Supplement 2 , V o l
6 , Aust. N . Z . J .
Med. (1976), p ~ >35-33 .
STRUCTURAL CHANGES I N HEART AND VESSELS DURING HYPERTENS I O N WITH ASPECTS ON THEIR REVERSIBILITY Bj6rn Fol k m Depar-mr?t
of P h y s i o l o q y , r J i - l ~ e r s i t yof G d t e b o r g , Sweden
I n recent s t u d i e s of primary hl'pertension, u t i l i z h g mainly t h e O k m t o type of spontaneously h y p r t e n s i v e rats (SJB) a s a model of man's e s s e n t i a l h y p r t e n s i o n , we have explored the haemcdynanuc i m p r t ance and qeneral c h a r a c t e r i s t i c s of the adaptive changes i n design which affcct the l e f t ventricLe, l a r g e arteries md precapillaxy r e s i s t a n c e v e s s e l s i n chronic h y p r t e n s i o n ( 1 , 2 , 3 ) . These s t u d i e s oriqi n a t e f r a n findinqs ir. man sane 20 years ago, where w e observed i n p a t i e n t s with e s s e n t i a l hypertension t h a t f o r e m resistance t o blood f l o w w a s higher than i n normotensive s u b j e c t s even when c c r p r d a t ccmplete vascular r e l a x a t i o n , l a t e r confirmed also f o r the hand (4,5,6). In f a c t , t h i s difference i n the s t r u c t u r a l l y determined, r g i o n a l r e s i s t a n c e t o flow a h s t equalled t h e d i f f e r e n c e in mean a r t e r i a l pressure (MAP) between t h e hypertensive and normotensive s u b j e c t s . Therefore, such a s t r u c t u r a l n a r c w i n g of t h e resistance v e s s e l s c m l d , i f generalized, l a r g e l y alone explain the r a i s e d r e s i s t a n c e during resting steady s t a t e i n hypertension witho u t n e c e s s i t a t i n g any enhanced math muscle tone, imrdying t h a t it r e p r e s e n t s a haarcdynamically most i m p r t a n t cnanqe i n vessel design. Further, there w a s much t o i n d i c a t e t h a t this narrowing of t h e intern a l r a d i u s ( r i ) of t h e p r e c a p i l l a r y resistance v e s s e l s was asscciated w i t h a r e l a t i v e increase i n w a l l thickness ( w ) , thus cons t i t u t i n g a "hypertrophic" w / r i increase of t h e s e v e s s e l s to adapt t h e i r a r c h i t e c t u r e t o t h e raiscrl transmural pressure in accord a r c e w i t h Laplace's l a w . Quantitative morphunetric s t u d i e s i n hypertensive subj e c t s by Suwa and h i s group ( 7 , 8 ) m r r o b o r a t e such a view, noting a close correl a t i o n between MAP increase and r e l a t i v e w a l l thickening i n terms of muscle hypertrophy, not only i n t h e l e f t v e n t r i c l e a d t h e conduit arteries but also i n the prec a p i l l a r y resistance vessels. F i r s t close t o t h e c a p i l l a r y l e v e l the latter v e s s e l s gradually normalize t h e i r w / r i , presumably because they are here no l m g e r exposed t o any r a i s e d pressure, thanks t o t h e raised upstream r e s i s t a n c e .
k c e t h e hammynanic importance of
t h e s e s t r u c t u r a l changes is r e a l i z e d , a n u n k r of questions arises concerning t h e i r general nature. For a m p l e , might it be so i n primary hypertension that they even precede t h e pressure rise, i n which case they w u l d c o n s t i t u t e one of the very initiatinq f a c t o r s i n this g e n e t i c a l l y t r a n s f e r r e d hypertension? A l t e r n a t i v e l y , is it so t h a t they are a f t e r a l l secondary t o f u n c t i o n a l l y i d u c e d pressure increases but then, by t h e i r 17ery presence, c r u c i a l f o r t h e establishment of a chronic hypert e n s i v e s t a t e ? Further, e x a c t l y which are then these causative, functional f a c t o r s , how extensive i s t h e s t r u c t u r a l adaptation and h m r a p i d l y can it be e s t a b l i s h e d ? What are t h e chances f o r i t s prevention, or r e q r e s s i o n , i f Che pressure rise is hindered, or reversed, by e.g. pharmaml o g i c a l means? P a r t i c u l a r l y t h e l a t t e r questiorls may be of g r e a t p r a c t i c a l imp x t a n c e i n therapy s i n c e p a r t i c u l a r l y t h e chanqes i n r e s i s t a n c e vessel design tend t o p o t e n t i a t e the haandynamic impact of a given s n m t h muscle shortening, thereby i n v i t i n g a v i c i o u s c i r c u i t and aggravating t h e hypertensive state by t h e i r very presence. J 3 SHR t h e d e w l o p e n t of t h e m e n t ioned hypertrophic changes in t h e highpressure s e c t i o n s of t h e cardiovascular s y s t a n cccurs, soth i n r a t e and i n e x t e n t , i n close p a r a l l e l t o t h e gradual rise i n a r t e r i a l pressure (unpublished observat i o n s ) , which in t h e s e animals cccurs mainly between t h e 5th - 1 2 t h week of l i f e t o judge f r a n estimations pxformed i n d i f f e r e n t age groups. Frcm observations on SHR alone it is t h e r e f o r e hpssible t o estimate t h e speed a t which tk s t r u c t u r a l changes can occur, because in these animals t h e r a t e - l i m i t i n g f a c t o r might simply be c o n s t i t u t e d by t h e r e l a t i v e l y slaw onset of t r i g g e r i n g functional influences. For such reasons young, g e n e t i c a l l y normot e n s i v e "control" r a t s (NCR) w e r e used f o r induction of renal hypertension (RHR) by u n i l a t e r a l renal a r t e r y c l i p p i n g , because i n this s i t u a t i o n a more than 50 per c e n t rise i n can occur within 1-2 w e e k s ( 9 ) . The r e s u l t s revealed t h a t l e f t v e n t r i c u l a r hypertrophy and the c h a r a c t e r i s t i c w / r i
increase of the resistance vessels w e r e largely canpleted within 3 weeks and w e r e obvious already a f t e r one week; i n f a c t , t h e pressure rise and the s t r u c t u r a l adapta t i o n seaned t o be so closely intenmven i n time t h a t t h e one might reinforce t h e other by a p s i t i v e feedback irterackion. Hodever, it was a l s o evident fran these experiments t h a t it is t h e pressure rise p r se which constitutes t h e duninant, i n i t i a t i n g s t k l u s f o r the change in cardiac and vessel design. This was a l s o clear frcm t h e f a c t tht the characteri s t i c resistance vessel changes f a i l e d t o cccur i n e.g. the h i d q u a r t e r vascular bed of SHR, in case these vessels were "protected" f r m tiae pressure rise by means of an a o r t i c obstruction while they were then still exposed t o the same nervous and h m o r a l influences as the upper, h p r t e n s i v e part of the animals ( 1 0 ) . This by no means denies t h a t nervous and/ or hormonal f a c t o r s might contribute t o the s t r u c t u r a l changes, perhaps by exerting "trophic" influences