31.05.

2013

CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE…

CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVENTS HYPERTENSION IN A RAT MODEL OF SLEEP APNEA
Ana Quenia Gomes da Silva, Marco Antônio Peliky Fontes, and Nancy Lapp Kanagy

Abstract
Sleep a pn ea is ch a r a ct er ized by in cr ea sed sy m pa t h et ic a ct iv it y a n d is a ssocia t ed w it h sy st em ic h y per t en sion . A n g iot en sin (A n g ) pept ides h a v e pr ev iou sly been sh ow n t o pa r t icipa t e in t h e r eg u la t ion of sy m pa t h et ic t on e a n d a r t er ia l pr essu r e in t h e h y pot h a la m ic pa r a v en t r icu la r n u cleu s (PV N) n eu r on s. W e in v est ig a t ed t h e r ole of en dog en ou s A n g pept ides w it h in t h e PV N t o con t r ol blood pr essu r e in a r a t m odel of sleep a pn ea -in du ced h y per t en sion . Ma le Spr a g u e Da w ley r a t s (2 5 0 g ), in st r u m en t ed w it h bila t er a l g u ide ca n n u la e t a r g et in g t h e PV N, r eceiv ed ch r on ic in fu sion of A n g a n t a g on ist s (A -7 7 9 , A n g -(1 -7 ) a n t a g on ist ; losa r t a n a n d ZD7 1 5 5 , A T 1 a n t a g on ist s; PD1 2 3 3 1 9 , A T 2 r ecept or a n t a g on ist , or sa lin e v eh icle). A sepa r a t e g r ou p r eceiv ed a n in fu sion of t h e GA BA A r ecept or a g on ist (m u scim ol) t o in h ibit PV N n eu r on a l a ct iv it y in depen den t of a n g iot en sin r ecept or s. A ft er ca n n u la pla cem en t , r a t s w er e ex posed du r in g t h eir sleep per iod t o eu ca pn ic in t er m it t en t h y pox ia (IH; n a dir 5 % O 2; 5 % CO 2 t o pea k 2 1 % O 2; 0 % CO 2) 2 0 cy cles/h ou r , 7 h ou r s/da y , for 1 4 da y s w h ile m ea n a r t er ia l pr essu r e (MA P) w a s m ea su r ed by t elem et r y . In r a t s r eceiv in g sa lin e, IH ex posu r e sig n ifica n t ly in cr ea sed MA P (+1 2 ±2 m m Hg v s Sh a m −2 ±1 m m Hg P<0 .0 1 ). In h ibit ion of PV N n eu r on s w it h m u scim ol r ev er sed t h e in cr ea se in MA P in IH r a t s (MUS: −9 ±4 m m Hg v s v eh icle +1 2 ±2 m m Hg ; P<0 .0 1 ). In fu sion of a n y of t h e A n g a n t a g on ist s a lso pr ev en t ed t h e r ise in MA P in du ced by IH (A -7 7 9 : −5 ±1 m m Hg , losa r t a n : −9 ±4 m m Hg , ZD7 1 5 5 : −1 1 ±4 m m Hg a n d PD1 2 3 3 1 9 : −4 ±3 m m Hg ; P<0 .0 1 ). Ou r r esu lt s su g g est t h a t en dog en ou s A n g pept ides a ct in g in t h e PV N con t r ibu t e t o IH-in du ced in cr ea ses in MA P obser v ed in t h is r a t m odel of sleep a pn ea -in du ced h y per t en sion .
Classification terms: h y pot h a la m ic-pit u it a r y -a dr en a l

r eg u la t ion , pept ides: a n a t om y a n d ph y siolog y ,

ca r diov a scu la r r eg u la t ion
Key words: sy m pa t h et ic

a ct iv it y , in t er m it t en t h y pox ia , h y per t en sion , r en in -a n g iot en sin sy st em ,

a n g iot en sin -(1 -7 )

Introduction
Ch r on ic in t er m it t en t h y pox ia (CIH), a ch a r a ct er ist ic of h u m a n sleep a pn ea , lea ds t o su st a in ed elev a t ion of sy m pa t h et ic n er v e a ct iv it y (SNA ) a n d m ea n a r t er ia l pr essu r e (A P). A lt h ou g h t h e m ech a n ism s by w h ich CIH a u g m en t s A P a r e in com plet ely u n der st ood, a ct iv a t ion of t h e sy m pa t h et ic n er v ou s sy st em seem s t o be essen t ia l for t h e m a in t en a n ce of h y per t en sion (Sica et al. , 2 0 0 0 ; Flet ch er , 2 0 0 3 ; Pr a bh a k a r et al. , 2 0 0 5 ). In deed, sev er a l m et h ods of sy m pa t h et ic block a de, in clu din g ca r ot id body den er v a t ion , r en a l sy m pa t h ect om y , a dr en a l dem edu lla t ion a n d sy m pa t h et ic n er v e a bla t ion pr ev en t t h e r ise in A P du e t o CIH ex posu r e (Flet ch er et al. , 1 9 9 9 ; Flet ch er , 1 9 9 2 a ). T h e h y pot h a la m ic pa r a v en t r icu la r n u cleu s (PV N) is a n im por t a n t sit e r eg u la t in g a r t er ia l pr essu r e a n d sy m pa t h et ic a ct iv it y (Da m pn ey , 1 9 9 4 ; T a g a w a & Da m pn ey , 1 9 9 9 ;). In h ibit ion of PV N n eu r on s w it h n it r ic ox ide don or (A llen , 2 0 0 2 ; Hor n et al. , 1 9 9 4 ; St er n et al. , 2 0 0 3 ) or γ -a m in obu t y r ic a cid (GA BA ) r ecept or a g on ist (Ka n n a n et al. , 1 9 8 9 ; A llen , 2 0 0 2 ; Silv a et al. , 2 0 0 5 ), r edu ces r en a l SNA a n d sy st em ic A P. Con v er sely , a ct iv a t ion of PV N n eu r on s by m icr oin ject ion of a n ex cit a t or y a m in o a cid (Ka n n a n et al. , 1 9 8 9 ) or GA BA A-r ecept or a n t a g on ist , in cr ea ses a r t er ia l pr essu r e a n d sy m pa t h et ic a ct iv it y in a n est h et ized (Ch en et al. , 2 0 0 3 ; Ch en & T on ey , 2 0 0 3 ) a n d con sciou s (Ka n n a n et al. , 1 9 8 9 ) r a t s. Sev er a l st u dies h a v e su g g est ed t h a t a u g m en t ed disch a r g e of PV N
www.ncbi.nlm.nih.gov/pmc/articles/PMC3018235/ 1/11

