Basic Res. Cardiol. 73, 482-496 (1978) 9 1978 Dr. Dietrich Steinkopff Verlag, Darmstadt ISSN 0300-8428

Research InstituteofAngiocardiology and CardiovascularClinic, Kyushu UniversityMedical School, Fukuoka (Japan)

Effects of nitroglycerin and d i p y r i d a m o l e on regional m y o c a r d i a l b l o o d flow*) Einflug yon Nitroglycerin u n d Dipyridamol auf die regionale B l u t s t r 6 m u n g im Myokard M. Nakamura,

O. N a k a g a k i , Y. N o s e , T. F u k u J , a m a , and Y. K i k u c h i With 2 figures and 5 tables (Received J u n e 29, 1978)

Summary The effects of intravenous administration of nitroglycerin or dipyridamole on distribution of myocardial blood flow in the heart after coronary underperfusion were investigated. I n 18 open chest, anesthetized dogs, flow of the tubing supplying the left circumflex coronary artery (LCA) was reduced and kept constant, and then t h e drug was given intravenously. Before and after an administration of saline, nitroglycerin (0.04 mg/kg) and dipyridamole (0.2 mg/kg), myocardial blood flow was measured by tracer microspheres (TM). The first and second carbonized 15 spheres (TM1 and TM 2) were injected into the left atrium and the cannulated LCA perfusion system respectively before medication. Similarly, the third and fourth spheres were given after drug. Thus, by using four different TMs (141Ce, 51Cr, 8SSr, 46Sc) regional myocardial blood flow from the LCA perfusion route (TM~ and TM4) was measured separately from that of the other normally perfused coronary route (TM1 and TM3). The effect of drugs on flow distribution of these two i n d e p e n d e n t routes was measured. The LCA underperfusion produced a significant d i m i n u t i o n of regional flow and its end/epi ratio in the LCA territory. Nitroglycerin increased end/epi ratio in the ischemic myocardium in the LCA perfusion route, but dipyridamole increased the normally perfused coronary flow but caused a shift of flow from the ischemic left ventricle to the atria and right ventricle within the LCA territory. T h e c l i n i c a l a n d p h a r m a c o l o g i c a l e f f e c t s of n i t r o g l y c e r i n a r e q u i t e d i f f e r e n t f r o m t h o s e of d i p y r i d a m o l e , o n e of t h e c o r o n a r y v a s o d i l a t o r drugs, since, nitroglycerin relieves a n g i n a l p a i n b u t d i p y r i d a m o l e does not (1, 2). N i t r o g l y c e r i n i n c r e a s e s c o r o n a r y f l o w v e r y t r a n s i e n t l y b u t d i p y r i d a m o l e c a u s e s a s u s t a i n e d i n c r e a s e i n c o r o n a r y f l o w of n o r m a l m y o c a r d i u m (3, 4). S e v e r a l r e p o r t s d e m o n s t r a t e d t h a t n i t r o g l y c e r i n i m p r o v e d a disproportionately reduced flow in the subendocardial ischemic myocard i u m (5-7), b u t d i p y r i d a m o l e d o e s n o t i n c r e a s e t h e c l e a r a n c e of e i t h e r r a d i o a c t i v e K r y p t o n or X e n o n f r o m t h e i s c h e m i c a r e a e x c e p t a t t h e b o r d e r *) This study was financed by grants from the Japanese Ministry of Education (No. 144051) and Mitsui Life Social Welfare Foundation. 762

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of nitroglycerin and dipyridamole

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TM1 TM3 LCA ~ .

/ /

) I

I

exchanger I

TM 2 TM4

\ \ ~ continuous infusion ] ~ a n d suction pump I

Fig. 1. Preparation of left circumflex coronary artery perfusion model. L C A : left circumflex coronary artery. LAD: left anterior descending coronary artery. No. 1, 2 and 3 represent stopcock. TM: tracer microspheres.