t h a t reinforce t h e more d i r e c t e f f e c t of an increased transmural pressure as w i l l be b r i e f l y discussed below. Towards the background of these findings i n r a t s it may be questioned how rapidly such s t r u c t u r a l changes can occur i n man. This i s d i f f i c u l t t o say for sure h t it seems reasonable t o assume t h a t they are slmer i n approximate proportion t o t h e lmer metabolic r a t e i n man, i.e. taking here perhaps a few months t o develop when it i s a m a t t e r of a few weeks i n r a t s . H m ever, this would s t i l l imply q u i t e a rapid prccess considering t h e usually quite qradu a l progression of hypertensim in m ' s s i t u a t i o n . In other words, a l s o here functional i n i t i a t i n g e l m n t s and t h e s t r u c t u r a l adaptation may w e l l be so closel y intertwined in time t h a t both contribute t o the very d e v e l o p a t of t h e pressure increase. J u s t l i k e t h e prompt functional autoregulation of the precapillary vessels represents the " f i r s t l i n e of defence" of these vessels when exposed t o an acute pressure rise, their hypertrophic adaptation i n design may be said t o form t h e i r "second line of defence", occurring whenever a pressure rise is more sustained. T h e r e f o e , t h i s l a t t e r process may be labelled "structural autoregulation" because, l i k e the functional autoregulation (11) it is locally induced and serves t o
protect t h e c a p i l l a r y level fran the arteri a l pressure rise. Thus, f o r the individs v e s s e l this local response appears most appropriate, but it w i l l have p t e n t i a l l y dangerous consequences once it a f f l i c t s &a t h e systemic precapillary vessels. Ran q u i t e recent studies on t h e SHR kidneys (12) it appears as i f particu l a r l y t h e preqlanemlar vessels exhibit "structural autoregulation" , which w u l d serve t o lover the g l m e r u l a r f i l t r a t i o n pressure and hence reset also kidney function t o a higher pressure level. Further, while the f u n c t i o m l autoregulation i s rapid i n onset and, i n return, vanishes within seconds when pressure is reduced, the s t r u c t u r a l autoregulation takes a few weeks t o be established i n r a t s and a l a r g e l y m p l e t e regression can be accanplished within the s m p i &of time i f a sustained pressure reduction i s irduced. This holds f o r both t h e cardiac and vascular wall hypertrophy, but only in case t h a t the duration of the hypertensive s t a t e has not exceeded sane 6-10 weeks o r so (9,13). when more prolonged p e r i d s of pressure increase are involved , the s i t u a t i o n s l m l y changes but i n an important way. Then a "third l i n e of defence" s e a s t o be gradually established w i t h respect t o the l c c a l changes i n vascular w a l l design by t h e increasixq formation of collagen and other i n t e r s t i t i a l supporting e l m e n t s (14). I t appears a s i f t h e smooth m u s c l e cells themselves are the origin of t h e collagen formation, j u s t l i k e their r e l a t i v e increase i n bulk s e a s t o be mainly responsible f o r the early " s t r u c t u r a l autoregulation". The increasing addition of collagen, etc., may gradually unload the c o n t r a c t i l e elements f r m the pressure i m p a c t , thus again changing the canplex s i t u a t i o n i n t h e vascular walls. Unfortunately, i n contrast t o t h e hypertrophic, r e l a t i v e increase i n smooth muscle bulk, collagen shows f a r less of regression once a pressure reduction is induced, t o judge f r a n Wolinsky's studies on t h e r a t aorta ( 1 4 ) In analogy, it has been observe3 i n SHR t h a t t h e longer t h e duration of t h e hypertensive state, t h e less t h e chances f o r a s u b s t a n t i a l regression of e i t h e r the l e f t ventricular hypertrophy or the precapillary vessel changes ( 1 0 ) . The extent of regression of t h e changes i n vessel design a d l e f t ventricular weight w a s here only partial, and r a t h e r p a r , despite the pro-
.
Supplement 2
v o l . 6 A u s t r a l i a n and New Zcaland J o u r n a l of Yedicipe !1976)
longed reduction i n pressure caused by t h e treatment. This may explain why hypertension now returns f a i r l y r a p i d l y t o near1.y pretreatment values d e s p i t e the long period of i n t e n s e hypotensive treatment, once t h i s treatment i s i n t e r r u p t e d a d t h e e f f e c t o r cells can regain t h e i r o r i g i n a l l e v e l of a c t i v i t y . A q u i t e r e c e n t study in RHR, where renal hypertension was allowed t o l a s t f o r 4-5 months instead of only a few weeks, gces i n t h e 93me general d i r e c t i o n ( 1 3 ) . when tk r e n a l a r t e r y c l i p was eliminated a f t e r t h i s ( f o r a r a t ) prolonged hypert e n s i o n , pressure no longer r e t m d t o normotensive c o n t r o l values, ht r m a i n e d increased sane 1 5 per c e n t o r so. Further, s t i l l a f t e r several months of pressure reduction l e f t v e n t r i c u l a r weight was not reduced i n proportion t o t h e pressure f a l l ht rgnained sane 30 per c e n t abwe control l e v e l s , king u s u a l l y increascd somc 40-45% during t h e 50-55% increase i n MAP i n t h e h m r t e n s i v e phase. Also t h e hmcdynamic a n a l y s i s of t h e r e s i s t a n c e v e s s e l s i n t h e s e animals indicated t h a t a considerable' w a l l thickening remained , b u t t h i s remaining w / r i increase semed t o be mainly due t o an increased bulj, of non-contractile elements. Thus, their maximal s t r e n g t h of c o n t r a c t i o n was only l i t t l e increased but t h e increased s t e p ness of t h e resistance curves ( c f . 1) suggested t h a t the w / r i r a t i o remai.nd considerably i n c r e a s d cmyred t o con-
trols. These findings concerning the extent of regression of s t r u c t u r a l cardiovascular changes i n SHR and €? wI i% t h prw? longed hypertension are i n s t r i k i n g contrast t o t h e s i t u a t i o n i n s h a r t l a s t i q renal hypertension, mentioned a b v e (9) , and a l s o when hypotensive treatment is s t a r t e d i n SHR already i n t h e e a r l y phase of m c d e s t , labile hypertension (10) If such "preventive" treatment w a s i n t . - e p t ed a t 7-8 months of age, when hypertension is f a i r l y marked i n untreated animals, the pressure rise w a s slm and q u i t e mcdest i n e x t e n t . I n f a c t , these animals never seaned t o reach t h e high pressure l e v e l s of their untreated s i b l i n g s and their l i f e s p a n was considerably prolonged (10)
.
