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Effects of Isosorblde Dinitrate and Nicardipine

Hydrochlorlde on Postprandial Blood Pressure

in Elderly Patients with S.ta.ble Angina Pectoris
or Healed Myocard,al Infarchon
Carolyn M Connelly, PhD, Carol Waksmonski, MD, Margaret M. Gagnon, RN,
and Lewis A. Lipsitz, MD

p ostprandlal hypotenslon is a common cause of falls lag characteristics Before each meal study, stroke vol-
and syncope in elderly patients, particularly those ume at supme rest was assessed by impedance cardiog-
with coronary artery disease and associated impairments raphy. 5 Although the absolute value of stroke volume
m ventncular diastohc relaxation. ~ These patients are determined by this method may differ from that obtamed
sensitwe to the development of hypotenslon in response by more invaslve methods, relative changes with vari-
to stresses that reduce cardiac preload, including meal ous interventions are reproducible and reliable. 5 Cardiac
ingestion, upright posture, 2 or nitrate medication, or a output was calculated as the product of stroke volume
combination of these. 1 The administration of mtrates m and heart rate. Systemic vascular resistance was calcu-
conjunction with a meal may enhance venous pooling lated as mean arterial blood pressure dwlded by cardiac
and aggravate postprandial blood pressure reduction. In output. Venous occlusion plethysmography6 was used to
contrast, calcium antagonists, such as nicardipme, have assess forearm blood flow, and forearm vascular resis-
less of an effect on cardiac preload and may improve tance was calculated from the mean arterial pressure
ventncular relaxation. 3 Therefore, we hypothesized that divided by the forearm blood flow.
calcium antagonists would have less of an effect on post- All meal studies were performed between 9 and 10
prandial blood pressure reduction than mtrates m elder- A.M. after a fast from midnight the night before. During
ly pauents with coronary artery disease and dlastohc dys- each drug phase of the study, subjects were gwen 1 dose
function. of medication 60 minutes before the study began. The
• • •
subjects were seated for the meal study. Blood pressure
To test flus hypothesis, we conducted a randomized, was measured with an oscdlometnc device (Dynamap TM,
double-blmd, crossover study of the effects of lSOSOrbide Tampa, Honda) at 5-mmute intervals for 10 minutes
dinitrate (Isordll ®, Wyeth-Ayerst Laboratories, Phila- before and for 60 minutes after consumption of a hquld
delphia, Pennsylvania) versus mcardiplne hydrochlonde meal (Instant Breakfast, Carnation, Glendale, Cahfor-
on blood pressure and heart rate responses to a meal. ma). SubJects consumed a total of 390 to 420 kcal over
The study group consisted of 17 subjects (11 men and 6 a 10-mmute period. Cardiac rate and rhythm were mon-
women, age [mean + SEM] 76 + 1 years). SubJects were
recruited from the community and had a history of either
stable angina (n = 10) or a previous myocardial mfarc- TABII: I Baseline Hemodynamlc Characteristics Dunng Each Drug
tion (n = 7) Each study subject underwent 3 meal stud- Phase (n = 17)
les. first, after at least a 1-week washout period without No Drug Isosorblde Nlcardlpme
medication except nltroglycenn as needed ("no drug"),
and after 2 sequential treatment periods w~th nlcardip- Premeal (seated)
Systohc blood 155 + 6 129 + 4* 127 ± 5*
me and isosorbide in random order. Isosorblde or nlcar- pressure (mm Hg)
dipme were each gwen for 3 weeks at a dose of 20 mg D~astohc blood 75 + 2 72 ± 2 67 ± 2*
orally 3 Umes a day. This dose was sufficient to mml- pressure (mm Hg)
m~ze symptoms of angina in all but 1 patient who re- Mean arterial 102 + 3 91 ± 2* 87 + 2*
qun'ed an mcrease in the lSOSOrblde dose to 4 times a pressure (mm Hg)
Heart rate 61 ± 2 66 ± 2 64 ± 2
day. During a 5-day crossover period, 1 drug was tapered (beats/mm)
off wtule the other was gradually increased to the study Supine
dose. Stroke volume (ml) 69 ± 5 62 ± 5 76 + 7
Within the same week as the meal study, a Doppler Cardiac output 4 1 ±03 39±03 50+04t
echocardlogram was recorded to assess diastolic func- Forearm vascular 67 ± 6 56 + 4 52 ± 5*
tion by measurement of mltral mflow mdexes 4 Mea- reststance (U)
surements of peak E velocity, peak A velocity, and E/A Systemic vascular 27 ± 2 27 ± 3 20 ± 3
ratio were used to evaluate left ventrlcular dlastohc fill- resistance (U)
Supine Doppler
From tb_ Hebrew Rehabdltation Center for the Aged, 1200 Centre PeakEveloclt',/ 061 ± 0 0 3 064+003 0634:003
Street, Roshndale, Massachusetts 02131, the Beth Israel Hospital, (m/s)
and the Harvard Medical School D~wsion on Aging, Boston, Mass- PeakAveloclty 076±004 081 4:004 0 8 0 ± 0 0 3
achusetts Thrs study was supported by Research Grant AGO9538 (m/s)
from the National Institute on Aging, Bethesda, Maryland, and by E/Arat~o 087±OO8 084+007 083 ±O05
Syntex Laboratones, Palo Alto, Cahfornla Manuscript received July
*p <0 05 versus no drug, l p <0 05 versus ~sosorb~de dmttrate
14, 1994, revised manuscnpt received September 22, 1994, and Dala are expressed as mean ± SEM
accepted September 23