of t h e i s c h e m i c z o n e (8-12). F a r o a n d M c G r e g o r r e p o r t e d t h a t n i t r o g l y c e r i n r e d u c e d c o r o n a r y v a s c u l a r r e s i s t a n c e of t h e l a r g e e p i c a r d i a l a r t e r i e s b u t d i p y r i d a m o l e r e d u c e d t h e r e s i s t a n c e of t h e s m a l l e r a r t e r i e s (12). I t c a n b e a s s u m e d t h a t d i f f e r e n c e s b e t w e e n t w o d r u g s o n t h e s i t e s of c o r o n a r y vascular resistance may cause difference in flow distribution in the i s c h e m i c h e a r t . H o w e v e r , t h e e f f e c t s of n i t r o g l y c e r i n a n d d i p y r i d a m o l e o n f l o w d i s t r i b u t i o n h a v e n o t b e e n s t u d i e d b y t h e t e c h n i q u e of s e p a r a t e l a b e l i n g of f l o w f r o m t h e r e s t r i c t e d c o r o n a r y a r t e r y a n d t h e o t h e r n o r m a l vessels. I n t h e p r e s e n t s t u d y , f l o w of t h e l e f t c i r c u m f l e x c o r o n a r y a r t e r y ( L C A ) w a s r e d u c e d a n d k e p t c o n s t a n t , a n d f l o w d i s t r i b u t i o n of t h e L C A w a s m e a s u r e d s e p a r a t e l y f r o m t h a t of t h e o t h e r , n o r m a l l y p e r f u s e d , c o r o n a r y a r t e r i e s i n v a r i o u s p a r t s of t h e h e a r t . T h e e f f e c t of n i t r o g l y c e r i n a n d d i p y r i d a m o l e o n f l o w d i s t r i b u t i o n of t h e s e t w o i n d e p e n d e n t c o r o n a r y perfusion routes was measured. The results demonstrated that nitroglycerin increased endocardial/epicardial flow ratio in the ischemic myocardium in the LCA perfusion route but dipyridamole increased the coronary f l o w of t h e n o r m a l l y p e r f u s e d a r e a b u t r e d u c e d t h e f l o w i n t h e i s c h e m i c left ventricle and caused a shift of flow from the ischemic left ventricle to the atria and right ventricle within the LCA territory. Methods Eighteen adult mongrel dogs weighing 13-25 kg were anesthetized with an intravenous dose of urethane (4 mg/kg) and chloralose (40 mg/kg), which was repeated as required. Ventilation was maintained with a Harvard p u m p respirator via an endotracheal t u b e and arterial PO2 was maintained in the normal range. As shown in figure 1, the LCA was ligated and cannulated near its origin using a stainless steel cannula (1.5 m m i.d.). The cannula was connected to a heat exchanger, w i n d k e s s e l and finger type constant flow p u m p (Tokyo Rikakikai Co.), which was continuously supplied with autoarterial blood by a t u b e inserted into the femoral artery. The perfusion flow was m e a s u r e d r e p e a t e d l y b y filling blood in the g r a d u a t e d cylinder by opening stopcock No. 2 in the perfusion system (fig. 1) and