.
F i n a l l y , a few words should be m e n t ioned concerning t h e extent of t h e cardiovascular s t r u c t u r a l changes i n h y p r t e n s i v e rats, when r k l a t e d t o tk MAP level during awake, " r e s t i n g " conditions. I t
37
then appears a s i f both t h e l e f t v e n t r i mlar hypertrophy and t h e changes i r ~prec a p i l l a r y r e s i s t a n c e vessel desiqn are rek a t i v e l y more pronouncec-l i n SHR than in q e n e t i c a l l y normotensive r a t s , t r a n s f o m d t o WR by u n i l a t e r a l r e n a l a r t f t r j 7 ~b.;truct i o n . The problem i s here, howe-,,Ter, whether t h e " r e s t i n g " MFP l e v e l r e a l l y r e f l e c t s t h e average pressur? icad on heart v e s s e l s i n t h e normal d a i l y l i f e of t h e animals. I t i s p s s i b l e t h a t ,*.is "control" pressure l e v e l s m h a t ~maei:-. estimates the load on heart and v c s s e l s in SHR, s i n c e t h e s e animals display a g r e a t e r v a r i a b i l i t y ir. pressxre and a l s c more pronounced pressure increases t o environmental s t i m u l i than e i t h e r N(3: and RHR ( 1 5 ) . Hmever, i f this is so it would mean t h a t t h e raiscd r e s i s t a n c e during rest is much m o r e dependent on t h e " s t r u c t u r a l autoregulation" i n SHR than i n FHR, i n which l a t t e r case t h e steady c o n t r i b u t i o n of functional pxcitatory i n fluences must be proportionally g r e a t e r . I n any case, i f a " t r u e " d i f f c r c n c e in extent of t h e cardiovascular strmtural changes e x i s t k t w e e n SHR and RHR, such a d i f f e r e n c e could a p r i o r i r e f l e c t e i t h e r a g e n e t i c a l l y linked t d e n c y of t h e SHR cardiovascular e f f e c t o r cells t o d i s p l a y mre pronounced chanqes i n design t o a given pressure load, or t h e presence of an increased influence of so-call& " t r o phic" f a c t o r s i n SHR. Such influences might then be consequences of t h e increased sympatho-adrcnal a c t i v i t y t h a t seems t o c h a r a c t e r i z e a t l e a s t e a r l y phases of I.ife i n SHR ( c f . 2). I t is k n m t h a t bath catecholandnes (16) and angiotensin (17) f a c i l i t a t e t h e incorporation of amino-acids i n m y a x d i a l c o n t r a c t i l e p r o t e i n s , which may represent e a r l y phases of a "trophic" influence on e f f e c t or cell d e s i g n , exerted by t h e mentioned hormontes as w e l l a s by t h e adrenergic transmitter. Fran t h i s b r i e f survey concerning t h e haancdynamic i m p r t a n c e , rate of development, e x t e n t and r e v e r s i b i l i t y of t h e s t r u c t u r a l changes , taking p l a c e within t h e high-pressure cardiovascular canpartm a t s i n hypertension, it should be clear t h a t t h e problem has many i n t e r e s t i n g and important aspects. EIowever, it is a l s o clear t h a t s e v e r a l of t h e s e aspects are p r l y understood and t h a t t h e t-echnical problems involved i n exploring t h e s e chanqes are o f t e n considerable and c a l l for a v a r i e t y of cxpe-rimental approaches.
38 __._
__ _-
__--
FOLKOW
The problem may, h m v e r , ks w e l l worth the effort. becase "he mcntioxd changes in d e s i g n sew t o constitut-e an important m o n de.Jliminator for- the e s t a b l i s h e n t and mairtenance of a raised pressure level in all t;.pc?s of h p s r t e n s i o n . The r e a s o n i.s ';hat these changes tend t o reset both +he r e s i s t a n c e , +he s h o r t - t e r m and longterm "barost.ats" to a higher p r e s s u r e e q i l i b r i i m ( f o r ref. see 18) ard a l s o the lFft ventricle i n a d i - r e l t i o n which considerably alters its functional c h a r a c t w istics ( 3 ) .
J u n e 1976-
______
and r e n a l k y p e r t e n s i o n . Acta P h y s i o l . Scand. 1974: Suppl.. 40R 1 0 . FjcISS, I,., A s p e c t s of t h e r e l a t i o n b e t ween f u n c t i o n a l and s t r u c t u r a l c a r d i o v a s c u l a r f a c t o r s i n primary hypertenA c t a P h y s i o l . Scand. 1 9 7 4 : sion. 409. Suppl
.
11. FOLKOW, B . a n d B . OBERG, A u t - o r e g a l a t i o n and b a s a l t o n e i n c o n s e c u t i v e v a s c u l a r s e c t i o n s of t h e s k e l e t a l muscles i r i reserpine-treated cats. Acta P h y s i o l 105-113 Scand. 1961:
z.
1 2 . GDTHRERG, G . , M. HALLBACK, S. I S J N D I N , S .Z RTCKSTEN a n d R . FOLKOW, A c o m p a r i s o n o f r e n a l flow r e s i s t a n c e i n NCR and SHR. Symp, on "Spont.aneoiis G e n e t i c H y p e r t e n s i o n i n Fats", D u n e d i n , New Z e a l a n d , 4 - 6 H a r c h , 1 9 7 6 .
.
1. FCILKOW, B . , M. HALLBACK, Y . LUCuDGRER, R. SIVERTSSON AN11 L WEISS, I m p o r t a n c e of a d a p t i v e chanqes i n v a s c u l a r d e s i g n f o r e s t a b l i s h m e n t of p r i m a r y h y p e r t e n s i o n , s t - l l d i e s i n man and i n s p o n t a n CLrculat.Res. e o u s l y tiyperterisjve r a t s . 1073: 3 2 dnd 33-. S u p p l . 1. 2-16 2.
FOLKOW, B . , C e n t r a l n e u r o h o r m o n a l mechanisms i n 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 r a t s compared w i t h human e s s e r i t i a l hyp e r t e n s i o n . C l i n i c a l S c i . M o l . Med. 1975: 48 295-214.
3 . HALLBACK, M . , I n t e r a c t i o n b e t w e e n cerit r a l n e u r o q e n i c mechanisms and c h a n q e s i n c a r d i o v a s c u l a r clesiqn i n p r i m a r y hyStag. 1975 : p e r t e n s i o n . Act-a P h y s i o l S u p p l . 424.
