MEDiCAL
JOURN
E v a M a r ia A u g u s t a B o e c k h H a e b is c h
Transderm al glyceryl trinitrate (nitroglycerin) in healthy
persons: acute effects on skin tem perature and
hem odynam ic orthostatic response
Pharmacology
Department
of the Instituto de Ciencias Biomedicas
of the Universidade de Slio Paulo, Brazil
In order to find an explanation for individual reactions to transderm al glyceryl trinitrate (G TN ) w e studied the skin tem perature and hem odynam ic reactions in 63 healthy persons. The data w ere obtained before and after the application of G TN and G lycerin (G L) placebo patches, during one hour. The skin tem perature w as m easured on both forearm s, the local (left sided) and system ic (right sided) reaction on G TN w as related to the skin fold and the calculated body fat content. The bilateral rise of skin tem perature and its duration w as higher and longer in obese than in lean persons m ainly in obese w om en. The U V induced therm o and the later phototherm o-reaction (E rythem a) w as reduced on the left forearm after the application of G TN and G L patches. The observed hem odynam ic G TN effect confirm ed know n postural reactions, such as decreased arterial pressure (i.\m A P
=
-2.9% ), increased heart rate (i.\H R=
+7,4% ) and aTc prolongation (i.\Q Tc = +4,9% ) in upright position. A n adverse drug effect w ith increased m ean blood pressure (i.\m A P=
+12% ) and increased heart rate (i.\H R=
+ 10.4% ) m ainly in supine position w as observed in 11% of the participants, but only in m en. S uch a reaction w as already described by M urell, 1879. Individual G TN effects w ere analyzed and related to habits and fam ily history. In m ale sm okers and in persons w ith hypertensive and diabetic close relatives, the hypotensive G TN effect w as accentuated in supine position. In the upright position the group w ith hypertensives in the fam ily presented a m oderate hypotensive reaction w ithout secondary tachycardia and the sm okers presented only a slightly increased heart rate. O ur observations suggest that individual reactions to transderm al glyceryl trinitrate (G TN ) w ith its active com ponent nitric oxide (N O ) depends on physiological conditions, related to endogenous vasoactive substances, m ainly the interaction w ith E D R F (the endogenous N O ) and the activity of the R enin-A ngiotensin S ystem .U N ITE R M S : Transderm al G lyceryl Trinitrate (G TN ). S kin tem perature. O rthostatic reaction. H ealthy persons.
W
illiamg ly cerin e"M u rellg iv en to frien d s,in 1 8 7 9 o b serv edan d o th er p erso n sth at "n itro -an d also tak en b y h im self in "six o r sev en m in u tes after an o ral d o se in creased th e p u lse p ressu re, h eart rate (H R ) an d th e sy sto lic arterial p ressu re (sA P ) an d th e d icro tic n o tch b ecam e m o re p ro m in en t" (1 ). W e b eliev e th at g ly cery l trin itrate (G T N ) n am ed at th at tim e as n itro g ly cerin , w as tested in h ealth y m en . T h isA d d r e s s f o r c o r r e s p o n d e n c e : E v a M a r ia A u g u s t a B o e c k h H a e b is c h R u a D a n ie l R o s s i, 1 6 4
S a o P a u lo / S P - B r a s il- C E P 0 2 0 1 9 - 0 1 0
o b serv atio n co n trasts w ith th e g en erally accep ted co n cep t th at G T N in n o rm al p erso n s d o es n o t alter b lo o d p ressu re an d h eart rate in su p in e p o sitio n , b u t m ay p ro v o k e a p o stu ral h y p o ten sio n w ith a seco n d ary "reflex " tach y card ia (2 ). W ith co n stan t, lo w o r h ig h p lasm a n itrate lev els, in d iv id u al reactio n s are k n o w n : fro m ab o lish ed (3 ), atten u ated (4 ) to o p p o site sy m p ath etic h em o d y n am ic d ru g effect w ith stim u latio n o f th e ren in -an g io ten sin sy stem (5 ). T h e in tro d u ctio n o f G T N p atch es, u sin g th e tran sd erm al ro u te o f ap p licatio n an d th u s av o id in g th e h ep atic d en itratio n o f tran sm u co sal ab so rp tio n is an attem p t to h alt th e d ev elo p m en t o f n itrate to leran ce w h ich cau ses d im in ish ed effect o n sy stem ic b lo o d p ressu re an d H R (6 ). T h e d ev elo p m en t o f n itrate to leran ce an d also th e w ith d raw al sy n d ro m e d ep en d s o n th e co n tin u o u s ex p o su re to n itrates, b u t
H A E B IS C H , E .M .A .B . - Transderm al glyceryl trinitrate (nitroglycerin) in healthy persons: acute effects on skin tem perature and hem odynam ic orthostatic response
M E T H O D S
S u b g r o u p N u m b e r ( nQ
) L O W ( k g ) F a t C o n te n t (% )
A to tal o f 6 3 h ealth y v o lu n teers (2 7 m en an d 3 6 w o m en ) w ere treated o n ce w ith tran s d erm al p atch es co n tain in g 1 0 m g o f G T N . In a seco n d tu rn , a to tal o f 2 1
(9 m en an d 1 2 w o m en ) receiv ed a g ly cerin (G L ) g au ze p atch as a p laceb o . V o lu n teers p erso n al d ata are g iv en as
th e m ean :t stan d ard d ev iatio n , fo r ag e: 3 4 .8 :t9 .9 y ears; fo r h eig h t: 1 6 1 .4 :t9 . 8 cm ; fo r b o d y w eig h t: 6 5 .3 :t 1 1 .9 k g ; an d fo r lean b o d y w eig h t (L B W ): 5 1 .9 :t8 .3 k g .
T h e L B W w as calcu lated acco rd in g to th e fo rm u la: E 2 x R , (E = h eig h t in cm ; R fo r m en = 0 .0 0 2 ; R fo r w o m en = O .O O 1 8 ) (1 0 ). T h e resu lts allo w ed th e calcu latio n o f th e p ercen tag e o f b o d y fat co n ten t acco rd in g to th e fo rm u la:
[B o d y w eig h t (k g ) - L ean b o d y w eig h t (k g )] / B o d y w eig h t (k g ).