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Fig. 2. S c h e m a t i c i l l u s t r a t i o n of t h e v e n t r i c u l a r f r e e w a l l v i e w e d f r o m t h e e p i c a r d i u m . T h e left v e n t r i c l e w a s d i v i d e d i n t o 36 b l o c k s as i n d i c a t e d b y lines. T h e a r e a i l l u s t r a t e d b y s t a r w a s c o n s i d e r e d to b e n o n - i s c h e m i c s t a n d a r d a r e a p e r f u s e d w i t h t h e n o r m a l L A D or r i g h t c o r o n a r y artery. T h e d a r k s h a d o w e d a r e a i n d i c a t e d L C A a r e a s u p p l i e d b y t h e u n d e r p e r f u s e d LCA. T h e L A D , m a r g i n a l a n d L C A a r e a are d e f i n e d b y t h e level of p e r c e n t f l o w of t h e s t a n d a r d area. b y m e a s u r i n g a d e c r e a s i n g r a t e of b l o o d v o l u m e b y c l o s i n g No. I s t o p c o c k . T h e p r e s s u r e of t h e p e r f u s e d L C A a n d t h e a o r t a w a s m o n i t o r e d t h r o u g h o u t t h e e x p e r i m e n t . Total v o l u m e of t h e p e r f u s i o n s y s t e m w a s a p p r o x i m a t e l y 20 ml. T h e initial L C A f l o w r a t e w a s s e t at level w h i c h g a v e a m e a n L C A p e r f u s i o n p r e s s u r e s l i g h t l y o v e r t h e m e a n aortic p r e s s u r e . T h i s initial f l o w r a t e w a s k e p t c o n s t a n t for 20 m i n as a c o n t r o l p e r i o d , a n d t h e n t h e L C A f l o w w a s r e d u c e d u n t i l t h e p r e s s u r e d i f f e r e n c e b e t w e e n t h e a o r t a a n d t h e distal L C A w a s a p p r o x i m a t e l y 60 m m H g a n d t h e m e a n L C A p e r f u s i o n p r e s s u r e 45 m m Hg. T h i s r e d u c e d f l o w r a t e w a s k e p t c o n s t a n t u n t i l t h e e n d of t h e e x p e r i m e n t as a n u n d e r p e r f u s e d p e r i o d . T h e e f f e c t s of n i t r o g l y c e r i n a n d d i p y r i d a m o l e o n h e a r t rate, aortic p r e s s u r e a n d f l o w w e r e t e s t e d i n t h i s u n d e r p e r f u s e d p e r i o d . A p p r o x i m a t e l y 20 r a i n w e r e a l l o w e d to e s t a b l i s h a s t e a d y s t a t e a n d t h e n r a d i o a c t i v e t r a c e r m i c r o s p h e r e s (TM) w e r e i n f u s e d . F o u r d i f f e r e n t TMs (141Ce, SlCr, 8SSr a n d 46Sc) w e r e u s e d a n d i n t e r c h a n g e d at r a n d o m s e q u e n c e . A p p r o x i m a t e l y 5-10 x 105 m i c r o s p h e r e s of t h e first T M (TM 1) in t h e left a t r i u m a n d 2.5 x 104 m i c r o s p h e r e s of t h e s e c o n d T M (TM 2) in t h e L C A p e r f u s i o n s y s t e m w e r e i n j e c t e d p r i o r to t h e a d m i n i s t r a t i o n of d r u g s in t h e u n d e r p e r f u s e d p e r i o d . Similarly, T1VI3 a n d ~ were injected after drug administration. In the d i p y r i d a m o l e g r o u p , d i p y r i d a m o l e (0.2 m g / k g ) w a s a d m i n i s t e r e d i n t r a v e n o u s l y o v e r 1 m i n , 10 m i n b e f o r e i n j e c t i o n of T M 3 a n d TM 4. While in t h e n i t r o g l y c e r i n g r o u p , 4 m i n b e f o r e i n j e c t i o n of TM 3 a n d T M 4, n i t r o g l y c e r i n (0.01 m g / k g / m i n ) w a s c o n s t a n t l y i n f u s e d i n t o t h e v e i n o v e r 4 m i n . I n t h e c o n t r o l g r o u p , s a l i n e (1 ml/kg), i n s t e a d of t h e d r u g , w a s a d m i n i s t e r e d i n t r a v e n o u s l y . T h e t i m e d i f f e r e n c e b e t w e e n arrival of T M 1 o r TM 3 a n d t h a t of TM2 or TM 4 i n t h e r e g i o n a l m y o c a r d i u m w a s e s t i m a t e d f r o m t h e p e r f u s i o n f l o w r a t e a n d t h e v o l u m e of t h e p e r f u s i o n s y s t e m . M i c r o s p h e r e s c a u s e d e m b o l i z a t i o n at n e a r l y t h e s a m e t i m e in t h e h e a r t via b o t h L C A a n d p h y s i o l o g i c a l r o u t e s . D u r i n g t w o m i n u t e s f r o m t h e s t a r t of i n j e c t i o n of T M 1 or T M 3 i n t o t h e left a t r i u m , L C A w a s p e r f u s e d w i t h t h e b l o o d filled in t h e c y l i n d e r b y c l o s i n g s t o p c o c k No. 1. T h u s , a n i n f l o w of TM1 or TM s into t h e L C A p e r f u s i o n s y s t e m w a s a v o i d e d b e c a u s e TM 1 a n d TM s w e r e r e m o v e d f r o m t h e s y s t e m i c arterial b l o o d 2 r a i n a f t e r i n j e c t i o n d u e to m i c r o e m b o l i z a t i o n (13). B y