ltored continuously by standard electrocardiographic pressure, postprandial blood pressure was expressed as
electrodes the change from the baseline (before meal) values. Data
Two-factor (treatment and time) repeated-measures are presented as mean + SEM.
analysis of variance was used to compare blood pres- Baseline hemodynamlc characteristics of subjects
sure and heart rate responses over tune within and dunng the no drug and the 2 treatment phases are report-
between the 3 treatment periods When significant treat- ed m Table I. Blood pressure and heart rate values are
ment effects were found, t tests (least significant differ- an average of the measurements taken at -10, -5, and 0
ence procedure) were performed to determine the time time points before the meal. Both medications reduced
points at which changes in blood pressure and heart rate systohc blood pressure slgmficantly by approximately 25
were significantly different between treatments. Because mm Hg and mean arterial pressure by approximately 15
drug treatment resulted in a reduction in baseline blood mm Hg (p <0 05 vs no drug). Nlcar&pme slgmficantly
decreased diastolic pressure and forearm
vascular resistance compared with no drug
treatment and resulted m a significant m-
crease m cardiac output compared with
lSOSOrblde. In contrast, lsosorbide had no
slgmficant effect on these hemodynarmc
variables. All subjects had evidence of Im-
R =

paired early diastolic ventncular fillmg as

E ~ -5
demonstrated by a reduction m peak E
I -,o velocity and a decreased E/A ratio.
Systolic blood pressure decreased slg-
mficantly (p = 0 01) after the meal dur-
mg the phase without drugs, but did not
change from premeal values during both
treatment phases (Figure 1). Diastolic
-26 I I I I i I I I I I I
blood pressure decreased after the meal
-6 0 5 10 15 20 25 30 35 40 45 60 66 60 dunng both the no drug and lsosorbide
time (minutes) treatment phases (p = 0.01), but did not
change with nicardipme treatment (Fig-
FIGURE 1. Systolic blood pressure change (~i) from prem.eal values (mean _+ ure 2). Heart rate increased significantly
SEM). Them was a signi~ant decline over time in systolic blood pressure during after the meal during the no drug phase
the no drug trealment phase (p = 0.01). Repeated-measures analysis of vari-
ance indicated a significant study effect (p = 0.02), with a statistically_significant (p = 0.02), but did not change during
difference in systolic blood pressure (p <0.05) between no drug and both drug either the lSOSOrblde or mcardipme treat-
treatments obr~rved at 35 and 60 minutes after the meal, andbetween no ment phases (Figure 3). All subjects
drug and nicardipine treatment at 25 and 50 minutes. remained asymptomaUc.
e I I