A cco rd in g to th e calcu lated L B W an d % o f fat co n ten t th e 6 3 p articip an ts w ere classified in th ree su b g ro u p s:
effectiv e in relatio n to th e p atch size, th e d ru g release area, an d is larg ely u n affected b y sk in ch aracteristics o r p atch
lo catio n (8 ). G T N p atch es w ith su stain ed release p rep aratio n s, led to u n ifo rm p lasm a co n cen tratio n s b u t cau sed "in ter-in d iv id u al v ariatio n s" in h ealth y v o lu n teers o n h em o d y n am ic p aram eters, in d ep en d en t o f th e G T N d o se an d p lasm a co n cen tratio n (9 ). O th erw ise, co n tin u o u s
h ig h p lasm a co n cen tratio n s in d u ced co n tra reg u lato ry m ech an ism s as th e acti v atio n o f th e sy m p ath etic sy stem w ith v aso co n strictio n (5 ).
T o u n d erstan d th e acu te effect o f tran sd erm al G T N in h ealth y p erso n s w e an aly zed th e facto rs in v o lv ed in d ru g ab so rp tio n : th e sk in fo ld , b o d y fat an d sk in tem p eratu re. H em o d y n am ic resp o n se to G T N w as stu d ied b y th e o rth o static reactio n an d related to in d iv id u al v ariab les as sex , su b jectiv e reactiv ity (as h ead ach e),
sm o k in g h ab it an d fam ily h isto ry o f h y p erten sio n an d d iab etes in clo se relati v es.
2 1
8
39
1 1
S m o k e r s ( m o r e th a n H y p e r te n s io n D ia b e te s 1 5 c ig a r e tte s /d a y )
G T N tr e a te d ( n = 6 3 ) 2 4 G L tr e a te d ( n = 2 1 ) 1 2 G r o u p
T ran sd erm al p atch es o f G T N (N itrad iscR
,
Searle)
o f1 0 m g an d a g au ze co n tain in g 5 m l o f G ly cerin (G L ) w ere ap p lied d u rin g 6 0 m in u tes o n th e left fo rearm in n ersid e, o v er an area o f 1 5 .9 cm 2 an d 4 .5 cm o f d iam eter o f G T N p atch n ear th e cu b ital reg io n .
T h e fo llo w in g p aram eters w ere o b tain ed :
J)
T h esk in tem p eratu re w as m easu red w ith an electrical th erm o m eter in C elsiu s (O C ) o n b o th fo rearm s b efo re an d im m ed iately after d ru g ap p licatio n fo r o n e h o u r. F u rth er m easu rem en ts w ere tak en ju st after a U V -B irrad iatio n fo r fiv e m in u tes (6 5 m in u tes) an d fin ally after 1 2 5 m in u tes fro m th e b eg in n in g o f th e d ru g ap p licatio n T h e in ten sity o f U V -B in d u ced ery th em a o n b o th arm s w as o b serv ed 2 4 h o u rs later; 2 ) T h e h em o d y n am ic p aram eters w ere stu d ied in su p in e (1 0 m in u tes) an d u p rig h t
(2 -3
m in u tes) p o sitio n b efo re an dafter th e d ru g (G T N o r G L ) ap p licatio n s (6 0 an d 1 2 5
m in u tes). T h e sy sto lic (sA P ) an d d iasto lic (d A P )
arterial b lo o d p ressu res (m m -H g ) w ere reg istered b y th e au scu ltato ry m eth o d an d th e m ean arterial p ressu re (m A P ) calcu lated b y th e eq u atio n :
m A P = [(sA P - d A P ) / 3 ]
+
d A PF ro m th e E C G (lead II), th e H R (b p m ) an d th e Q T -in terv al (m s) w ere tak en an d co rrected to Q T c b y B azett fo rm u la (1 1 ).
T h e d o u b le p ro d u ct (D P ) w as calcu lated as D P = H R x sA P x
10-
2 .T ak en fro m a n o m o g ram (F ig .l), o n e v alu e w as u sed to ch aracterize th e o rth o static ratio (O R ) b ased o n th e d ifferen ce b etw een su p in e an d u p rig h t p o sitio n s fo r H R an d m A P . A g o o d h em o d y n am ic ad ap tatio n o n stan d in g p o sitio n reach ed v alu es clo se to 1 0 0 .
o b tain ed w as 9 .6 :t3 .6 m m . B ased o n th is p aram eter
th ree su b g ro u p s w ere fo rm ed : L ean w ith 6 .0 :tl.8 m m , in term ed iate w ith 9 .6 :t3 .6 m m an d o b ese w ith 1 2 .2 :t4 .4
m m .
In relatio n to sm o k in g h ab its an d h y p erten siv e o r
d iab etic clo se relati v es, all th e p articip an ts w ere classified as fo llo w s:
< 1 2 1 2 - 1 7
> 1 7 4 2 .3 :t2 .7
5 2 .6 :t2 .7 6 0 .7 :t2 .9 3 1
1 5
1 7
L e a n In te r m e d ia te O b e s e
9 7 5
S T A T IS T IC A L M E T H O D S
F ig u re 1 - N o m o g ra m u s e d to o b ta in a s in g le v a lu e c h a ra c te riz in g th e o rth o s ta tic re a c tio n (O R ). T h e O R is d e te rm in e d b y th e d iffe re n c e /). in s u p in e a n d u p rig h t p o s itio n fo r th e h e a rt ra te (H R ) a n d th e m e a n a rte ria l p re s s u re (m A P ). T h e s e p a ra m e te rs a re re la te d to re la tiv e v a lu e s (fro m 0 to 1 0 0 ) in d ic a tin g in d iv id u a l p e rfo rm a n c e .