2 0 0 1 . In t h is st u dy w e in v est ig a t ed t h e con t r ibu t ion of A n g II a n d A n g -(1 -7 ) r ecept or s in t h e PV N t o h y per t en sion dev eloped du r in g fou r t een da y s of IH ex posu r e.05. 2 0 0 5 ). A n g iot en sin (A n g ) pept ides a ct a s im por t a n t n eu r om odu la t or s in br a in sit es con t r ollin g sy m pa t h et ic ou t pu t a n d a r t er ia l pr essu r e (Da m pn ey et al. 2 0 0 2 ).. a n im a ls w it h in ject ion sit es ou t side t h e PV N w er e a n a ly zed a s a "con t r ol" g r ou p.ncbi. Fi gur e 1 Gr ouped data show i ng 1 2 hour av er age r ec or di ngs of mean ar ter i al pr essur e (MA P. 2 0 0 7 ). . 2 0 0 4 ). 1 9 9 4 . T h e A T 2 r ecept or block er a lso t en ded t o decr ea se HR a n d HR w a s sig n ifica n t ly low er t h a n du r in g t h e con t r ol per iod on da y 1 4 in bot h g r ou ps (Fig u r e 2 D). .2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… n eu r on s m a y be in v olv ed in t h e su st a in ed sy m pa t h oex cit a t ion in pa t h olog ica l con dit ion s in clu din g con g est iv e h ea r t fa ilu r e (Zu ck er et al. V eer a sin g h a m & Ra iza da . sa lt -sen sit iv e h y per t en sion (W eiss et al.nih. 2 0 0 3 ). losa r t a n (Fig u r e 3 A a n d 3 B) or ZD7 1 5 5 (Fig u r e 3 C a n d 3 D).nlm. c hr oni c al l y i nf used w i th sal i ne (200 nL/hr ) i nto the PV N . Bot h a n t a g on ist s r edu ced MA P in t h e IH a n d Sh a m ex posed r a t s com pa r ed t o v eh icle t r ea t ed r a t s bu t did n ot ch a n g e HR. 2 0 0 2 . . Hea r t r a t e w a s a lso n ot differ en t bet w een g r ou ps (Fig u r e 2 B). W e h a v e pr ev iou sly r epor t ed t h a t bot h A n g II a n d A n g -(1 -7 ) con t r ibu t e t o t h e m a in t en a n ce of r en a l SNA a n d t h a t m icr oin ject ion s of t h ese pept ides in t o t h e PV N in cr ea se sy m pa t h et ic t on e (Silv a et al. P<0 .gov/pmc/articles/PMC3018235/ 2/11 .0 1 .31. Angiotensin receptor blockade Ch r on ic block a de of A n g (1 -7 ) r ecept or s w it h A -7 7 9 pr ev en t ed a n in cr ea se in MA P in t h e IH ex posed r a t s so t h a t MA P w a s n ot differ en t fr om Sh a m ex posed r a t s on a n y da y (Fig u r e 2 A ).. Ca t o & T on ey . Results IH exposure and GABAA inhibition A n im a ls w er e su bdiv ided a ft er h ist olog ica l a n a ly sis of ca n n u la e pla cem en t : t h ose w it h in ject ion sit es loca t ed w it h in or on t h e bor der s of t h e PV N w er e t h e ex per im en t a l g r ou p. MA P w a s n ot differ en t bet w een Sh a m a n d IH r a t s. Day ti me MA P and hear t r ate c or r espond to X-ax i s w hol e numb er s . Fig u r e 3 sh ow s MA P a n d HR in Sh a m a n d IH r a t s r eceiv in g ch r on ic in fu sion of t h e A T 1 r ecept or block er s. Fi gur e 2 www. Tab l e 1 Basal v al ues f or MA P and HR b ef or e IH or sham x posur e w i th dr ug i nf usi on i nto the PV N . in cr ea se t h e fir in g r a t e of n eu r on s by a ct in g on specific r ecept or s (A m bu h l et al. Specifica lly in t h e PV N. t w o pept ides pr odu ced by t h e r en in -a n g iot en sin sy st em (RA S) ca sca de. Fig u r e 1 ). T a ble 1 sh ow s ba selin e v a lu es of MA P a n d HR befor e IH or Sh a m ex posu r e for a ll ex per im en t a l g r ou ps. T h e A T 2 r ecept or a n t a g on ist a lso pr ev en t ed a n in cr ea se in MA P in t h e IH ex posed g r ou p bu t MA P st ill t en ded t o be h ig h er in t h e com pa r ed t o Sh a m r a t s r eceiv in g PD1 2 3 3 1 9 (Fig u r e 2 C). ion t oph or et ic a pplica t ion of A n g II a n d A n g -(1 -7 ). 2 0 0 2 ). 2 0 0 5 ). a n d g en et ic h y per t en sion (A llen . In t h e r a t s r eceiv in g t h e A T 1 r ecept or block er s. . . m y oca r dia l in fa r ct ion (Zh a n g et al. IH ex posu r e sig n ifica n t ly in cr ea sed MA P in v eh icle-t r ea t ed r a t s com pa r ed t o v eh icle-t r ea t ed Sh a m r a t s (IH: +1 2 ±2 m m Hg v s Sh a m : −2 ±1 m m Hg . . A ) and hear t r ate (B) i n Sham and IH ex posed r ats.