1 3 . LUNDGREN, Y . and L. WEISS, C a r d i o vascular "design" a f t e r r e v e r s a l of To long-standing r e n a l hypertension. be p u b l . i n A c t a P h y s i o l . S c a n d .
14. WOLINSKY, H . ,
E f f e c t s of h y p e r t - e n s i o n and i t s r e v e r s a l on t h e t h o r a c i c a o r t a C i r c u l a t Res. o f m a l e and female r a t s . 1971: 28. 622-637
a n d B. FOLKOW, C a r d i o vascular responses t o acute mental "stress" i n 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. A c t a P h y s i o l . Scand. 1974: 90. 684-698 -
15. HALLBKCK, M.
.
4.
FOLKOW, B . , S t r u c t u r a l , m y o g e n i c , humo r a l and n e r v o u s f a c t o r s c o n t r o l l i n q
15. MLLFELT, R . J . , A . C .
HJALMARSSON arid O . G . ISAKSSON, I n v i t r o e f f e c t s of catecholamines on p r o t e i n s y n t h e s i s J. Mol. C e l l . i n p e r f u s e d r a t heart-. Cardiol. 1976: Ts b e p u b l i s h e d .
peripheral resistance. Hypotensive D r u l ~ s . Perqamon P r e s s . 1 9 5 6 : 1 6 3 - 1 7 4 5 . FOLKOW, B . , G . GRIMBY and (0. TIKJLESIUS, A d a p t i v e s t r u c t u r a l c h a n g e s of the v a s c u l a r w a l l s i n h y p e r t e n s i o n and t h e i r r e l a t i o n t o t h e c o n t r o l of t.he p e r i Acta P h y s i o l . Scand. p h e r a l r e s i s t a n c e . __-_-_195R: 255-272
17
R . , The hernodynamic i m p o r t ance of s t r u c t u r a l v a s c u l a r changes i n A c t a Physiol. e s s e n t i a l hypertension. Scand. 1070: Suppl. 343 SIVE?TSSON,
.
TARAZl,
P.A. KHAIRSALLAH
arid F M . RUMPUS, C a r d i a c h y p e r t r o p h y i n spontaneously hypertensive r a t s . C i r c u l a t . R e s . 1974: 35. 775-.?81 -
44
6 .
SEN, S., R . C .
19
, R e l a t i o n s h i p between p h y s i c a l v a s c u l a r p r o p e r t i e s and i t s importance smooth miisclc f u n c t i o n : f o r v a s c u l . a r c o n t r o l and r e a c t i v i t y . C l i n . Exp. €'ham. P h y s i o l . 1975: S ~ p p l .2 . 55-61. FOLKOW, H .
I _ -
7 . FURUYAMA, M . , H i s t c w e t r i c a l i n v e s t i g a t i o n s of arteries i n reference t o arterial hypertension. Tohoku J . Exp. 56 388-414Med. 1962: 8 . SUWA, N . a n d T . TAKAHASHI, M o r p h o l o q i c a l a n d m o r p h o m e t r i c a l a n a l y s i s of r i r c u l a t i o n i n h y p e r t e n s i o n and i s c h e m i c kidney. Munchen-Berlin-Wien, Urban & Schwa 17 enhe r y . 9 , LUNDGFE?I, Y., A d a p t i v e c h a n g e s o f c a r d i o v a s c u l a r d e s i q n i n spontaneoxJs
Supplement 2
Vol.
6 A u s t r a l i a n and New Zealand J o u r n a l o f Medicine (1976)
DR. SIMPSON: I would l i k e D r . Folkow's comment on an a p p a r e n t change i n r e a c t i v i t y of blood v e s s e l s which w e have observed i r a perfused mesenteric a r t e r y p r e p a r a t i o n . I n our s t r a i n of g e n e t i c a l l y h y p e r t e n s i v e r a t s we n o t i c e d a g r e a t l y i n c r e a s e d r e a c t i v i t y t o n o r a d r e n a l i n e and 5-hydroxytryptamine i n t h e m e s e n t e r i c a r t e r y when p e r f u s e d w i t h p h y s i o l o g i c a l s a l i n e . With blood p e r f u s i o n t h e d i f f e r e n c e between +he g e n e t i c a l l y h y p e r t e n s i v e and t h e normotens i v e r a t s seemed t o d i s a p p e a r , thiis cast.ir.q d o u b t on t h e r e l e v a n c e of t h i s r e a c t i v i t y change i n t h e i n t a c t p r e p a r a t i o n .
DR. FOLKOW:
The qroup i n Iowa C i t y h a s compared b o t h t h e blood p e r f u s i o n and t h e s a l i n e p e r f u s i o n i n t h e SHR, arid t h e y f i n d t h e same h y p e r - r e a c t i v i t y t v n o r a d r e n a l i n e d u r i n g blood p e r f u s i o n a s you f i n d w i t h o u t i t . But t h e New Zealand h y p e r t e n s i v e r a t and t h e S H R r a t s may d i f f e r i n many p o i n t s j.n g e n e t i c c h a r a c t e r i s t i c s , s o I t h i n k i t i s interesting t o trace these differences and t o f i n d o u t where t h e y l i e .
DR. F'LYTXER: I a m s t i l l a l i t t l e confused o v e r t h e i n t e r p r e t a t i o n of D r . B o h r ' s experiments - My i n t e r p r e t a t i o n would be t h a t i n t h e rats with r e n a l hypertension, w i t h t h e high and low p r e s s u r e l e g s , t h e i n c r e a s e i n s e n s i t i v i t y , which concerned b o t h t h r e s h o l d and s e n s i t i v i t y , was unrelated t o structural factors. I would l i k e D r . Folkow's comment on t h a t . DR. FOLKOW:
I t h i n k t h i s cur-.'^ colild i n d i c a t e t h a t b o t h f a c t o r s were t h e r e : s u p e r s e n s i t i v i t y i n i t s own r i g h t and s t r u c t u r a l change. With b o t h t h e s e element s o p e r a t i n q yo11 can have a s i i b - s e n s i t i v i t y w i t h a h y p e r r e a c t i v i t y due t o change i n s i g n . I n f a c t , one can p l a y around w i t h t h e v a s c u l a r bed. F7e have done q u i t e a l o t of changing smooth muscle s e n s i t i v i t y indep e n d e n t l y from s t r u c t u r e and you c a n g e t any s o r t of c u r v e . However, I t h i n k , D r . Rohr, your f i n d i n g s t h e r e c o n t r a s t a l i t t l e w i t h what D r . Speden found i n t h e r a b b i t s w i t h r e n a l h y p e r t e n s i o n , because he had a d e c r e a s e d s e n s i t i v i t y t h e r e . The f i - e l d is complex: t h e r e s u l t s depend on t h e animal, t h e a r t e r y , t h e v e s s e l and the technique.