F o r d iffe re n t v a ria b le s a d e sc rip tiv e a n a ly sis w a s
a p p lie d (B M D P -2 D ) a n d fo llo w e d b y B M D P -A M (1 2 ) to
d e te c t o u tlie rs. T h e se o u tlie rs c a rrie d so m e p a th o lo g ic a l
d a ta a n d w e re e lim in a te d fro m fu rth e r stu d ie s. T h e
e v a lu a tio n c o n tin u e d b y B M D P -2 D fo r th e G T N (n = 6 3 )
a n d G L (n = 2 1 ) g ro u p s re su ltin g in h o m o g e n e o u s g ro u p s
w ith n o rm a l lim it p a ra m e te rs. T h e sig n ific a n c e o f th e
c h a n g e s in th e se n se o f "a fte r" v e rsu s "b e fo re " o f a ll
p a ra m e te rs w a s a n a ly z e d b y S tu d e n t's t-te st fo r p a ire d
m e a su re m e n ts (p < 0 .0 5 ) (1 3 ).
T h e se c o n d p h a se in c lu d e d : th e re la tio n sh ip o f th e
g ro u p v a ria b le s a s sk in fo ld , a n d b o d y fa t c o n te n t to sk in
te m p e ra tu re o n b o th fo re a rm s; a n d , th e re la tio n sh ip o f th e
g ro u p v a ria b le s a s g e n d e r, sm o k in g h a b it, fa m ily
h y p e rte n sio n , fa m ily d ia b e te s a n d h e a d a c h e to th e G T N
e ffe c t o n h e m o d y n a m ic p a ra m e te rs (A P , H R , Q T c ) in
su p in e a n d u p rig h t p o sitio n , in c lu d in g th e e v a lu a tio n o f
th e o rth o sta tic re a c tio n (O R ).
G ly c e rin (G L ) p a tc h e s a p p lie d in 2 1 v o lu n te e rs, o n
th e le ft fo re a rm d id n o t a lte r th e im m e d ia te (6 0 m in .) a n d
p o ste rio r (1 2 5 m in .) sk in te m p e ra tu re . T h e G T N p a tc h e s
in 6 3 p a rtic ip a n ts, a lso a p p lie d d u rin g 6 0 m in . o n th e le ft
fo re a rm c a u se d a sig n ific a n t sk in te m p e ra tu re e le v a tio n
o n b o th a rm s (F ig . 2 ).
T h e U V -in d u c e d im m e d ia te th e rm o re a c tio n (sk in
te m p e ra tu re a fte r 6 5 m in .) a n d a lso th e la te r
p h o to th e rm o re a c tio n (E ry th e m a a fte r 2 4 h o u rs) w e re
a tte n u a te d a fte r th e p re v io u s a p p lic a tio n o f G L a n d G T N
p a tc h e s o n th e le ft fo re a rm .
C o m p a rin g th e sk in te m p e ra tu re o n b o th fo re a rm s
a fte r 6 0 a n d 1 2 5 m in . w e o b se rv e d th a t th e le ft sid e d e ffe c t
w a s d istin c t a n d p ro lo n g e d .
T h e le ft sid e d sk in te m p e ra tu re o f p e rso n s w ith a
1 3 .2 m m sk in fo ld (n = 1 7 ) w a s h ig h b o th a fte r 6 0 a n d 1 2 5
m in . in 3 .2 a n d 3 .6 % w h e n c o m p a re d w ith v a lu e s o b ta in e d
"b e fo re ". T h e rig h t sid e d e le v a tio n o f th e sk in te m p e ra tu re
w a s sm a lle r b u t a lso p ro lo n g e d (2 .6 % a fte r 1 2 5 m in .).
A fte r th e a p p lic a tio n o f th e G T N p a tc h e s, o b e se p e rso n s
w ith m o re th a n 1 7 % o f fa t c o n te n t, sh o w e d a d istin c t
e le v a tio n o f th e le ft sid e d sk in te m p e ra tu re . T h is
o b se rv a tio n w a s c le a rly se e n in m e n ; o th e rw ise , o b e se
w o m e n h a d a g re a te r a n d lo n g e r e le v a tio n o f th e rig h t sid e d
sk in te m p e ra tu re th a n o b e se m e n . (T a b le I)
A c o m p a ra ti v e stu d y o f G L a n d G T N e ffe c ts re v e a le d
th a t G ly c e rin (G L ) d id n o t a lte r th e a rte ria l p re ssu re , th e
h e a rt ra te (H R ) a n d th e Q T c d u ra tio n o b ta in e d fro m th e
E C G (F ig 3 . a n d T a b le II).
GTN effect on hemodynamic-orthostatic
reaction
GTN effect on skin temperature
R E S U L T S
F o r v a lu e s o b ta in e d "b e fo re " a n d "a fte r" th e
tra n sd e rm a l a p p lic a tio n o f G T N in c o m b in a tio n o f th e .
v a ria b le s o f th e su b g ro u p s, th e sta tistic a l m o d e l u se d w a s
o n e o f th e ty p e "sp lit-p lo t" (1 4 ). S ig n ific a n c e o f 5 % is
g iv e n fo r p o sitiv e in te ra c tio n "b e fo re " a n d "a fte r" in a ll
v a ria b le s a n d th e ir c o m b in a tio n s.
F o r th e sk in te m p e ra tu re th e re p e titio n in c lu d e d e ig h t
le v e ls d u e to sig n ific a n t in te ra c tio n s w ith in te rv a ls o f
c o n fid e n c e fo r m u ltip le c o m p a riso n b y th e B o n fe rro n i
M e th o d (1 4 ).