0 1 . t h er e w er e n o sig n ifica n t differ en ces in a ct iv it y bet w een g r ou ps or w it h in g r ou ps ov er t im e (da t a n ot sh ow n )... a s sh ow n in Fig u r e 1 . Day ti me MA P .05. P<0 . Day ti me MA P and hear t r ate c or r espond to X-ax i s w hol e numb er s . Fi gur e 4 Gr ouped data show i ng 1 2 hour av er age r ec or di ngs of mean ar ter i al pr essur e (MA P. Ex a m ples of t h e in ject ion sit es con sider ed w it h in a n d ou t of t h e PV N a r e illu st r a t ed in Su pplem en t a l Fig u r e 1 B T h e a ct iv it y da t a for t h e t w o g r ou ps in dica t ed a t en den cy for a ll of t h e IH ex posed r a t s in depen den t of a n t a g on ist t r ea t m en t t o m ov e less du r in g t h e da r k h ou r s (a w a k e) a n d m or e du r in g t h e lig h t h ou r s (sleep/ex posu r e t im e) bu t du e t o t h e bet w een a n im a l v a r ia bilit y . m u scim ol. losa r t a n : −1 2 ±8 bpm a n d PD1 2 3 3 1 9 : −1 8 ±4 bpm .0 1 ) a n d a ll a n g iot en sin a n t a g on ist s low er ed MA P ev en m or e by da y 1 4 com plet ely pr ev en t in g t h e in cr ea se in MA P obser v ed in t h e v eh icle g r ou p a t da y 1 4 (A -7 7 9 : −5 ±1 m m Hg . pr ev en t ed t h e in cr ea se in MA P a n d decr ea sed HR in IH r a t s a n d t en ded t o low er MA P in t h e Sh a m ex posed r a t s so t h a t MA P w a s n ot differ en t bet w een SHA M a n d IH r a t s t r ea t ed w it h m u scim ol (Fig u r e 4 ).2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… Gr ouped data show i ng 1 2 hour av er age r ec or di ngs of mean ar ter i al pr essur e (MA P) and hear t r ate (HR) i n Sham and IH ex posed r ats c hr oni c al l y i nf used w i th A -7 7 9 (A and B.nih. Day ti me MA P (A and C) and .. ZD7 1 5 5 : −1 1 ±4 m m Hg a n d PD1 2 3 3 1 9 : −4 ±3 m m Hg v s v eh icle: +1 2 ±2 m m Hg . t h e GA BA A r ecept or a g on ist . losa r t a n . A ) and hear t r ate (B) i n Sham and IH ex posed r ats c hr oni c al l y i nf used w i th musc i mol (20 pmol /h) i nto the PV N . 2 nmol /h) i nto the PV N . Ch r on ic t r ea t m en t w it h A -7 7 9 a n d ZD7 1 5 5 low er ed MA P com pa r ed t o v eh icle t r ea t m en t a t da y 7 (A -7 7 9 : −3 ±1 m m Hg a n d ZD7 1 5 5 : −6 ±1 m m Hg v s v eh icle: +3 ±1 m m Hg . Discussion www. l osar tan (2 nmol /h). Fi gur e 5 Gr ouped data show i ng the c hange i n mean ar ter i al pr essur e (MA P) and hear t r ate (HR) on day s 7 and 1 4 of Sham ex posed r ats (A and B) and IH ex posed r ats (C and D) c hr oni c al l y i nf used w i th sal i ne (200 nL/h)... 2 nmol /h) or ZD 7 1 55 (C and D.0.nlm. a t da y 1 4 ).31. A -7 7 9 . A n g iot en sin a n t a g on ist in fu sion in t o sit es com plet ely ou t side PV N bor der s h a d n o effect on t h e IH ex posu r e-in du ced r ise in MA P or in HR dem on st r a t in g t h a t t h e effect s of A n g block a de a r e du e t o a n t a g on ist -r ecept or in t er a ct ion s w it h in t h e PV N (Su pplem en t a l Fig u r e 1 A ). 2 nmol /h) or PD 1 2331 9 (C and D. A and C) and hear t r ate (B and D) i n Sham and IH ex posed r ats c hr oni c al l y i nf used w i th l osar tan (A and B.gov/pmc/articles/PMC3018235/ 3/11 .ncbi.0 1 ). ZD7 1 5 5 or PD1 2 3 3 1 9 bila t er a lly in t o t h e PV N. Fi gur e 3 Gr ouped data show i ng 1 2 hour av er age r ec or di ngs of mean ar ter i al pr essur e (MA P. P<0 . Fig u r e 5 sh ow s MA P a n d HR a t da y 7 a n d 1 4 in Sh a m a n d IH ex posed r a t s r eceiv in g ch r on ic in fu sion of sa lin e. ZD7 1 55 . losa r t a n : −9 ±4 m m Hg . Sim ila r t o t h e A T 1 r ecept or a n t a g on ist s. bu t ZD7 1 5 5 in fu sion in du ced a sig n ifica n t in cr ea se in HR com pa r ed t o t h e ot h er a n g iot en sin a n t a g on ist s (ZD7 1 5 5 : +2 1 ±9 bpm v s A -7 7 9 : −1 4 ±6 bpm . IH ex posu r e in du ced a g r a du a l in cr ea se in MA P pea k in g a t da y 1 4 . T h er efor e t h e differ en ces in MA P a n d HR bet w een g r ou ps do n ot a ppea r t o be du e t o differ en t lev els of a ct iv it y ... A -7 7 9 (2 nmol /h). P<0 .2 nmol /h) i nto the PV N . HR did n ot ch a n g e in a n y g r ou p..