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t h i s p r o c e d u r e , w e m e a s u r e d r e g i o n a l m y o c a r d i a l flow f r o m t h e L C A p e r f u s i o n r o u t e (TM 2 or T M ~ s e p a r a t e l y f r o m t h e o t h e r c o r o n a r y r o u t e (TM 1 or TMs). A r e f e r e n c e flow w a s m e a s u r e d w i t h a c o n s t a n t w i t h d r a w a l r a t e of a r t e r i a l b l o o d for 2 m i n (30 ml). A t t h e e n d of t h e e x p e r i m e n t , t h e h e a r t w a s r e m o v e d a n d t h e left v e n t r i c u l a r wall (LV), r i g h t v e n t r i c u l a r w a l l (RV), i n t e r v e n t r i c u l a r s e p t u m (IVS) a n d t o t a l a t r i a w e r e s e p a r a t e d . T h e left v e n t r i c l e w a s d i v i d e d i n t o 36 b l o c k s as s h o w n i n f i g u r e 2. E a c h b l o c k w a s f u r t h e r s h c e d i n t o s u b e n d o c a r d i a l , m i d d l e a n d s u b e p i c a r d i a l layers. T h e r i g h t v e n t r i c l e , i n t e r v e n t r i c u l a r s e p t u m a n d a t r i a w e r e also d i v i d e d i n t o 16, 14 a n d 9 b l o c k s r e s p e c t i v e l y . T i s s u e s w e r e w e i g h e d , d i g e s t e d i n 10% N a O H a n d m e a s u r e d for r a d i o a c t i v i t y of e a c h n u c l i d e b y a g a m m a c o u n t e r w i t h 5 1 2 - c h a n n e l a n a l y z e r ( N u c l e a r C h i c a g o ) w i t h i n 2% s t a t i s t i c a l error. T h e s p e c t r u m w a s c o r r e c t e d b y c o m p u t e r (JEC-6) for b a c k g r o u n d r a d i a t i o n , h a l f hfe, s e n s i t i v i t y for v a r i a b l e g a m m a energy and overlap produced by Compton scattering. Since, TM flowed into the c o r o n a r y s i n u s w a s u s u a l l y n e g l i g i b l e (15), r e g i o n a l m y o c a r d i a l b l o o d f l o w f r o m t h e L C A p e r f u s i o n r o u t e w a s c a l c u l a t e d as follows: 1) F l o w f r o m t h e L C A r o u t e ( m l / g / m i n ) = L C A p e r f u s i o n f l o w ( m l / m i n ) r a d i o a c t i v i t y of T M 2 or TM4 i n t h e r e g i o n a l m y o c a r d i u m ( C P M / g t i s s u e ) t o t a l r a d i o a c t i v i t y of T M 2 or T M 4 i n t h e e n t i r e h e a r t (CPM) 2) F l o w f r o m t h e o t h e r c o r o n a r y r o u t e ( m l / g / m i n ) = r a d i o a c t i v i t y of T M 1 o r T M s i n t h e r e g i o n a l m y o c a r d i u m (CPM]g) m e a n r a d i o a c t i v i t y of T M 1 o r T M s i n t h e a r t e r i a l b l o o d ( C P M / m l / m i n ) R e g a r d i n g t h e r a d i o a c t i v i t y of T M 1, w h i c h d i d n o t e n t e r t h e L C A r o u t e , t h e L A D , m a r g i n a l a n d L C A a r e a s w e r e d e f i n e d as follows, n a m e l y t h r e e b l o c k s of t h e a n t e r i o r a n d b a s a l free w a l l of t h e L V w e r e d e f i n e d first as t h e s t a n d a r d a r e a as s h o w n i n f i g u r e 2. B l o c k s w h i c h s h o w e d m o r e t h a n 75% r a d i o a c t i v i t y of T M l of t h e s t a n