Ii H R :s u p in e / u p rig h t 0 -7 p o s itio n
8 -1 4
-1 0 -IS -2 0
-S o
Ii m A P : s u p in eIu p rlQ h t p o s itio n
.S 8 0
2 0
10
70
5 0
4 0
90
60
1 0 0
H A E B IS C H , E .M A B . - T ra n s d e rm a l g ly c e ry l trin itra te (n itro g ly c e rin ) in h e a lth y p e rs o n s : a c u te e ffe c ts o n s k in te m p e ra tu re a n d h e m o d y n a m ic o rth o s ta tic re s p o n s e
Left F orearm R ight F orearm
n
B efore A fter 60 65 125 m in B efore A fter 60 65 125 m inG lycerin 21 32.3 32.5 35.4* 32.3 32.1 32.3 35.8* 32.1
(G L) :t1.2 :t1.1 :t1.1 :t1.2 :t1.2 :t1.0 :to.9 :t1.1
~ % + 0.4 + 9.4* :to.0 + 0.5 + 11.4* + 0.0
N itroglycerin 63 31.1 31.9* 34.2* 31.7 31.1 31.4* 34.6* 31.4
(G T N ) :t1.1 :t1.0 :t1.3 :t1.2 :t1.1 :t1.2 :t1.6 :t1.2
~ % + 2.3* + 9.7* + 1.8* + 1.1 * + 11.4* + 0.9*
N itroglycerin S kin F old ~ %
6.0:t1.8 m m 31 + 1.7 + 7.5 + 1.3 + 0.9 + 8.7 + 0.2
9.6:t3.6 15 + 2.4 + 11.7 + 0.8 + 1.0 + 14.2 -0.4
13.2:t4.4 17 + 3.2 + 11.1 + 3.6 + 1.5 + 12.4 + 2.6
B ody F at and G ender~ %
< 12%
~
18 + 0.9 + 4.8 -3.2 + 0.8 + 7.8 -1.312 - 17%
~
8 + 2.1 + 6.8 + 1.3 + 2.1 + 9.8 + 0.8> 17%
~
10 + 2.5 + 11.4 + 2.4 + 2.6 + 10.4 + 1.9< 12%
cJ'
13 + 1.4 + 7.7 + 2.3 + 1.0+ 8.9 + 2.1
12 - 17%
cJ'
6 + 2.4 + 8.7 + 1.6 + 1.5 + 10.7 + 1.0> 17%
cJ'
8 + 3.4 + 10.4 + 1.9 + 1.6 + 10.1 -0.1(*)
=
Significance p<0.05
In a ll v o lu n te e rs (n = 6 3 ) a s ig n ific a n t G T N e ffe c t
a p p e a re d in th e s u p in e b o d y p o s itio n 6 0 m in u te s a fte r th e
p a tc h a p p lic a tio n w ith o n ly a s m a ll d e c re a s e in th e a rte ria l
p re s s u re (-1 .8 % ); in th e u p rig h t p o s itio n , G T N p a tc h e s
c a u s e d a s ig n ific a n t d e c re a s e o f th e s y s to lic (-3 .1 % ) a n d
d ia s to lic (-3 .2 % ) p re s s u re s a n d a n in c re a s e in h e a rt ra te
(+ 7 .4 % ), w h e n c o m p a re d to " b e fo re " . C o n s e q u e n tly th e
o rth o s ta tic re a c tio n (O R ) w a s re d u c e d in 8 % . T h e Q T c
d u ra tio n fro m th e E C G w a s p ro lo n g e d fro m 0 .4 0 6 0 :t0 .0 3
m s " b e fo re " to 0 .4 2 6 0 :t0 .0 4 m s (p < O .O S ) " a fte r" th e G T N
a p p lic a tio n , in d ic a tin g a s ig n ific a n t p ro lo n g a tio n o f 4 .9 %
(T a b le
ill).
T h e p ro lo n g a tio n o f th e Q T c in te rv a l w a s a ls o fo u n d
in s u p in e p o s itio n , b u t o n ly in m e n (n = 2 7 ), re g a rd le s s o f
c o m p la in s o f G T N in d u c e d h e a d a c h e .
D iffe re n t g ro u p s p re s e n te d s ig n ific a n t a lte re d
o rth o s ta tic re a c tio n (O R ) in a ra n g e o f -6 .6 to -1 4 .1 % re la te d
to th e s itu a tio n " b e fo re " . T h e O R w a s n e g a tiv e (-8 .0 % )
in th e g ro u p w ith a p o s itiv e fa m ily h is to ry o f h y p e rte n s io n
a n d d ia b e te s a n d a ls o in m a le s m o k e rs . In th e s e g ro u p s th e
G T N p a tc h e s p ro v o k e d in th e s u p in e p o s itio n a s ig n ific a n t
d e c re a s e in a rte ria l p re s s u re (s A P a n d d A P ). In th e u p rig h t
p o s itio n , o n ly in th e g ro u p w ith h y p e rte n s iv e s in th e fa m ily
(n = 3 9 ) a n d m a le s m o k e rs (n = IS ) w e o b s e rv e d a c le a r
h y p o te n s iv e re a c tio n . In th is b o d y p o s itio n a ta c h y c a rd ia l
re a c tio n b u t w ith o u t h y p o te n s io n w a s s e e n in th e g ro u p w ith
d ia b e te s in c lo s e re la tiv e s .
M e n (n = 7 ) w h o p re s e n te d h e a d a c h e a fte r th e th e
a p p lic a tio n o f G T N p a tc h e s d u rin g 6 0 m in . re s p o n d e d
d iffe re n tly : in th e s u p in e p o s itio n , w ith a in c re a s e d
s y s to lic p re s s u re (+ 2 3 % ), w ith a d e c re a s e d d ia s to lic
p re s s u re (-1 0 .4 % ) a n d a p ro lo n g e d Q T c in te rv a l (+ S .4 % );
in u p rig h t p o s itio n , o n ly a d e c re a s e d d ia s to lic p re s s u re
(-1 0 .4 % ) a n d a in c re a s e d h e a rt ra te (R R ) (+ 1 7 .7 % ) w a s
o b s e rv e d .
S ao P aulo M edical Journal/R P M 113(5): 973-982,1995 H A E B IS C H , E .M .A .B . - T ransderm al glyceryl trinitrate (nitroglycerin) in healthy persons:
9 7 7
D IS C U S S IO N
G T N effect on skin tem perature
O n ly th e G T N p a tc h e s a n d n o t th e G L (p la c e b o ) p a tc h e s c a u s e d a s ig n ific a n t e le v a tio n o f th e s k in te m p e ra tu re o n b o th a rm s . T h is o b s e rv a tio n s u g g e s ts a lo c a l (le ft s id e d ) a n d a s y s te m ic (rig h t s id e d ) v a s o d ila tin g e ffe c t. T h e lo c a l a s w e ll a s th e in itia l (6 0 m in .) a n d la te r (1 2 5 m in .) G T N e ffe c t o n s k in te m p e ra tu re w a s a c c e n tu a te d w h e n c o m p a re d w ith th e s y s te m ic e ffe c t.