2 0 0 5 . 2 0 0 8 ) t o m or e closely m im ic t h e ch a n g es in a r t er ia l g a ses a n d sy m pa t h et ic a ct iv a t ion ex per ien ced in sleep a pn ea .ncbi. . 2 0 0 8 ). 2 0 0 3 ) a n d en h a n ced sy m pa t h o-ex cit a t or y r espon ses t o ch em or eflex a ct iv a t ion a ft er IH ex posu r e (Gr een ber g et al. 1 9 9 4 . . T h u s t h e PV N a ppea r s t o be a n in t eg r a l pa r t of t h e cen t r a l n eu r on a l cir cu it r y pr ocessin g t h e sy m pa t h oex cit a t or y com pon en t of t h e per iph er a l ch em or eflex (Oliv a n et al. a s w ell a s A T 1. . 2 0 0 1 ).05. 2 0 0 7 ) a n d w e r epor t ed pr ev iou sly t h a t www. 2 0 0 5 ). 2 0 0 7 ) w it h ev en t u a l r eset t in g of sy m pa t h et ic t on e a n d a r t er ia l pr essu r e t o h ig h er set poin t s (Na r k iew icz et al. Reddy et al. Cu t ler et al. 2 0 0 3 . Cr u z et al. Sh ela t et al. . .31. T h is a lso in dica t es t h a t GA BA A m edia t ed in h ibit ion is fu n ct ion a l follow in g IH ex posu r e. A llen . T h e h y pot h a la m ic PV N is on e of t h e m a jor pr em ot or n eu r on cell g r ou ps con t r ibu t in g t o sy m pa t h et ic con t r ol of t h e ca r diov a scu la r sy st em a n d a r t er ia l pr essu r e (Da m pn ey . 1 9 9 2 a . 2 0 0 3 ) lea ds t o su st a in ed r eflex sy m pa t h et ic a ct iv a t ion (Na r k iew icz & Som er s. T h is is su ppor t ed by t h e obser v a t ion t h a t IH lea ds t o sen sit iza t ion a n d lon g -t er m fa cilit a t ion of t h e ca r ot id body r espon ses t o h y pox ia (Pen g et al. 2 0 0 4 ). V eer a sin g h a m & Ra iza da . . 1 9 9 4 . 2 0 0 1 . com bin in g h y pox ia w it h h y per ca pn ia m or e pr ofou n dly st im u la t es t h e sy m pa t h et ic n er v ou s sy st em (Mor g a n et al. 1 9 9 6 . 1 9 9 2 b. . . 2 0 0 6 . Pr ev iou s st u dies in dica t e RA S pept ides im por t a n t ly m odu la t e sy m pa t h et ic ou t pu t a n d t h a t a dy sfu n ct ion a l br a in RA S pa r t icipa t es in t h e pa t h og en esis of som e for m s of h y per t en sion (Da m pn ey et al. 1 9 9 5 . 1 9 9 0 . . 2 0 0 3 ). A T 2 (W r ig h t & Ha r din g . Ou r m odel of IH sim ila r ly com bin ed in cr ea sed in h a led CO 2 du r in g h y pox ia per iods t o m a in t a in eu ca pn ia in t h e fa ce of t h e h y pox ia -in du ced h y per v en t ila t ion (Sn ow et al. 2 0 0 7 ). . 2 0 0 1 . 2 ) a n g iot en sin -(1 -7 ) r ecept or s a lon g w it h bot h A T 1 a n d A T 2 a n g iot en sin II r ecept or s a r e n ecessa r y for t h is PV N-depen den t in cr ea se in A P. 1 9 9 8 ). 2 0 0 2 . . Flet ch er . Sleep a pn ea is ch a r a ct er ized by r ecu r r en t br ief cessa t ion s in br ea t h in g du r in g sleep w h ich r epea t edly r edu ces a r t er ia l blood ox y g en sa t u r a t ion (h y pox ia ) a ccom pa n ied by sm a ll in cr ea ses in cir cu la t in g CO 2 (W olk et al. block a de of n eu r ot r a n sm ission in t h e PV N in a n est h et ized r a t s a t t en u a t ed r en a l a n d ph r en ic n er v e r espon ses t o per iph er a l ch em or eflex a ct iv a t ion (Reddy et al. 2 0 0 5 ) w h ile per iph er a l ch em or eflex a ct iv a t ion in cr ea sed Fos ex pr ession in PV N n eu r on s (Cr u z et al. . 