39
6 , Aust. N . Z . J .
Med. (1976), p ~ >35-33 .
STRUCTURAL CHANGES I N HEART AND VESSELS DURING HYPERTENS I O N WITH ASPECTS ON THEIR REVERSIBILITY Bj6rn Fol k m Depar-mr?t
of P h y s i o l o q y , r J i - l ~ e r s i t yof G d t e b o r g , Sweden
I n recent s t u d i e s of primary hl'pertension, u t i l i z h g mainly t h e O k m t o type of spontaneously h y p r t e n s i v e rats (SJB) a s a model of man's e s s e n t i a l h y p r t e n s i o n , we have explored the haemcdynanuc i m p r t ance and qeneral c h a r a c t e r i s t i c s of the adaptive changes i n design which affcct the l e f t ventricLe, l a r g e arteries md precapillaxy r e s i s t a n c e v e s s e l s i n chronic h y p r t e n s i o n ( 1 , 2 , 3 ) . These s t u d i e s oriqi n a t e f r a n findinqs ir. man sane 20 years ago, where w e observed i n p a t i e n t s with e s s e n t i a l hypertension t h a t f o r e m resistance t o blood f l o w w a s higher than i n normotensive s u b j e c t s even when c c r p r d a t ccmplete vascular r e l a x a t i o n , l a t e r confirmed also f o r the hand (4,5,6). In f a c t , t h i s difference i n the s t r u c t u r a l l y determined, r g i o n a l r e s i s t a n c e t o flow a h s t equalled t h e d i f f e r e n c e in mean a r t e r i a l pressure (MAP) between t h e hypertensive and normotensive s u b j e c t s . Therefore, such a s t r u c t u r a l n a r c w i n g of t h e resistance v e s s e l s c m l d , i f generalized, l a r g e l y alone explain the r a i s e d r e s i s t a n c e during resting steady s t a t e i n hypertension witho u t n e c e s s i t a t i n g any enhanced math muscle tone, imrdying t h a t it r e p r e s e n t s a haarcdynamically most i m p r t a n t cnanqe i n vessel design. Further, there w a s much t o i n d i c a t e t h a t this narrowing of t h e intern a l r a d i u s ( r i ) of t h e p r e c a p i l l a r y resistance v e s s e l s was asscciated w i t h a r e l a t i v e increase i n w a l l thickness ( w ) , thus cons t i t u t i n g a "hypertrophic" w / r i increase of t h e s e v e s s e l s to adapt t h e i r a r c h i t e c t u r e t o t h e raiscrl transmural pressure in accord a r c e w i t h Laplace's l a w . Quantitative morphunetric s t u d i e s i n hypertensive subj e c t s by Suwa and h i s group ( 7 , 8 ) m r r o b o r a t e such a view, noting a close correl a t i o n between MAP increase and r e l a t i v e w a l l thickening i n terms of muscle hypertrophy, not only i n t h e l e f t v e n t r i c l e a d t h e conduit arteries but also i n the prec a p i l l a r y resistance vessels. F i r s t close t o t h e c a p i l l a r y l e v e l the latter v e s s e l s gradually normalize t h e i r w / r i , presumably because they are here no l m g e r exposed t o any r a i s e d pressure, thanks t o t h e raised upstream r e s i s t a n c e .
k c e t h e hammynanic importance of
t h e s e s t r u c t u r a l changes is r e a l i z e d , a n u n k r of questions arises concerning t h e i r general nature. For a m p l e , might it be so i n primary hypertension that they even precede t h e pressure rise, i n which case they w u l d c o n s t i t u t e one of the very initiatinq f a c t o r s i n this g e n e t i c a l l y t r a n s f e r r e d hypertension? A l t e r n a t i v e l y , is it so t h a t they are a f t e r a l l secondary t o f u n c t i o n a l l y i d u c e d pressure increases but then, by t h e i r 17ery presence, c r u c i a l f o r t h e establishment of a chronic hypert e n s i v e s t a t e ? Further, e x a c t l y which are then these causative, functional f a c t o r s , how extensive i s t h e s t r u c t u r a l adaptation and h m r a p i d l y can it be e s t a b l i s h e d ? What are t h e chances f o r i t s prevention, or r e q r e s s i o n , i f Che pressure rise is hindered, or reversed, by e.g. pharmaml o g i c a l means? P a r t i c u l a r l y t h e l a t t e r questiorls may be of g r e a t p r a c t i c a l imp x t a n c e i n therapy s i n c e p a r t i c u l a r l y t h e chanqes i n r e s i s t a n c e vessel design tend t o p o t e n t i a t e the haandynamic impact of a given s n m t h muscle shortening, thereby i n v i t i n g a v i c i o u s c i r c u i t and aggravating t h e hypertensive state by t h e i r very presence. J 3 SHR t h e d e w l o p e n t of t h e m e n t ioned hypertrophic changes in t h e highpressure s e c t i o n s of t h e cardiovascular s y s t a n cccurs, soth i n r a t e and i n e x t e n t , i n close p a r a l l e l t o t h e gradual rise i n a r t e r i a l pressure (unpublished observat i o n s ) , which in t h e s e animals cccurs mainly between t h e 5th - 1 2 t h week of l i f e t o judge f r a n estimations pxformed i n d i f f e r e n t age groups. Frcm observations on SHR alone it is t h e r e f o r e hpssible t o estimate t h e speed a t which tk s t r u c t u r a l changes can occur, because in these animals t h e r a t e - l i m i t i n g f a c t o r might simply be c o n s t i t u t e d by t h e r e l a t i v e l y slaw onset of t r i g g e r i n g functional influences. For such reasons young, g e n e t i c a l l y normot e n s i v e "control" r a t s (NCR) w e r e used f o r induction of renal hypertension (RHR) by u n i l a t e r a l renal a r t e r y c l i p p i n g , because i n this s i t u a t i o n a more than 50 per c e n t rise i n can occur within 1-2 w e e k s ( 9 ) . The r e s u l t s revealed t h a t l e f t v e n t r i c u l a r hypertrophy and the c h a r a c t e r i s t i c w / r i
increase of the resistance vessels w e r e largely canpleted within 3 weeks and w e r e obvious already a f t e r one week; i n f a c t , t h e pressure rise and the s t r u c t u r a l adapta t i o n seaned t o be so closely intenmven i n time t h a t t h e one might reinforce t h e other by a p s i t i v e feedback irterackion. Hodever, it was a l s o evident fran these experiments t h a t it is t h e pressure rise p r se which constitutes t h e duninant, i n i t i a t i n g s t k l u s f o r the change in cardiac and vessel design. This was a l s o clear frcm t h e f a c t tht the characteri s t i c resistance vessel changes f a i l e d t o cccur i n e.g. the h i d q u a r t e r vascular bed of SHR, in case these vessels were "protected" f r m tiae pressure rise by means of an a o r t i c obstruction while they were then still exposed t o the same nervous and h m o r a l influences as the upper, h p r t e n s i v e part of the animals ( 1 0 ) . This by no means denies t h a t nervous and/ or hormonal f a c t o r s might contribute t o the s t r u c t u r a l changes, perhaps by exerting "trophic" influences t h a t