E a rlie r s tu d ie s h a d a ls o s h o w n th a t th e s u b lin g u a l n itro g ly c e rin in n o rm a l s u b je c ts (n = ll) in c re a s e d th e fo re a rm b lo o d flo w , lo w e re d th e fo re a rm v a s c u la r re s is ta n c e d u e to a re d u c e d v e n o u s to n e . T h e m e a n a rte ria l p re s s u re (m A P ) d e c lin e d s lig h tly (1 5 ).
A n U V in d u c e d th e rm o re a c tio n w a s u s e d to d iffe re n tia te a lte ra tio n s o f th e s k in te m p e ra tu re d u e to c a p illa ry o r v a s c u la r d ila tio n . T h e U V in d u c e d e ry th e m a w a s e v id e n t o n th e rig h t a rm a n d p a le o r n o t v is ib le o n th e le ft a rm , in d ic a tin g a n in h ib itio n o f th e lo c a l U V e ffe c t a fte r p re v io u s ly a p p lie d G L a n d G T N p a tc h e s . T h is o b s e rv a tio n m a y b e re la te d to a k n o w n in h ib itio n o f h e p a rin a c tiv ity d u e to g ly c e ry ltrin itra te (G T N ) (1 6 , 1 7 ). A n
in te ra c tio n o f G L a n d G T N w ith s tim u la n ts w h ic h re le a s e s h e p a rin a n d a ls o h is ta m in m a y b e c o n s id e re d . G T N a s a n in h ib ito r o f h e p a rin a c tiv ity m a y a ls o d e c re a s e th e U V in d u c e d h is ta m in e rg ic re a c tiv ity in th e s k in .
L o c a l fa c to rs m a y fa c ilita te th e d ru g a b s o rp tio n a n d in flu e n c e th e G T N e ffe c t. In o b e s e m e n a n d w o m e n , th e lo c a l a n d s y s te m ic d ru g e ffe c t o n s k in te m p e ra tu re is h ig h e r. In p e rs o n s w ith a g re a te r s k in fo ld a n d a g re a te r b o d y fa t c o n te n t w e o b s e rv e d a g re a te r lo c a l, a n d a m o d e ra te s y s te m ic e le v a tio n o f th e s k in te m p e ra tu re , w h e n c o m p a re d to le a n p e rs o n s . A p p ro x im a te ly tw o h o u rs (1 2 5 .m in .) a fte r th e a p p lic a tio n o f th e G L p a tc h e s a n d U V a p p lic a tio n th e s k in te m p e ra tu re re tu rn e d to th e v a lu e s o b ta in e d " b e fo re " . A fte r G T N p a tc h e s a n d U V irra d ia tio n th e s k in te m p e ra tu re re a c h e d th is le v e l o n ly in le a n w o m e n a n d o b e s e m e n ; th e G T N e ffe c t in th e s e g ro u p s is a b b re v ia te d .
T h e tra n s d e rm a l a b s o rp tio n o f G T N , a lip o p h y lic c o m p o u n d , s e e m s to b e h ig h e r in o b e s e p e rs o n s . In o b e s e w o m e n th e re m a y b e a re d is trib u tio n o f th e d ru g , a s k n o w n to o c c u r w ith b a rb itu ra te s , w h ic h e x p la in s th e p ro lo n g e d e ffe c t o n s k in te m p e ra tu re n o t s e e n in le a n w o m e n . A s h o rt d ru g e ffe c t w a s o b s e rv e d in o b e s e m e n ; a ra p id b re a k d o w n a n d in a c tiv a tio n o f th e d ru g , o r m o re lik e ly , a c o u n te ra c tin g v a s o c o n s tric to r G T N e ffe c t m a y b e re s p o n s ib le fo r th is e ffe c t.
T a b le II
N itr o g ly c e r in - H e m o d y n a m ic p a r a m e te r s o f g r o u p s
B e fo re / A fte r S u p in e P o s itio n (1 0 m in ) U p rig h t p o s itio n (2 - 3 m in )
~ % n s A P d A P m A P H R d P Q T c s A P d A P m A P H R d P Q T c O R
A ll p e rs o n s 6 3 -1 .8 * -1 .6 -1 .7 * -0 .9 -2 .8 -0 .5 -3 .1 * -3 .2 * -2 .9 * + 7 .4 * + 4 .4 * + 4 .9 * -8 .0 * o F . h y p o 2 4
+ F . h y p o 3 9 -4 .4 * -3 .5 * -4 .8 * -5 .3 * -4 .4 * -4 .8 * + 5 .7 * -8 .0 *
o F . d ia b . 4 2 -1 4 .1 *
+ F . d ia b . 2 1 -6 .3 * -4 .8 * -4 .9 * 9 .6 * + 8 .9 * -6 .6 *
o S m o k e rs 3 9 + 7 .5 *
+ S m o k e rs 2 4 + 8 .5 * + 6 .2 *
d " S m o k e rs 1 5 -8 .3 * -6 .8 * -7 .2 * -9 .5 *
o H e a d a c h e 4 5 -2 .1 * -6 .4 *
+ H e a d a c h e 1 8 -1 2 .0 *
d " 0 H e a d a c h e d " 2 0 -4 .8 * + 3 .6 *
d " + H e a d a c h e d " 7 + 2 3 .1 * + 1 8 .7 * + 1 1 .8 * + 1 0 .4 * + 5 .4 * + 1 0 .4 * + 1 7 .7 * + 1 7 .5 *
sA p, dA p, m A P
=
systolic, diastolic, m ean arterial blood pressure (m m H g); H R=
heart rate (bpm ); D P=
double product; Q T c=
corrected systolic interval;O R
=
orthostatic reaction; 0 %=
percent difference related to before values; (* ) = significance p< 0.05.H A E B IS C H , E .M .A .B . - T ra n s d e rm a l g ly c e ry l trin itra te (n itro g ly c e rin ) in h e a lth y p e rs o n s :
a c u te e ffe c ts o n s k in te m p e ra tu re a n d h e m o d y n a m ic o rth o s ta tic re s p o n s e
-3 6
o -3 5 o
'l \ \
\ \
\ \
\ \
\
---j
\J
j
•~
•t.