2 0 0 2 . Silv a et al. . McKin ley et al. Oliv a n et a l dem on st r a t ed t h a t bila t er a l elect r oly t ic lesion of t h e PV N a t t en u a t ed pr essor r espon ses t o ch em or eflex a ct iv a t ion in a w a k e r a t s (Oliv a n et al. 1 9 9 4 ). 2 0 0 1 ). Br a g a et al. . 1 9 9 8 . Dick et al. In a ddit ion . . Flet ch er . 2 0 0 4 ). 3 ) bot h A T 1 a n d A T 2 r ecept or s a ppea r t o r eg u la t e A P in Sh a m r a t s w h ile A n g (1 -7 ) r ecept or s on ly con t r ibu t e t o A P con t r ol a ft er IH. . T h e m ech a n ism s by w h ich IH ex posu r e lea ds t o h y per t en sion a r e n ot com plet ely u n der st ood. A lt h ou g h h y pox ia is t h ou g h t t o be t h e pr im a r y st im u lu s for in du cin g h y per t en sion in sleep a pn ea pa t ien t s a n d IH m odels. . . T h u s t h e in cr ea sed A P follow in g IH is m or e lik ely du e t o ex a g g er a t ed ex cit a t or y m ech a n ism s in t h e PV N r a t h er t h a n t o loss of GA BA A r ecept or fu n ct ion . . . Na r k iew icz & Som er s. 2 0 0 3 . 1 9 9 9 .2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… T h e m a in fin din g s in t h is st u dy w er e 1 ) PV N n eu r on s a ppea r t o m odu la t e IH-in du ced in cr ea ses in A P in r a t s. 2 0 0 0 ) a n d A n g -(1 -7 ) (Block et al. Oliv a n et al. . .nlm. .nih. .gov/pmc/articles/PMC3018235/ 4/11 . 2 0 0 8 ). 2 0 0 3 ) a n d Ma s r ecept or s (Beck er et al. . . 2 0 0 3 ). Flet ch er et al. 2 0 0 1 . A llen et al. . Pr a bh a k a r et al. Ka r a et al. Sev er a l st u dies h a v e su g g est ed h y pox ia st im u la t ion of ca r ot id body ch em or ecept or s (Sm it h et al. Fu r t h er m or e. 2 0 0 1 . Ion t oph or et ic a pplica t ion of A n g II or A n g -(1 -7 ) h a s a lso been sh ow n t o in cr ea se fir in g in PV N n eu r on s (A m bu h l et al. 2 0 0 3 . 1 9 8 8 ). . Beck er et al. . . . 2 0 0 7 ) in t h e PV N. Cu t ler et a l sh ow ed t h a t sy m pa t h et ic a ct iv a t ion st im u la t ed by h y pox ia com bin ed w it h eit h er h y per ca pn ia or eu ca pn ia in cr ea sed sy m pa t h et ic a ct iv it y m or e t h a n h y poca pn ic h y pox ia (Cu t ler et al. . Im m u n ocy t och em ica l st u dies h a v e iden t ified bot h A n g II (Eg li et al. T h e PV N m odu la t es SNA a n d A P r espon ses t o ch em or eflex a ct iv a t ion t h r ou g h bot h dir ect pr oject ion s t o t h e sy m pa t h et ic pr eg a n g lion ic n eu r on s in t h e spin a l cor d a n d v ia in dir ect sy n a pt ic r ela y s w it h t h e r ost r a l v en t r ola t er a l m edu lla (RV LM) a n d con n ect ion s w it h t h e n u cleu s t r a ct u s solit a r ii (NT S) (Ba doer . 1 9 9 8 . t h e effect of m u scim ol t o low er A P a n d HR in Sh a m a s w ell a s in IH r a t s r eflect s t h a t PV N n eu r on s a r e n or m a lly a ct iv e a n d con t r ol A P (Deca v el & V a n den Pol. . Pr a bh a k a r et al. X ie et al. . 2 0 0 7 ). bu t a ct iv a t ion of t h e sy m pa t h et ic n er v ou s sy st em a ppea r s n ecessa r y (Flet ch er et al.