d a r d a r e a w e r e t h e n d e f i n e d as t h e L A D area. T h e L A D a r e a w a s d i v i d e d f u r t h e r i n t o t h e b a s a l a n d a p i c a l L A D a r e a s a c c o r d i n g to t h e i r l o c a t i o n as s h o w n i n f i g u r e 2. B l o c k s w h i c h s h o w e d r a d i o a c t i v i t y b e t w e e n 25% a n d 74% of T M 1 of t h e s t a n d a r d a r e a w e r e d e f i n e d as t h e m a r g i n a l area. T h e m y o c a r d i a l b l o c k s h a v i n g r a d i o a c t i v i t y of T M 1 l e s s t h a n 24% of t h e s t a n d a r d a r e a w e r e d e f i n e d as t h e L C A area. T h e d i s t r i b u t i o n of t h e b a s a l a n d a p i c a l L A D , m a r g i n a l a n d L C A a r e a s w a s s h o w n s c h e m a t i c a l l y i n f i g u r e 2. T h e r a d i o a c t i v i t i e s of e a c h n u c l i d e i n t h e r i g h t v e n t r i c l e , i n t e r v e n t r i e u l a r s e p t u m a n d a t r i a w e r e a v e r a g e d a n d u s e d for c a l c u l a t i o n of flow as d e s c r i b e d a b o v e . T h e n u m b e r of m i c r o s p h e r e s i n e a c h m y o c a r d i a l b l o c k w a s g r e a t e r t h a n 400 e x c e p t T M 1 or T M s i n t h e s l i c e d t i s s u e s a m p l e s of t h e L C A a r e a a n d T M 2 or TM~ i n t h e L A D area. M y o c a r d i a l f l o w of full t h i c k n e s s L V w a s o b t a i n e d b y a v e r a g i n g t h e f l o w of t h e s u b e n d o c a r d i a l , s u b e p i c a r d i a l a n d m i d d l e layers. F l o w r a t i o (I/O) of s u b e n d o c a r d i u m (D t o s u b e p i c a r d i u m (O) w a s c a l c u l a t e d t o s h o w t h e f l o w d i s t r i b u t i o n b e t w e e n subendocardium and subepieardium. T h e d i s t r i b u t i o n r a t e of flow f r o m t h e L C A r o u t e or o t h e r c o r o n a r y r o u t e i n t h e left a n d r i g h t v e n t r i c l e s , i n t e r v e n t r i c u l a r s e p t u m a n d a t r i a w a s e x p r e s s e d as p e r c e n t of t o t a l f l o w i n t h e e n t i r e h e a r t . F o r e x a m p l e , [% of t h e L C A flow i n t h e v a r i o u s p a r t s of t h e h e a r t ] = r a d i o a c t i v i t y of T M 2 or TM~ i n t h e v e n t r i c l e o r s e p t u m or a t r i a t o t a l r a d i o a c t i v i t y of T M 2 o r T I ~ i n t h e e n t i r e h e a r t . C o r o n a r y v a s c u l a r r e s i s t a n c e of t h e left a n d r i g h t v e n t r i c l e , i n t e r v e n t r i c u l a r s e p t u m a n d a t r i a w e r e d e f i n e d as t h e ratio of m e a n L C A p e r f u s i o n p r e s s u r e (in t h e L C A r o u t e ) o r a o r t i c p r e s s u r e (in t h e o t h e r c o r o n a r y r o u t e ) to t h e i r r e g i o n a l m y o c a r d i a l f l o w of t h e L C A o r L A D a r e a r e s p e c t i v e l y . C h a n g e s i n v a s c u l a r r e s i s t a n c e a f t e r m e d i c a t i o n w e r e e x p r e s s e d as a p e r c e n t of t h a t r e s i s t a n c e e x i s t i n g b e f o r e t h e d r u g .