•• --- •t.
B E F O R E I 6 0 6 5 1 2 5 m in B E F O R E 6 0 6 5 1 2 5 m in A F T E R Il!J L Y C E R IN U v A F T E R U V _
- - - .----. 2 4 h : P A L E - E R Y T H E M A ----. 2 4 h : E R Y T H E M A N IT R A D IS C 1 0 m R (N D )
- 3 1
-33
z
~ -3 2
F ig u re 2 - S k in te m p e ra tu re (Q C ) m e a s u re d o n b o th fo re a rm s , b e fo re a n d 6 0 , 6 5 a n d 1 2 5 m in u te s a fte r le ft s id e d g ly c e rin (G L ) o r n itro g ly c e rin (G T N ) a p p lic a tio n .
GTN effect on
hemodynamic-orthostatic
reaction
O u r resu lts o b tain ed fro m 6 3 h ealth y m id d le ag ed p erso n s co n firm k n o w n acu te G T N effects (1 8 , 9 ). In th e stan d in g p o sitio n , th e d ecrease o f th e arterial b lo o d p ressu re w ith in creased h eart rate (H R ) resu lted in a red u ced p erfo rm an ce o f th e o rth o static reactio n (O R ) n o t o b serv ed after ap p licatio n o f G L p atch es. A n eg ati v e o rth o static reactio n (O R ) in d icates a m o d erate G T N effect w ith h y p o ten sio n an d tach y card ia. T h e sam e resu lt (-8 % ), as th e m ean v alu e fro m all v o lu n teers, w as also o b serv ed in th e g ro u p w ith a p o sitiv e fam ily h isto ry o f h y p erten sio n , w h ere in b o th b o d y p o sitio n s th e arterial b lo o d p ressu re w as d ecreased b u t o n ly in u p rig h t p o sitio n th e h eart rate in creased .
G T N in creases th e p erip h erical b lo o d flo w red u cin g th e v en o u s to n e (1 5 ); w ith lo w G T N co n cen tratio n s th e v en o u s d ilatatio n p red o m in ates o v er th at o f arterio les (1 9 ). A G T N in d u ces p o stu ral h y p o ten sio n d u e to "v en o u s p o o lin g ", en h an ces th e activ ity o f b aro recep to rs, lead in g to a seco n d ary "reflex " ch an g e o f th e h eart rate (H R ) b y a sy m p ath etic d isch arg e. S im u ltan eo u sly an ad ren erg ic stim u latio n o f th e left stellate g an g lio n , resp o n sib le fo r th e "lo n g Q T sy n d ro m e"
(20Y
m ay ex p lain th e Q T c p ro lo n g atio n after G T N , as rep o rted earlier (2 1 ). S u p p o sin g th e stim u latio n o f th e left stellate g an g lio n d u eto G T N is co rrect an d resp o n sib le fo r th e Q T c p ro lo n g atio n th en th e m en stu d ied , resp o n d ed to G T N w ith an au g m en ted sy m p ath etic d isch arg e.
In h ealth y p erso n s, a p rev io u s in d iv id u al p h y sio lo g ical co n d itio n m ay ex p lain th e d ifferen ces in th e d ru g effect.
In th e g ro u p w ith a p o sitiv e h isto ry o f d iab etes in th e fam ily an d also in m ale sm o k ers, G T N p atch es p ro v o k ed in th e su p in e p o sitio n , a clear h y p o ten siv e reactio n an d in u p rig h t p o sitio n , a tach y card ial resp o n se, w ith o u t h y p o ten sio n .
In d i v id u al an d ad v erse resp o n ses to o n e sm all d o se o f tran sd erm al ap p lied G T N m ay b e d u e to in teractio n s o f en d o g en o u s v ersu s ex o g en o u s v aso d ilato rs, n itric o x id e (N O ) (2 2 ,2 3 ), en d o th eliu m d eriv ed relax in g facto r (E D R F = N O ) v ersu s co n tractin g facto rs (E D C F ) (2 4 ) an d en d o g en o u s v aso activ e su b stan ces (2 5 ) an d also th e ren in -an g io ten sin sy stem (5 ,2 6 ).
N itric o x id e (N O ) as an ex o g en o u s v aso d ilato r, is d eriv ed fro m G T N , n am ed n itro g ly cerin . G T N is m etab o lized in th e p resen ce o f th e su lfid ry l g ro u p (S H ) to
,
n itric o x id e (N O ) in th e v ascu lar sm o o th m u scle cells. T h e sm o o th m u scle relax in g facto r is cy clic g u an o sin e 3 '5 ' m o n o p h o sp h ate (cG M P ) p ro d u ced b y th e activ atio n o f th e S H co n tain in g -en zy m e, th e g u an y late-cy clase (2 7 ). T h e cG M P is th e m ed iato r fo r th e ex o g en o u s N O an d also th e9 7 9
F ig u r e 3 - H e m o d y n a m ic p a r a m e t e r s , s y s t o lic , d ia s t o lic a n d m e a n a r t e r ia l b lo o d p r e s s u r e ( s A P ; d A P ; m A P ) in m m - H g , h e a r t r a t e ( H R ) in b p m , a n d Q T c in t e r v a l in m s a r e g iv e n a s m e a n v a lu e s w it h t h e ir s t a n d a r d d e v ia t io n , b e f o r e a n d 6 0 m in u t e s a f t e r a t r a n s d e r m a l n it r o g ly c e r in ( G T N ) o r g ly c e r in ( G L ) a p p lic a t io n .