2 0 0 2 ). 2 0 0 3 ).gov/pmc/articles/PMC3018235/ 5/11 . In pa t h oph y siolog ica l st a t es w it h elev a t ed sy m pa t h et ic disch a r g e fr om t h e PV N su ch a s con g est iv e h ea r t fa ilu r e (Sh ela t et al. . T h e in com plet e blood-br a in ba r r ier of t h e CV O (W r ig h t & Ha r din g . 2 0 0 5 ). 2 0 0 2 ) pa t h w a y s h a v e been r epor t ed. 2 0 0 5 ) su g g est A T 2 r ecept or s in t h e PV N ca n a lso m edia t e a sig n ifica n t por t ion of A n g II effect s slig h t ly differ en t fr om t h ose ex er t ed by A T 1 r ecept or s a s sh ow n by t h e g r ea t er fa ll in A P a t da y 1 4 in t h e Sh a m r a t s r eceiv in g t h e A T 1 r ecept or a n t a g on ist . Ba doer . w e obser v ed t h a t t h e A n g -(1 -7 ) r ecept or block er did n ot a ffect A P in Sh a m r a t s w h ile A T 1 r ecept or a n t a g on ist s in t h e PV N sig n ifica n t ly r edu ced a n d t h e A T 2 r ecept or a n t a g on ist t en ded t o r edu ce A P in Sh a m r a t s. 2 0 0 1 ). . a few r eg ion s. Pr ev iou s st u dies h a v e dem on st r a t ed t h a t t h e A n g pept ides pla y a n ex cit a t or y r ole in t h e PV N (A m bu h l et al. it did n ot a ffect A P (Silv a et al. 2 0 0 0 ). . . . Silv a et al. . . . 1 9 9 8 . T h u s t h e effect s on a r t er ia l pr essu r e of t h e differ en t a n t a g on ist s m a y h a v e occu r r ed t h r ou g h block a de of u n iqu e r ecept or s w h ich ea ch sepa r a t ely con t r ibu t e t o A P r eg u la t ion . . . Ot h er s h a v e sh ow n t h a t A T 1 r ecept or s in t h e PV N r eg u la t e bot h ba selin e A P (Zh u et al. In t h is st u dy . w it h especia lly h ig h den sit ies in t h e ca r diov a scu la r a n d sy m pa t h et ic r eg u la t or y pa r v icellu la r a r ea (Bla ir et al.05. A ddit ion a lly . Ca t o & T on ey . . 2 0 0 7 ). 2 0 0 5 ). 2 0 0 3 ). St r on g st a in in g for Ma s in bot h pa r v i a n d m a g n ocellu la r por t ion s of t h e PV N (Beck er et al. . T h ese fin din g s cor r obor a t e pr ev iou s dem on st r a t ion s t h a t A T 1 r ecept or s in t h e PV N con t r ibu t e t o A P con t r ol u n der n or m a l con dit ion s t h r ou g h t on ic a ct iv a t ion (Zh u et al. . 1 9 9 6 . 2 0 0 3 ). dir ect a ct iv a t ion of A n g -(1 -7 ) r ecept or s in t h e PV N in cr ea ses t h e fir in g r a t e of PV N n eu r on s (Sa n t os et al. A P did n ot ch a n g e sig n ifica n t ly in Sh a m a n im a ls r eceiv in g A -7 7 9 or PD1 2 3 3 1 9 . In a ddit ion . A lt er n a t iv ely t h er e m a y be fu n ct ion a l in t er a ct ion s bet w een t h e r ecept or s a s sh ow n in pr ev iou s dem on st r a t ion s of in t er a ct ion s bet w een t h ese r ecept or su bt y pes.nlm. Zh a n g et al. 2 0 0 4 ) a n d h y per t en sion (W eiss et al. A lt h ou g h a cu t e block a de of A n g -(1 -7 ) a n d A T 2 r ecept or s in n or m ot en siv e a n est h et ized r a t s dr a m a t ica lly r edu ced r en a l SNA in a pr ev iou s st u dy .. . In t h e pr esen t st u dy .2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… A n g II a n d A n g -(1 -7 ) a dm in ist er ed in t o t h e PV N in cr ea se RSNA a n d A P (Silv a et al. 1 9 9 1 ). .. . 2 0 0 5 ). . . .31. T h u s ca r diov a scu la r a ct ion s ex er t ed by A n g II in t h is r eg ion m a y be m ost ly m edia t ed by A T 1 r ecept or s bu t t h is st u dy a n d ou r pr ev iou s w or k (Silv a et al. 2 0 0 7 ). 1 9 9 4 . Zu ck er et al. Zu ck er et al. 2 0 0 5 ) a n d fu r t h er su g g est in g t h a t A T 2 r ecept or s in t h e PV N m a y a lso pla y a r ole in t on ic A P con t r ol. 2 0 0 2 . m u lt iple a n g iot en sin r ecept or s on PV N n eu r on s con t r ibu t e t o t h e v a som ot or r espon se in con sciou s r a t s. 2 0 0 1 . 2 0 0 1 ) a n d GA BA A (Zh a n g et al. 2 0 0 2 .. T h e PV N h a s a pr edom in a n ce of A T 1 r ecept or s. t h e ex cit a t or y effect s pr odu ced by A n g -(1 -7 ) in PV N n eu r on s ca n be block ed by A T 1 or A T 2 r ecept or a n t a g on ist s (A m bu h l et a l. V er y r ecen t ly . 1 9 9 2 ) a n d a fu n ct ion a l in t er a ct ion bet w een A n g -(1 -7 ) a n d A T 1 r ecept or s h a s been dem on st r a t ed in ot h er br a in r eg ion s (V on Boh len u n d Ha lba ch et a l. 2 0 0 3 ). A T 1 a n d A T 2 r ecept or s a r e 3 4 % h om olog ou s a n d h a v e h ig h a ffin it y for A n g II (St oll & Un g er . Silv a et al. . A lt h ou g h m ost br a in a r ea s ex pr ess on ly on e su bt y pe.nih. McKin ley et al. 2 0 0 1 ) or w h en PV N n eu r on s a r e disin h ibit ed (Ch en & T on ey . IH ex posu r e w a s sh ow n t o be a ssocia t ed w it h r edu ced n NOS ex pr ession in t h e PV N a n d a u g m en t ed A T 1 ex pr ession in cir cu m v en t r icu la r or g a n (CV O) n eu r on s pr oject in g t o t h e PV N (W eiss et al. . in clu din g t h e PV N. A llen et al. 2 0 0 2 . ex pr ess bot h (McKin ley et al. A llen . 1 9 9 8 . . A n g III a n d A n g -(1 -7 ) in t h e PV N ca n be block ed by a n A T 2 r ecept or a n t a g on ist (Felix et a l. 2 0 0 1 . bu t bot h a n t a g on ist s pr ev en t ed A P in cr ea ses in t h e IH r a t s a n d t h e www. it h a s been dem on st r a t ed t h a t t h e ex cit a t or y effect s pr odu ced by A n g II. 2 0 0 7 ). . For ex a m ple. 2 0 0 2 . 2 0 0 7 . T h u s a n g iot en sin r ecept or s a ppea r t o m odu la t e PV N n eu r on a l a ct iv it y u n der ba sa l a n d ex cit ed con dit ion s. 2 0 0 4 ) a n d dow n r eg u la t ion of in h ibit or y n NOS (Zh a n g et al.ncbi. T h u s t h e sim plest ex pla n a t ion for t h e cu r r en t fin din g s seem s t o be t h a t follow in g 1 4 da y s of IH ex posu r e. 1 9 9 4 ) w ou ld a llow PV N n eu r on s t o be st im u la t ed du r in g IH by A n g pept ides pr odu ced loca lly or deliv er ed by n eu r on a l pr oject ion s fr om t h e CV O w h ich a r e st im u la t ed by t h e cy clic h y pox ia (W eiss et al. 2 0 0 5 ) a n d t h e a u g m en t ed A P a n d RSNA obser v ed du r in g cen t r a l h y per osm ola r st im u la t ion (Ch en & T on ey . bot h ov er ex pr ession of A T 1 r ecept or s (Zu ck er . a r e con sist en t w it h A n g -(1 -7 ) r ecept or s a lso r eg u la t in g sy m pa t h et ic t on e or ig in a t in g in t h e PV N.