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A paired t-test was used to compare the differences between interventions before and after medication within the group of experiments and Student t-test to compare the differences between groups or other interventions. Results

1. C h a n g e s o f h e m o d y n a m i c s The m e a n L C A p e r f u s i o n p r e s s u r e was a p p r o x i m a t e l y 110 m m H g b e i n g slightly over the m e a n aortic p r e s s u r e d u r i n g the control period a n d t h e n was significantly r e d u c e d to 41-45 m m H g d u r i n g the u n d e r p e r f u s e d period. H e a r t rate a n d aortic p r e s s u r e were not c h a n g e d significantly in a period of L C A u n d e r p e r f u s i o n . The m e a n L C A p e r f u s i o n p r e s s u r e before d r u g a d m i n i s t r a t i o n was the s a m e in the e x p e r i m e n t a l groups. N i t r o g l y c e r i n (O.04mg/kg) r e d u c e d significantly the m e a n aortic p r e s s u r e f r o m 103 to 87 m m H g and the m e a n L C A p e r f u s i o n p r e s s u r e f r o m 41 to 37 m m Hg. D i p y r i d a m o l e also r e d u c e d significantly the m e a n aortic p r e s s u r e f r o m 111 to 93 m m H g a n d the m e a n L C A p e r f u s i o n p r e s s u r e f r o m 45 to 39 m m Hg. T h e d e g r e e of r e d u c t i o n of m e a n aortic a n d L C A p e r f u s i o n p r e s s u r e s was n o t different statistically in the g r o u p s receiving n i t r o g l y c e r i n a n d dipyridamole. D i p y r i d a m o l e r e d u c e d heart rate significantly f r o m 155 to 146 (p < 0.01), b u t nitroglycerin did not. A n i m a l s after saline a d m i n i s t r a t i o n d e m o n s t r a t e d no significant c h a n g e s of t h o s e variables.

2. R e g i o n a l m y o c a r d i a l b l o o d f l o w o f the l e f t ventricular free waft The m e a n regional m y o c a r d i a l b l o o d flow in the basal a n d apical LAD, m a r g i n a l a n d L C A areas of the left v e n t r i c u l a r free wall in the three e x p e r i m e n t a l g r o u p s is d e m o n s t r a t e d in tables 1-3. T h e regional m y o c a r dial flow was classified into flow f r o m the L C A r o u t e a n d f r o m the o t h e r c o r o n a r y route. I n all t h r e e groups, the m y o c a r d i a l flow of the L C A area was r e d u c e d b y u n d e r p e r f u s i o n to 50-70% of that of the L A D area. I/O ratio of L C A flow in the L C A area was r e d u c e d b e l o w u n i t y a n d was significantly l o w e r t h a n that of the L A D area in all t h r e e groups. T h u s significant m y o c a r d i a l i s e h e m i a w a s . p r o d u c e d b y L C A u n d e r p e r f u s i o n in the L C A area. I n the basal L A D area, flow was m o r e t h a n 1.0 m l l g / m i n a n d I/O ratios a p p r o x i m a t e l y unity, i n d i c a t i n g no i s c h e m i a in the L A D area. Before d r u g administration, subepieardial (outer) flow in all t h r e e g r o u p s of the apical L A D area was greater t h a n s u b e n d o e a r d i a l (inner) flow c a u s i n g a d e c r e a s e of I/O ratio below unity. Myocardial flow of the apical L A D area and especially of the s u b e p i c a r d i a l (outer) layer, was signific a n t l y greater t h a n that of the basal L A D area. In the m a r g i n a l area, I / O ratio of flow f r o m the L C A r o u t e a p p e a r e d to be l o w e r t h a n that f r o m the o t h e r c o r o n a r y route. This difference, however, was n o t significant statistically prior to d r u g a d m i n i s t r a t i o n in all groups. I n t r a v e n o u s infusion of saline did n o t c h a n g e the regional m y o c a r d i a l flow n o r the I/O ratio of various parts of the L V free wall in b o t h p e r f u s i o n r o u t e s (table 1). After a d m i n i s t r a t i o n of nitroglycerin, regional m y o c a r d i a l flow f r o m the L C A r o u t e in the L C A area d e c r e a s e d in the s u b e p i c a r d i u m and t e n d e d to increase in the s u b e n d o c a r d i u m . Thus, the I/O ratio increased significantly f r o m 0.68 to 0.86 (p < 0.02) (table 2). A similar

Nakarnura et al., Effects o f nitroglycerin and dipyridarnole

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Basic Res. Cardiol. 73, 482-496 (1978) 9 1978 Dr. Dietrich Steinkopff Verlag, Darmstadt ISSN 0300-8428 Research InstituteofAngiocardiology and Cardio...
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