistical analysis were performed using Student's t test and a n a l y s i s of v a r i a n c e . V a l u e s of p < 0 . 0 5 were r e g a r d e d as s t a t i s t i c a l l y s i g n i f i c a n t . All v a l u e s w e r e e x p r e s s e d as m e a n + SEM. RESULTS F i g u r e 1 d e m o n s t r a t e d c h a n g e s in h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by i n d o m e t h a c i n (IND). IND i n c r e a s e d h i n d q u a r t e r s V R in S H R - s p but not in WKY. The i n c r e a s e in h i n d q u a r t e r s V R by IND was g r e a t e r in high salt fed S H R - s p t h a n in n o r m a l salt fed S H R - s p (p < 0 . 0 1 ) . H i n d q u a r t e r s v a s c u l a r r e s p o n s e s to s y m p a t h e t i c nerve s t i m u l a t i o n and n o r e p i n e p h r i n e (NE) b e f o r e and a f t e r IND are s u m m a r i z e d in T a b l e i. Hindquarters v a s c u l a r r e s p o n s e s to SNS or NE w e r e not d i f f e r e n t b e f o r e and a f t e r IND in S H R - s p t r e a t e d w i t h e i t h e r high or n o r m a l salt as w e l l as in e i t h e r g r o u p of WKY. DISCUSSION The r e s u l t s of this study i n d i c a t e that v a s o c o n s t r i c t o r r e s p o n s e s to i n t r a a r t e r i a l l y a d m i n i s t e r e d nore p i n e p h r i n e (NE) or to SNS w e r e not a l t e r e d by indom e t h a c i n (IND) in the h i n d q u a r t e r s vessels. These r e s u l t s s u g g e s t that e n d o g e n o u s PGs do not m o d u l a t e r e s p o n s e s to a d r e n e r g i c v a s o c o n s t r i c t o r s t i m u l i in the h i n d q u a r t e r s r e s i s t a n c e v e s s e l s in rats. R e p o r t e d e v i d e n c e i n d i c a t e that e x o g e n o u s l y a d m i n i s tered PGs m o d u l a t e v a s c u l a r r e s p o n s e s to a d r e n e r g i c s t i m u l i in the d i f f e r e n t v a s c u l a r beds (1,7,8). Effects of PGs m a y d i f f e r in v a s c u l a r beds and in s p e c i e s , but m o d u l a t i o n of v a s c u l a r r e s p o n s e s to a d r e n e r g i c s t i m u l i by e x o g e n o u s l y a d m i n i s t e r e d PGs is shown in the v a s c u l a r beds of the s k e l t a l m u s c l e of rats (i). M a l i k et al. r e p o r t e d that in the m e s e n t e r i c a r t e r y of rats, IND i n h i b i t e d the r e s p o n s e s to a d r e n e r g i c s t i m u l i and that e x o g e n o u s l y a d m i n i s t e r e d PGEI and PGE 2 p o t e n t i a t e d the v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c s t i m u l i (i).
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Figure. C h a n g e s in h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by i n d o m e t h a c i n . Note that i n d o m e t h a c i n i n c r e a s e d h i n d q u a r t e r s VR in SHR-sp but not in WKY. I n c r e a s e in h i n d q u a r t e r s VR by i n d o m e t h a c i n was g r e a t e r in SHR-sphigh salt than in S H R - s p - n o r m a l salt ( p < 0 . 0 1 ) (n=8-10). L o n i g r o et al. r e p o r t e d that IND did not p o t e n t i a t e the v a s o c o n s t r i c t o r e f f e c t of a n g i o t e n s i n in the hindlimb of the dog (9). H o w e v e r they c o n s i d e r e d that the f a i l u r e of a u g m e n t a t i o n of r e s p o n s e s to a n g i o t e n s i n by IND was due to the low level of e n d o g e n o u s PGs s y n t h e s i s in the r e s t i n g h i n d l i m b of the dog. In this study, the i n c r e a s e in the h i n d q u a r t e r s v a s c u l a r r e s i s t a n c e (VR) by IND w e r e d i f f e r e n t in S H R - s p on h i g h salt, SHR-sp on n o r m a l salt and WKY on e i t h e r h i g h or n o r m a l salt, w h i c h s u g g e s t e d that s y n t h e s i s of e n d o g e n o u s PGs w e r e d i f f e r e n t b e t w e e n three g r o u p s of rats. Thus we e x a m i n e d v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c s t i m u l i at the three d i f f e r e n t levels of e n d o g e n o u s PGs. Our r e s u l t s indicate that v a s o c o n s t r i c t o r r e s p o n s e s to a d r e n e r g i c stimuli w e r e not a l t e r e d by IND in any of these g r o u p s of rats. These r e s u l t s s u g g e s t that an a b s e n c e of m o d u l a t i o n of v a s o c o n s t r i c t o r r e s p o n s e s by IND was not due to the low level of e n d o g e n o u s PGs. 69
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It is not clear why inhibition of endogenous PGs did not augment responses to adrenergic stimuli, whereas exogenously a d m i n i s t e r e d PGs alters v a s c u l a r responses to adrenergic v a s o c o n s t r i c t i o n (7,8). However, the difference in the m o d u l a t i n g effects of adrenergic stimuli between endogenous PGs and exogenously a d m i n i s t e r e d PGs might be accounted for by the difference in PGs. It is suggested that major endogenous PG in the blood vessels is PGI 2 (13) and that PGI 2 may have little or no inhibitory effects on the n e u r o t r a n s m i t t e r release. For example, it is shown that PGI 2 had no inhibitory effects on the transmitter release in rabbit pulmonary artery strips (14) and that PGI2 did not inhibit n e u r o t r a n s m i t t e r release in the isolated p e r f u s e d rabbit kidney (15). In summary, our results indicate that inhibition of endogenous PGs by IND did not modulate v a s o c o n s t r i c t o r responses to adrenergic stimuli in the h i n d q u a r t e r s vessels in rats and that the lack of m o d u l a t i o n was not related to the level of endogenous PGs. ACKNOWLEDGEMENT We wish to acknowledge Tomoko Hirokawa.
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