A lt h ou g h on ly dir ect m ea su r es of sy m pa t h et ic a ct iv it y ca n con fir m t h e su g g est ed ch a n g es in A n g r eg u la t ion of sy m pa t h et ic disch a r g es follow in g ex posu r e t o IH. t h ese obser v a t ion s su g g est t h a t u n der n or m a l con dit ion s. a ct iv a t ion of a n g iot en sin r ecept or s in t h e PV N a ppea r s n ecessa r y for in cr ea sed A P in t h is r a t m odel of sim u la t ed sleep a pn ea . 2 0 0 6 ) a n d A n g -(1 -7 ) a t t en u a t ed t h e pr essor effect of A n g II in t h e a n t er ior h y pot h a la m u s (Hoch t et al. befor e t h e in it ia t ion of ex posu r e pr ot ocols.05.gov/pmc/articles/PMC3018235/ 6/11 . 0 % CO 2). . Ha r la n Spr a g u e Da w ley ). t w o 3 0 -g a u g e m icr oin ject ion n eedles con n ect ed t o a pr im ed osm ot ic m in ipu m p (A lzet m odel 2 0 0 2 ) w er e in ser t ed bila t er a lly in t o t h e pa r a v en t r icu la r n u cleu s (PV N) u sin g a st er eot a x ic a ppa r a t u s a n d cem en t ed in t o pla ce.5 m m la t er a l t o t h e br eg m a . Eucapnic Intermittent Hypoxia Protocol Ra t s w er e h ou sed in Plex ig la s box es w it h fr ee a ccess t o food a n d w a t er a n d ex posed t o eit h er in t er m it t en t h y pox ia w it h CO 2 su pplem en t a t ion t o m a in t a in eu ca pn ia (IH. How ev er . 2 0 0 6 ). In a pr ev iou s st u dy in a n est h et ized r a t s.nlm. 5 % CO 2 t o pea k 2 1 % O 2. . n a dir 5 % O 2. A ft er 5 da y s of r ecov er y . A T 1 a n d per h a ps A T 2 r ecept or s m edia t e t on ic ex cit a t ion in PV N n eu r on s t o m odu la t e A P. 2 0 0 7 ). T h is ba la n ce m a y be a lt er ed in pa t h oph y siolog ica l con dit ion s su ch a s ch r on ic IH sin ce on ly block a de of A T 1 r ecept or s decr ea sed A P in Sh a m a n im a ls a n d IH r a t s below ba selin e. Ou r r esu lt s in con sciou s r a t s su g g est in g a n ex cit a t or y r ole for bot h A n g II a n d A n g -(1 -7 ) in t h e PV N follow in g IH su g g est t h e effect of cen t r a l a n g iot en sin s on sy m pa t h et ic a ct iv it y m ig h t depen d u pon t h e ba la n ce bet w een t on ic ex cit a t or y a n d in h ibit or y effect s on sy m pa t h et ic pr em ot or n eu r on s (Da m pn ey et al. . . . 2 0 0 5 ). A r den Hills.31. A ll a n im a l pr ot ocols w er e r ev iew ed a n d a ppr ov ed by t h e in st it u t ion a l a n im a l ca r e a n d u se com m it t ee of t h e Un iv er sit y of New Mex ico Hea lt h Scien ces Cen t er a n d con for m t o Na t ion a l In st it u t es of Hea lt h Gu idelin es for t h e Ca r e a n d Use of La bor a t or y A n im a ls. 2 0 0 2 . Clin ica l st u dies a lso su g g est t h e RA S is a ct iv a t ed in sleep a pn ea .8 m m post er ior a n d 0 . Telemeter implantation and PVN cannula placement Ra t s w er e in st r u m en t ed w it h blood pr essu r e t elem et r y dev ices (DSI m odel PA -C4 0 . bot h A n g -(1 -7 ) a n d A n g II r ecept or s in t h e PV N pa r t icipa t e in g en er a t in g t h e in cr ea sed A P. MN) u n der isoflu or a n e (2 %) a n est h esia . Experimental Procedures Ex per im en t s w er e per for m ed in m a le Spr a g u e-Da w ley r a t s (2 5 0 t o 3 0 0 g . A lt h ou g h ot h er m ech a n ism s m a y be r ecr u it ed t o pa r t icipa t e in t h e sy st em ic pr essor r espon se. 2 0 0 5 ) su g g est t h a t t h e differ en t a n g iot en sin r ecept or t y pes a ll r eg u la t e A P bu t t h r ou g h differ en t m ech a n ism s a n d u n der differ en t con dit ion s. Silv a et al. . block a de of A T 1 r ecept or s in t h e RV LM in cr ea sed sy m pa t h et ic a ct iv it y u n der h y pox ic con dit ion s (Sh er iff et al. a t a dept h of 7 . 0 % CO 2 ev er y 9 0 secon ds) or r oom a ir (Sh a m . T h er efor e. t h e a bilit y of t h e A n g -(1 -7 ) a n t a g on ist t o low er a r t er ia l pr essu r e in t h e IH r a t s a n d n ot in t h e Sh a m r a t s su g g est s t h is m ig h t be a n im por t a n t t a r g et for t a r g et ed ph a r m a colog ica l in t er v en t ion s. T h e ca t h et er por t ion w a s in ser t ed in t o t h e a bdom in a l a or t a t h r ou g h t h e fem or a l a r t er y a n d t h e t r a n sm it t er fix ed in t h e per it on ea l ca v it y . h ow ev er r a t s w er e con st a n t ly m a in t a in ed a t 2 1 % O 2.ncbi. T h e coor din a t es u sed w er e 1 .8 m m below du r a (Silv a et al. a llow in g 2 4 h ou r r ecor din g s of m ea n a r t er ia l pr essu r e (MA P) a n d h ea r t r a t e (HR). Perspectives Ou r r esu lt s su g g est sy m pa t h et ic pr em ot or n eu r on s in t h e PV N im por t a n t ly m edia t e in cr ea ses in A P in du ced by IH in r a t s. sa m e en v ir on m en t a l con dit ion s a s IH. t h e differ en t ia l effect s of t h e a n t a g on ist s com bin ed w it h pr ev iou s st u dies (Zh u et al.nih. T h e g a s com posit ion in side t h e www. a ft er IH ex posu r e.2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… A T 2 a n t a g on ist t en ded t o decr ea se A P in t h e Sh a m r a t s below t h a t in t h e IH r a t s t h r ou g h ou t t h e ex posu r e per iod su g g est in g t h a t a cu t e a n d ch r on ic effect s of Ma s a n d A T 2 r ecept or a ct iv a t ion m a y differ . T og et h er . Ra t s w er e a llow ed t o r ecov er for 2 m or e da y s.