reinforce t h e more d i r e c t e f f e c t of an increased transmural pressure as w i l l be b r i e f l y discussed below. Towards the background of these findings i n r a t s it may be questioned how rapidly such s t r u c t u r a l changes can occur i n man. This i s d i f f i c u l t t o say for sure h t it seems reasonable t o assume t h a t they are slmer i n approximate proportion t o t h e lmer metabolic r a t e i n man, i.e. taking here perhaps a few months t o develop when it i s a m a t t e r of a few weeks i n r a t s . H m ever, this would s t i l l imply q u i t e a rapid prccess considering t h e usually quite qradu a l progression of hypertensim in m ' s s i t u a t i o n . In other words, a l s o here functional i n i t i a t i n g e l m n t s and t h e s t r u c t u r a l adaptation may w e l l be so closel y intertwined in time t h a t both contribute t o the very d e v e l o p a t of t h e pressure increase. J u s t l i k e t h e prompt functional autoregulation of the precapillary vessels represents the " f i r s t l i n e of defence" of these vessels when exposed t o an acute pressure rise, their hypertrophic adaptation i n design may be said t o form t h e i r "second line of defence", occurring whenever a pressure rise is more sustained. T h e r e f o e , t h i s l a t t e r process may be labelled "structural autoregulation" because, l i k e the functional autoregulation (11) it is locally induced and serves t o
protect t h e c a p i l l a r y level fran the arteri a l pressure rise. Thus, f o r the individs v e s s e l this local response appears most appropriate, but it w i l l have p t e n t i a l l y dangerous consequences once it a f f l i c t s &a t h e systemic precapillary vessels. Ran q u i t e recent studies on t h e SHR kidneys (12) it appears as i f particu l a r l y t h e preqlanemlar vessels exhibit "structural autoregulation" , which w u l d serve t o lover the g l m e r u l a r f i l t r a t i o n pressure and hence reset also kidney function t o a higher pressure level. Further, while the f u n c t i o m l autoregulation i s rapid i n onset and, i n return, vanishes within seconds when pressure is reduced, the s t r u c t u r a l autoregulation takes a few weeks t o be established i n r a t s and a l a r g e l y m p l e t e regression can be accanplished within the s m p i &of time i f a sustained pressure reduction i s irduced. This holds f o r both t h e cardiac and vascular wall hypertrophy, but only in case t h a t the duration of the hypertensive s t a t e has not exceeded sane 6-10 weeks o r so (9,13). when more prolonged p e r i d s of pressure increase are involved , the s i t u a t i o n s l m l y changes but i n an important way. Then a "third l i n e of defence" s e a s t o be gradually established w i t h respect t o the l c c a l changes i n vascular w a l l design by t h e increasixq formation of collagen and other i n t e r s t i t i a l supporting e l m e n t s (14). I t appears a s i f t h e smooth m u s c l e cells themselves are the origin of t h e collagen formation, j u s t l i k e their r e l a t i v e increase i n bulk s e a s t o be mainly responsible f o r the early " s t r u c t u r a l autoregulation". The increasing addition of collagen, etc., may gradually unload the c o n t r a c t i l e elements f r m the pressure i m p a c t , thus again changing the canplex s i t u a t i o n i n t h e vascular walls. Unfortunately, i n contrast t o t h e hypertrophic, r e l a t i v e increase i n smooth muscle bulk, collagen shows f a r less of regression once a pressure reduction is induced, t o judge f r a n Wolinsky's studies on t h e r a t aorta ( 1 4 ) In analogy, it has been observe3 i n SHR t h a t t h e longer t h e duration of t h e hypertensive state, t h e less t h e chances f o r a s u b s t a n t i a l regression of e i t h e r the l e f t ventricular hypertrophy or the precapillary vessel changes ( 1 0 ) . The extent of regression of t h e changes i n vessel design a d l e f t ventricular weight w a s here only partial, and r a t h e r p a r , despite the pro-
.
Supplement 2
v o l . 6 A u s t r a l i a n and New Zcaland J o u r n a l of Yedicipe !1976)
longed reduction i n pressure caused by t h e treatment. This may explain why hypertension now returns f a i r l y r a p i d l y t o near1.y pretreatment values d e s p i t e the long period of i n t e n s e hypotensive treatment, once t h i s treatment i s i n t e r r u p t e d a d t h e e f f e c t o r cells can regain t h e i r o r i g i n a l l e v e l of a c t i v i t y . A q u i t e r e c e n t study in RHR, where renal hypertension was allowed t o l a s t f o r 4-5 months instead of only a few weeks, gces i n t h e 93me general d i r e c t i o n ( 1 3 ) . when tk r e n a l a r t e r y c l i p was eliminated a f t e r t h i s ( f o r a r a t ) prolonged hypert e n s i o n , pressure no longer r e t m d t o normotensive c o n t r o l values, ht r m a i n e d increased sane 1 5 per c e n t o r so. Further, s t i l l a f t e r several months of pressure reduction l e f t v e n t r i c u l a r weight was not reduced i n proportion t o t h e pressure f a l l ht rgnained sane 30 per c e n t abwe control l e v e l s , king u s u a l l y increascd somc 40-45% during t h e 50-55% increase i n MAP i n t h e h m r t e n s i v e phase. Also t h e hmcdynamic a n a l y s i s of t h e r e s i s t a n c e v e s s e l s i n t h e s e animals indicated t h a t a considerable' w a l l thickening remained , b u t t h i s remaining w / r i increase semed t o be mainly due t o an increased bulj, of non-contractile elements. Thus, their maximal s t r e n g t h of c o n t r a c t i o n was only l i t t l e increased but t h e increased s t e p ness of t h e resistance curves ( c f . 1) suggested t h a t the w / r i r a t i o remai.nd considerably i n c r e a s d cmyred t o con-
trols. These findings concerning the extent of regression of s t r u c t u r a l cardiovascular changes i n SHR and €? wI i% t h prw? longed hypertension are i n s t r i k i n g contrast t o t h e s i t u a t i o n i n s h a r t l a s t i q renal hypertension, mentioned a b v e (9) , and a l s o when hypotensive treatment is s t a r t e d i n SHR already i n t h e e a r l y phase of m c d e s t , labile hypertension (10) If such "preventive" treatment w a s i n t . - e p t ed a t 7-8 months of age, when hypertension is f a i r l y marked i n untreated animals, the pressure rise w a s slm and q u i t e mcdest i n e x t e n t . I n f a c t , these animals never seaned t o reach t h e high pressure l e v e l s of their untreated s i b l i n g s and their l i f e s p a n was considerably prolonged (10)
.