1 0 0
L
*
~
m A P
....•
9 0
&---..1
b---.l
L
- 1 ~d A P
8 0
l- _ _ _ _ _
- !
l- - - _ J
b p m
~
HR
8 0r---i
7 0m . 0 . 4 3
~
7
a T e
0 . 4 2
0 . 4 1
0 . 4 0
B e f o r . A f t e r B . f o r e A f t . r ( 6 0 m in l ( 6 0 m in l
0 - - - 0 G L Y C E R I N
---....
N I T R A D I S C 1 0 m q Re n d o g e n o u s E D R F = N O in d u c e d s m o o th m u s c le r e la x a tio n ( 2 2 ) .
T h e e n d o th e liu m d e r iv e d r e le a s in g E D R F ( = N O ) in te r a c ts w ith th e m o d u la tio n o f th e v a s c u la r r e a c tiv ity b y o th e r e n d o g e n o u s v a s o a c tiv e s u b s ta n c e s ( 2 5 ) . I t h a s b e e n e x p e r im e n ta lly p r o v e d th a t th e e n d o th e lia l c e lls h a v e th e c a p a c ity to in a c tiv a te n o r a d r e n a lin , s e r o to n in a n d b r a d y k in in , w h e r e a s p r o s ta g la n d in f o r m a tio n is e n h a n c e d ( 2 6 ) . O th e r w is e n itr o g ly c e r in , th e e x o g e n o u s N O in d u c e s th e p r o d u c tio n o f p r o s ta c y c lin b y h u m a n e n d o th e lia l c e lls ( 2 7 ) .
T h e a c tiv a tio n o f c G M P b y n ltn c o x id e is c o m p e titiv e . T h e e n d o th e liu m d e r iv e d N O is a n in h ib ito r o f th e G T N d e r iv e d N O . A r e d u c e d E D R F r e le a s e lik e u n d e r p a th o lo g ic a l c o n d itio n s , f a ile s to in h ib it th e e x o g e n o u s N O a c tiv ity o n g u a n y la te c y c la s e , th u s p o te n c ia tin g th e G T N e f f e c t. I n h e a lth y y o u n g p e o p le , d u e to a N O c o m p e titio n , th e G T N d e r iv e d N O a c tiv ity m a y b e r e d u c e d ( 2 5 ) .
T h e in te r a c tio n o f th e v a s o d ila tin g G T N d e r iv e d " e x o g e n o u s " n itr ic o x id e ( N O ) a n d th e e n d o th e liu m d e r iv e d " e n d o g e n o u s " f a c to r ( E D R F = N O ) is im p o r ta n t b u t e x tr a r e n a l r e n in r e le a s e c o n tr o lle d b y d ie ta r y p o ta s s iu m m u s t b e c o n s id e r e d ( 2 8 ) .
T h e r e n in - a n g io te n s in s y s te m is in v o lv e d in h e m o d y n a m ic r e g u la tio n a s c a n b e s e e n in th e in te r a c tio n o f G T N a n d C a p to p r il ( 2 9 ) . C a p to p r il, a c o m p o u n d c o n ta in in g a s u lp h y d r y l g r o u p in h ib its th e a n g io te n s in c o n v e r tin g e n z y m e ( A C E ) a n d a ls o th e b r e a k d o w n o f b r a d y k in in . C a p to p r il r e v e r ts n itr a te to le r a n c e p r o b a b ly d u e to a n a c tiv a tio n o f th e S H - c o n ta in in g g u a n y la te c y c la s e
( 3 0 ) .
L o w a s w e ll a s a h ig h r e n in a c tiv ity m e d ia te d b y a n g io te n s in , m o d if ie s th e a d r e n a l c o r te x s e n s itiv ity le a d in g to h y p e r - o r h y p o te n s io n ( 3 1 ) . W ith a s u p p o s e d r e d u c e d a d r e n a l c o r te x s e n s itiv ity d u e to h ig h r e n in a c tiv ity , th e G T N in d u c e d h y p o te n s io n is a c c e n tu a te d a s s e e n in m a le s m o k e r s a n d p e r s o n s w ith h y p e r te n s iv e a n d d ia b e tic c lo s e r e la tiv e s .
W e o b s e r v e d th a t th e tr a n s d e r m a l G T N p r o v o k e d a m a in ly p o s tu r a l h y p o te n s io n in 8 9 % a n d a h y p e r te n s iv e r e a c tio n in 1 1% o f a ll p a r tic ip a n ts . I n th e s a m e v o lu n te e r s w h o p a r tic ip a te d in a n e a r lie r c lin ic a l s tu d y ( 3 2 ) a n d a ls o in th is s tu d y w e o b s e r v e d lo w p o ta s s iu m ( K + ) le v e l in p la s m a a s w e ll a s a n o r th o s ta tic h y p o d ia s to lic h y p o te n s io n ( 3 3 ) . T h e a d v e r s e p a r a d o x a l h y p e r te n s iv e G T N e f f e c t w a s o n ly s e e n in m e n a n d w a s q u ite s im ila r to th e e f f e c t d e s c r ib e d b y M u r r e l in 1 8 7 9 , a f te r o r a l n itr o g ly c e r in d o s e s ( 1 ) . T h e m e n w h o r e s p o n d e d to G T N w ith a h e a d a c h e h a d a te n d e n c y to a n e v id e n t a c tiv ity o f v a s o a c tiv e s u b s ta n c e s ( s e r o to n in , h is ta m in , b r a d ik in in a n d o th e r s ) a s s o c ia te d w ith a s y m p a th e tic r e a c tio n c o m p a tib le w ith a " lo w r e n in h y p e r te n s io n " . T h e g r e a te r g r o u p w ith a G T N in d u c e d p o s tu r a l h y p o te n s io n m a y h a v e a n u n d e r ly in g " h ig h r e n in " a c tiv ity . D ie ta r y p o ta s s iu m h a s a ls o a n in f lu e n c e o v e r th e r e n in r e le a s e ( 2 8 ) a n d m a y b e o n e o f th e d e te r m in in g f a c to r s f o r in d iv id u a l r e a c tio n s to G T N ( f ig . 4 ) . C o u n te r r e g u la to r y n e u r o h u m o r a l f a c to r s a n d m e c h a n is m s s u c h a ~ e n h a n c e d c a te c h o la m in a c tiv ity a n d s tim u la tio n o f th e r e n in a n g io te n s in s y s te m m a y a ls o b e in v o lv e d in th e v a r ia b ility o f n itr a te to le r a n c e ( 3 4 ) .