T h is r esea r ch w a s su ppor t ed by FA PEMIG. 2 n m ol/h r . Statistical Analysis A ll da t a a r e ex pr essed a s m ea n ± SEM. and review of the resulting proof before it is published in its final citable form.bu t n ot m a s-r ecept or s in t h e PV N low er ed blood pr essu r e in Sh a m r a t s Ma s-r ecept or s on ly a ppea r t o r eg u la t e blood pr essu r e in pa t h olog ica l con dit ion s A n g iot en sin r ecept or s in t h e PV N a r e n ecessa r y for IH t o in cr ea se a r t er ia l pr essu r e Supplementary Material 01 Click h er e t o v iew . . Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. (162K. Specia l t h a n k s t o Dr . T h e ch osen fr equ en cy of a pn ea s w a s u sed t o m im ic m oder a t e sleep a pn ea . a s descr ibed pr ev iou sly (Silv a et al. . 2 0 0 5 ).gov/pmc/articles/PMC3018235/ 7/11 . available in PMC 2012 January 12. T h e dr u g s a dm in ist er ed w er e: A -7 7 9 (A n g -(1 -7 ) a n t a g on ist . Please note that during the production process errors may be discovered which could affect the content. The manuscript will undergo copyediting. PD1 2 3 3 1 9 (A T 2 r ecept or a n t a g on ist . Author manuscript. Ky a n A lla h da di for h is t ech n ica l a ssist a n ce a n d cr it ica l com m en t s. MA P a n d HR v a lu es a r e ex pr essed a s t h e a v er a g e of a 1 2 h ou r per iod t o m on it or diu r n a l v a r ia t ion in A P.nih. A ddit ion a l da t a ex pr essin g 2 4 h ou r a v er a g e is sh ow n in Fig u r e 5 . MA P a n d HR w er e r ecor ded con t in u ou sly a n d osm ot ic m in ipu m ps deliv er ed eit h er v eh icle or dr u g s bila t er a lly in t o t h e PV N (0 . a k in d g ift fr om Dr . Robson Sa n t os). Article information Brain Res.31. As a service to our customers we are providing this early version of the manuscript. ZD7 1 5 5 (A T 1 r ecept or a n t a g on ist . r a t s w er e deeply a n est h et ized w it h sodiu m pen t oba r bit a l (1 5 0 m g /k g i. A T 2.nlm. HL8 2 7 9 9 a n d a Resea r ch A lloca t ion s Com m it t ee g r a n t fr om UNM (NLK). a pow er fu l GA BA A a g on ist k n ow n t o r edu ce MA P w h en in ject ed a cu t ely in t o t h e PV N. losa r t a n (A T 1 r ecept or a n t a g on ist . 2 0 0 5 ) (Su pplem en t a l Fig u r e 1 ). Differ en ces bet w een g r ou ps w er e ev a lu a t ed u sin g t w o-w a y r epea t ed m ea su r es A NOV A follow ed by Bon fer r on i post -h oc t est .05. EPA g r a n t RD-8 3 1 8 6 0 0 1 . A ddit ion a lly .) a n d br a in s fix ed (pa r a for m a ldeh ey de 4 % a n d su cr ose 3 0 %) t o st a in for h ist olog ica l iden t ifica t ion of in ject ion sit es. 2 n m ol/h r ).2 n m ol/h r ). Du r in g t h e 1 4 da y s of IH ex posu r e.p. ICB. A t t h e en d of a ll pr ot ocols. and all legal disclaimers that apply to the journal pertain. 0 . 2 n m ol/h r ). Na Cl 0 . Research Highlights Block in g A T 1-. pdf) Acknowledgments A n a Qu ên ia Gom es da Silv a w a s a r ecipien t of a CNPq Ph D-fellow sh ip a t t h e Post -Gr a du a t ion Pr og r a m in Biolog ica l Scien ce: Ph y siolog y a n d Ph a r m a colog y .or m a s-r ecept or s in t h e PV N pr ev en t s IH-in du ced h y per t en sion Block in g A T 1. . www. Differ en ces w er e con sider ed sig n ifica n t for P<0 . w e com pa r ed t h e effect s of A n g a n t a g on ist s w it h t h ose ev ok ed by m u scim ol (2 0 pm ol/h r ). UFMG. NLK is a n Est a blish ed In v est ig a t or of t h e A m er ica n Hea r t A ssocia t ion .5 µl/h r ).T h e doses of dr u g s a dm in ist er ed w er e ba sed on t h e a bilit y of t h e sa m e doses t o a cu t ely low er eit h er blood pr essu r e or r en a l sy m pa t h et ic n er v e a ct iv it y in sim ila r ly pr epa r ed a n a est h et ized r a t s (Silv a et al. 2 0 0 5 ).0 5 . a n d t h e r edu ct ion in br ea t h in g ox y g en lev els w a s su fficien t t o in du ce h y pox ia w it h ou t pr om ot in g a r ou sa l a ft er a cclim a t iza t ion .9 % w a s u sed a s v eh icle sin ce a ll a dm in ist er ed dr u g s w er e pr epa r ed in sa lin e solu t ion .2013 CHRONIC INFUSION OF ANGIOTENSIN RECEPTOR ANTAGONISTS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS PREVE… ch a m ber s w a s con t r olled by t im ed solen oid sw it ch es oper a t in g 7 h r /da y du r in g t h e r a t s’ sleep per iod for 1 4 da y s a s descr ibed pr ev iou sly (A lla h da di et al.ncbi. typesetting.

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