.
F i n a l l y , a few words should be m e n t ioned concerning t h e extent of t h e cardiovascular s t r u c t u r a l changes i n h y p r t e n s i v e rats, when r k l a t e d t o tk MAP level during awake, " r e s t i n g " conditions. I t
37
then appears a s i f both t h e l e f t v e n t r i mlar hypertrophy and t h e changes i r ~prec a p i l l a r y r e s i s t a n c e vessel desiqn are rek a t i v e l y more pronouncec-l i n SHR than in q e n e t i c a l l y normotensive r a t s , t r a n s f o m d t o WR by u n i l a t e r a l r e n a l a r t f t r j 7 ~b.;truct i o n . The problem i s here, howe-,,Ter, whether t h e " r e s t i n g " MFP l e v e l r e a l l y r e f l e c t s t h e average pressur? icad on heart v e s s e l s i n t h e normal d a i l y l i f e of t h e animals. I t i s p s s i b l e t h a t ,*.is "control" pressure l e v e l s m h a t ~maei:-. estimates the load on heart and v c s s e l s in SHR, s i n c e t h e s e animals display a g r e a t e r v a r i a b i l i t y ir. pressxre and a l s c more pronounced pressure increases t o environmental s t i m u l i than e i t h e r N(3: and RHR ( 1 5 ) . Hmever, i f this is so it would mean t h a t t h e raiscd r e s i s t a n c e during rest is much m o r e dependent on t h e " s t r u c t u r a l autoregulation" i n SHR than i n FHR, i n which l a t t e r case t h e steady c o n t r i b u t i o n of functional pxcitatory i n fluences must be proportionally g r e a t e r . I n any case, i f a " t r u e " d i f f c r c n c e in extent of t h e cardiovascular strmtural changes e x i s t k t w e e n SHR and RHR, such a d i f f e r e n c e could a p r i o r i r e f l e c t e i t h e r a g e n e t i c a l l y linked t d e n c y of t h e SHR cardiovascular e f f e c t o r cells t o d i s p l a y mre pronounced chanqes i n design t o a given pressure load, or t h e presence of an increased influence of so-call& " t r o phic" f a c t o r s i n SHR. Such influences might then be consequences of t h e increased sympatho-adrcnal a c t i v i t y t h a t seems t o c h a r a c t e r i z e a t l e a s t e a r l y phases of I.ife i n SHR ( c f . 2). I t is k n m t h a t bath catecholandnes (16) and angiotensin (17) f a c i l i t a t e t h e incorporation of amino-acids i n m y a x d i a l c o n t r a c t i l e p r o t e i n s , which may represent e a r l y phases of a "trophic" influence on e f f e c t or cell d e s i g n , exerted by t h e mentioned hormontes as w e l l a s by t h e adrenergic transmitter. Fran t h i s b r i e f survey concerning t h e haancdynamic i m p r t a n c e , rate of development, e x t e n t and r e v e r s i b i l i t y of t h e s t r u c t u r a l changes , taking p l a c e within t h e high-pressure cardiovascular canpartm a t s i n hypertension, it should be clear t h a t t h e problem has many i n t e r e s t i n g and important aspects. EIowever, it is a l s o clear t h a t s e v e r a l of t h e s e aspects are p r l y understood and t h a t t h e t-echnical problems involved i n exploring t h e s e chanqes are o f t e n considerable and c a l l for a v a r i e t y of cxpe-rimental approaches.
38 __._
__ _-
__--
FOLKOW
The problem may, h m v e r , ks w e l l worth the effort. becase "he mcntioxd changes in d e s i g n sew t o constitut-e an important m o n de.Jliminator for- the e s t a b l i s h e n t and mairtenance of a raised pressure level in all t;.pc?s of h p s r t e n s i o n . The r e a s o n i.s ';hat these changes tend t o reset both +he r e s i s t a n c e , +he s h o r t - t e r m and longterm "barost.ats" to a higher p r e s s u r e e q i l i b r i i m ( f o r ref. see 18) ard a l s o the lFft ventricle i n a d i - r e l t i o n which considerably alters its functional c h a r a c t w istics ( 3 ) .
J u n e 1976-
______
and r e n a l k y p e r t e n s i o n . Acta P h y s i o l . Scand. 1974: Suppl.. 40R 1 0 . FjcISS, I,., A s p e c t s of t h e r e l a t i o n b e t ween f u n c t i o n a l and s t r u c t u r a l c a r d i o v a s c u l a r f a c t o r s i n primary hypertenA c t a P h y s i o l . Scand. 1 9 7 4 : sion. 409. Suppl
.
11. FOLKOW, B . a n d B . OBERG, A u t - o r e g a l a t i o n and b a s a l t o n e i n c o n s e c u t i v e v a s c u l a r s e c t i o n s of t h e s k e l e t a l muscles i r i reserpine-treated cats. Acta P h y s i o l 105-113 Scand. 1961:
z.
1 2 . GDTHRERG, G . , M. HALLBACK, S. I S J N D I N , S .Z RTCKSTEN a n d R . FOLKOW, A c o m p a r i s o n o f r e n a l flow r e s i s t a n c e i n NCR and SHR. Symp, on "Spont.aneoiis G e n e t i c H y p e r t e n s i o n i n Fats", D u n e d i n , New Z e a l a n d , 4 - 6 H a r c h , 1 9 7 6 .
.
1. FCILKOW, B . , M. HALLBACK, Y . LUCuDGRER, R. SIVERTSSON AN11 L WEISS, I m p o r t a n c e of a d a p t i v e chanqes i n v a s c u l a r d e s i g n f o r e s t a b l i s h m e n t of p r i m a r y h y p e r t e n s i o n , s t - l l d i e s i n man and i n s p o n t a n CLrculat.Res. e o u s l y tiyperterisjve r a t s . 1073: 3 2 dnd 33-. S u p p l . 1. 2-16 2.
FOLKOW, B . , C e n t r a l n e u r o h o r m o n a l mechanisms i n 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 r a t s compared w i t h human e s s e r i t i a l hyp e r t e n s i o n . C l i n i c a l S c i . M o l . Med. 1975: 48 295-214.
3 . HALLBACK, M . , I n t e r a c t i o n b e t w e e n cerit r a l n e u r o q e n i c mechanisms and c h a n q e s i n c a r d i o v a s c u l a r clesiqn i n p r i m a r y hyStag. 1975 : p e r t e n s i o n . Act-a P h y s i o l S u p p l . 424.