B O D Y - P O S I T I O N S U P I N E i i U P R I G H T
L : : J
c :
b..__---l
&-_---1
1 1 0 1 2 0 m m H q
1 3 0
s A P
H A E B f S C H , E . M A B . -T r a n s d e r m a l g ly c e r y l t r in it r a t e ( n it r o g ly c e r in ) in h e a lt h y p e r s o n s : a c u t e e f f e c t s o n s k in t e m p e r a t u r e a n d h e m o d y n a m ic o r t h o s t a t ic r e s p o n s e
R E N IN R E L E A S E
L O W R E N IN
A C T IV IT Y
t S E N S IT IV IT Y
A D R E N A L C O R T E X
N O P O S T U R A L
H Y P O T E N S IO N
A N G IO T E N S IN I I
G T N
h
N IT R O G L Y C E R IN ~
R - O - N 0 2 ~
I~
N O
H E M O D Y N A M IC
R E A C T IO N S
H IG H R E N IN
A C T IV IT Y
+
S E N S IT IV IT Y A D R E N A L C O R T E XE N D O G E N O U S V A S O A C T IV E S U B S T A N C E S
t
E D R F ( N O )
F ig u r e 4 - In d iv id u a l c o n d itio n s s u c h a s d ie ta r y p o ta s s iu m ( K + ) a n d b a s ic a lly d iffe r e n t a c tiv ity o f e n d o g e n o u s v a s o a c tiv e s u b s ta n c e s m a y b e r e s p o n s ib le fo r a m o d ifie d g ly c e r y ltr in itr a te ( G T N ) d r u g e ffe c t. T r a n s d e r m a l G T N p r o v o k e d a h y p e r te n s iv e r e a c tio n in 1 1% a n d a m a in ly p o s tu r a l h y p o te n s io n in 8 9 % o f th e in v e s tig a te d p e r s o n s ( n = 6 3 ) .
C O N C L U S IO N S
The
individual
reactions
to transdermal
GTN
revealed:
I) that one hour of application
produces an effect
on skin temperature
mainly
in obese women;
2) that the
local and systemic
GTN effect depends
on arteriolar
and
not on (UV induced)
capillary
dilation;
3) that in healthy
persons
(n=63)
transdermal
GTN
caused
a moderate
orthostatic
reaction
with
a slightly
decreased
arterial
pressure,
increased
heart rate and QTc prolongation;
4)
that
GTN
in the supine
position
provoked
individual
reactions;
in men (n=7) an adverse
sympathetic
reaction
was observed
associated
with
headache
in supine
and
upright position.
A K N O W L E D G M E N T S
To M.T. Cavalcante,
for technical
assistance,
to D.A.
Botter and C. Qu. Aubin for the statistical
analysis
and to
J.1. Leite
for the revision
of the paper.
981
RESUMO
M a te ria is e M e to d o s : E m 6 3 p e s s o a s , a n te s e a p e s a p lic a g 8 0 te p ic a d e d is c o s c o m n itro g lic e rin a @ o u g lic e rin a c o m o p la c e b o , fo ra m a v a lia d a s : a te m p e ra tu ra c u ta n e a e m a m b o s o s a n te b ra g o s e a s re la g o e s h e m o d in a m ic a s e m p o s ig 8 0 s u p in e o rto s ta tic a . R e s u lta d o s : A s re s p o s ta s fo ra m a s s e g u in te s : 1 . U m a h o ra a p e s a p lic a g 8 0 u n ila te ra l (n o a n te b ra g o e s q u e rd o ) h o u v e a u m e n to d a te m p e ra tu ra c u ta n e a ta m b e m n o a n te b ra y o d ire ito , in d ic a n d o e fe ito s is te m ic o ; e s s e e fe ito e ra m a is a c e n tu a d o e p ro lo n g a d o e m m u lh e re s o b e s a s . 2 . A fo to te rm o -re a g 8 0 (e rite m a ) in d u z id a c o m lu z u ltra v io le ta (U V ) fo i m e n o r n o a n te b ra g o e s q u e rd o , s u g e rin d o q u e a n itro g lic e rin a a g e m a is s o b re a rte rfo la s d o q u e s o b re c a p ila re s d o s is te m a v a s c u la r. 3 . A a p lic a y 8 0 tra n s d e rm ic a d e n itro g lic e rin a c a u s o u u m a m o d e ra d a re a y 8 0 o rto s ta tic a c o m d im in u iy 8 0 d a p re s s 8 0 a rte ria l e a u m e n to d a fre q u e n c ia c a rd fa c a . A d U ra y 8 0 d o O tc n o E G G e ra p ro lo n g a d a . 4 . F o ra m o b s e rv a d a s a s s e g u in te s re a g o e s in d iv id u a is e m p O S iy 8 0 s u p in a : e m 7 h o m e n s h o u v e u m a re a y 8 0 a d v e rs a c o m a u m e n to d a p re s s 8 0 m e d ia e m + 1 2 % e a u m e n to d a fre q u e n c ia c a rd ia c a e m + 1 0 % ; a m e s m a re a g 8 0 (s im p a tic a ? ) fo i d e s c rito p o r M u re ll e m 1 8 7 9 , a p e s n itro g lic e rin a v .o . E m h o m e n s fu m a n te s e a q u e le s c o m h ip e te n s 8 0 e d ia b e te s e m m e m b ro s p re x im o s d a fa m ilia , 0 e fe ito h ip o te n s o r a p e s n itro g lic e rin a tra n s d e rm ic a e ra a c e n tu a d o e m p O S ig 8 0 s u p in a .
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