1 3 . LUNDGREN, Y . and L. WEISS, C a r d i o vascular "design" a f t e r r e v e r s a l of To long-standing r e n a l hypertension. be p u b l . i n A c t a P h y s i o l . S c a n d .
14. WOLINSKY, H . ,
E f f e c t s of h y p e r t - e n s i o n and i t s r e v e r s a l on t h e t h o r a c i c a o r t a C i r c u l a t Res. o f m a l e and female r a t s . 1971: 28. 622-637
a n d B. FOLKOW, C a r d i o vascular responses t o acute mental "stress" i n 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. A c t a P h y s i o l . Scand. 1974: 90. 684-698 -
15. HALLBKCK, M.
.
4.
FOLKOW, B . , S t r u c t u r a l , m y o g e n i c , humo r a l and n e r v o u s f a c t o r s c o n t r o l l i n q
15. MLLFELT, R . J . , A . C .
HJALMARSSON arid O . G . ISAKSSON, I n v i t r o e f f e c t s of catecholamines on p r o t e i n s y n t h e s i s J. Mol. C e l l . i n p e r f u s e d r a t heart-. Cardiol. 1976: Ts b e p u b l i s h e d .
peripheral resistance. Hypotensive D r u l ~ s . Perqamon P r e s s . 1 9 5 6 : 1 6 3 - 1 7 4 5 . FOLKOW, B . , G . GRIMBY and (0. TIKJLESIUS, A d a p t i v e s t r u c t u r a l c h a n g e s of the v a s c u l a r w a l l s i n h y p e r t e n s i o n and t h e i r r e l a t i o n t o t h e c o n t r o l of t.he p e r i Acta P h y s i o l . Scand. p h e r a l r e s i s t a n c e . __-_-_195R: 255-272
17
R . , The hernodynamic i m p o r t ance of s t r u c t u r a l v a s c u l a r changes i n A c t a Physiol. e s s e n t i a l hypertension. Scand. 1070: Suppl. 343 SIVE?TSSON,
.
TARAZl,
P.A. KHAIRSALLAH
arid F M . RUMPUS, C a r d i a c h y p e r t r o p h y i n spontaneously hypertensive r a t s . C i r c u l a t . R e s . 1974: 35. 775-.?81 -
44
6 .
SEN, S., R . C .
19
, R e l a t i o n s h i p between p h y s i c a l v a s c u l a r p r o p e r t i e s and i t s importance smooth miisclc f u n c t i o n : f o r v a s c u l . a r c o n t r o l and r e a c t i v i t y . C l i n . Exp. €'ham. P h y s i o l . 1975: S ~ p p l .2 . 55-61. FOLKOW, H .
I _ -
7 . FURUYAMA, M . , H i s t c w e t r i c a l i n v e s t i g a t i o n s of arteries i n reference t o arterial hypertension. Tohoku J . Exp. 56 388-414Med. 1962: 8 . SUWA, N . a n d T . TAKAHASHI, M o r p h o l o q i c a l a n d m o r p h o m e t r i c a l a n a l y s i s of r i r c u l a t i o n i n h y p e r t e n s i o n and i s c h e m i c kidney. Munchen-Berlin-Wien, Urban & Schwa 17 enhe r y . 9 , LUNDGFE?I, Y., A d a p t i v e c h a n g e s o f c a r d i o v a s c u l a r d e s i q n i n spontaneoxJs
Supplement 2
Vol.
6 A u s t r a l i a n and New Zealand J o u r n a l o f Medicine (1976)
DR. SIMPSON: I would l i k e D r . Folkow's comment on an a p p a r e n t change i n r e a c t i v i t y of blood v e s s e l s which w e have observed i r a perfused mesenteric a r t e r y p r e p a r a t i o n . I n our s t r a i n of g e n e t i c a l l y h y p e r t e n s i v e r a t s we n o t i c e d a g r e a t l y i n c r e a s e d r e a c t i v i t y t o n o r a d r e n a l i n e and 5-hydroxytryptamine i n t h e m e s e n t e r i c a r t e r y when p e r f u s e d w i t h p h y s i o l o g i c a l s a l i n e . With blood p e r f u s i o n t h e d i f f e r e n c e between +he g e n e t i c a l l y h y p e r t e n s i v e and t h e normotens i v e r a t s seemed t o d i s a p p e a r , thiis cast.ir.q d o u b t on t h e r e l e v a n c e of t h i s r e a c t i v i t y change i n t h e i n t a c t p r e p a r a t i o n .
DR. FOLKOW:
The qroup i n Iowa C i t y h a s compared b o t h t h e blood p e r f u s i o n and t h e s a l i n e p e r f u s i o n i n t h e SHR, arid t h e y f i n d t h e same h y p e r - r e a c t i v i t y t v n o r a d r e n a l i n e d u r i n g blood p e r f u s i o n a s you f i n d w i t h o u t i t . But t h e New Zealand h y p e r t e n s i v e r a t and t h e S H R r a t s may d i f f e r i n many p o i n t s j.n g e n e t i c c h a r a c t e r i s t i c s , s o I t h i n k i t i s interesting t o trace these differences and t o f i n d o u t where t h e y l i e .
DR. F'LYTXER: I a m s t i l l a l i t t l e confused o v e r t h e i n t e r p r e t a t i o n of D r . B o h r ' s experiments - My i n t e r p r e t a t i o n would be t h a t i n t h e rats with r e n a l hypertension, w i t h t h e high and low p r e s s u r e l e g s , t h e i n c r e a s e i n s e n s i t i v i t y , which concerned b o t h t h r e s h o l d and s e n s i t i v i t y , was unrelated t o structural factors. I would l i k e D r . Folkow's comment on t h a t . DR. FOLKOW:
I t h i n k t h i s cur-.'^ colild i n d i c a t e t h a t b o t h f a c t o r s were t h e r e : s u p e r s e n s i t i v i t y i n i t s own r i g h t and s t r u c t u r a l change. With b o t h t h e s e element s o p e r a t i n q yo11 can have a s i i b - s e n s i t i v i t y w i t h a h y p e r r e a c t i v i t y due t o change i n s i g n . I n f a c t , one can p l a y around w i t h t h e v a s c u l a r bed. F7e have done q u i t e a l o t of changing smooth muscle s e n s i t i v i t y indep e n d e n t l y from s t r u c t u r e and you c a n g e t any s o r t of c u r v e . However, I t h i n k , D r . Rohr, your f i n d i n g s t h e r e c o n t r a s t a l i t t l e w i t h what D r . Speden found i n t h e r a b b i t s w i t h r e n a l h y p e r t e n s i o n , because he had a d e c r e a s e d s e n s i t i v i t y t h e r e . The f i - e l d is complex: t h e r e s u l t s depend on t h e animal, t h e a r t e r y , t h e v e s s e l and the technique.
39