Thus, both lSOSOrbide and nlcardlpme

prevented rather than enhanced the post-
prandial decrease m systolic blood pres-
sure observed without treatment m elder-
ly persons with coronary artery disease.
:,1 The improvement m postprandial hypo-
tension observed with these drugs may be
~I / due to their effects m reducmg premeal
8 E -6~ systolic and/or diastolic blood pressure
However, only nlcardipme attenuated the

ill postprandial decline m both systolic and

diastolic blood pressure. Our hemody-
namlc measurements before each meal
show that mcardlpine decreased forearm
.16L I I I i ' ~ i I I I I I I I I vascular resistance and systemic vascular
6 0 s ,0 ,s tiOmeilSmln3uOte~) 4o 4s so ss 6o resistance, and increased cardiac output,
probably by decreasing afterload.
In contrast, lsosorbide had no effect on
FIGURE 2. Diastolic blood pressure change (~i) from premeal values (mean + vascular resistance or cardiac output, and
SEM). Them was a significant change over time in diastolic blood pressure dur- was associated with a postprandial decline
ing the no drug (p = 0.01) and isomrbide (ISORDIL) (p = 0.01) tmalment phas- in diastolic blood pressure. The different
es, but not dun' "ng nicardipine tmahnent. Repeated-measures analysis c& vari- effects of these medications on cardiac
ance indicatecl a significant time effect (p = 0.0001), with a significant
difference (p <0.05) between nicardipine versus no drug and isosorbide dini- output have been reported previously 7
~,~,;e at 35 minutes after the meal, and between no drug and nicardipine treat- The increase in cardiac output associated
ment at 55 and 60 minutes. with nlcar&pme may have prevented the


development of postprandial hypoten-
slon. Our findmgs are compatible with 12-

those of Jansen et at,8 who reported that

the calcium channel blocker mtrendlpme
improved blood pressure homeostasis af-
ter oral glucose loading m hypertensive
elderly patients In addition, our data sug- '~O 3"
gest that this beneficial effect is not due
to improvements in dmstohc ventncular
filling or to enhanced cardioacceleratmon
after the meal.
Although our subjects experienced a
mild degree of postprandial hypotenslon
in the unmedicated state, our results
should not be wewed as supporting the -9- ,I I I I ! I I I I I I ,1,
use of mcardipme for the treatment of
.s o e ,o , . t~0m2is L e ~ 4o 45 5o se eo
postprandial hypotenslon. The differences
m postprandial blood pressure change
with and without treatment were small FIGURE 3. Heart rate change (A) from pren~l values (mean + SEM). There was
and of uncertain climcal slgmficance. We a significant change over time in heart rate during Ihe no drug treatment phase
did not study subjects with symptomatic, (p = 0.02), but not during eilher drug tmateumt phase. Repmtnd-measures
meal-related blood pressure reducuon analysis of variance indimtnd a significant study (p = 0.002) and lime dfect
(p = 0.05), with a significant differbnce (p <0.02} between no drug and both
who may have autonomic failure that drug Ireatments at 25 to 55 minutes aftra the meal, and between no drug and
could be worsened by vasoddators. isosorbide diniirate (ISORDIL] at 15 and 60 minutes after the meal.
We have shown that most elderly
patients with impaired diastolic function can he ment with calcium antagonists on left venmcular diastolic function in stable angi-
na and heart failure Circulation 1990,81(suppl III) III-130-II1-138
treated safely with nicardipine for coronary artery 4 Appleton CP, Hafle LK, Popp RL Relation of transrmtral flow velocity patterns
disease without fear of exacerbating or precipitating to left ventncular diastolic function new insights from a combined hemodynarmc
postprandial hypotension. and Doppler echocamhographlc study J Am Coil Cardiol 1988,12 426-440
5. Buell JC A pracncal, cost-effeclave, nonmvasive system for cardiac output and
hemodynamm analysis Am Heart J 1988.116 657--664
6. L~psaz LA, Bm M, Staebelmg M, McArdle C Foreama blood flow response to
posture change in the very old non-mvasive measurement by venous occlusion
I Jonsson PV, Ltpsaz LA, Kelley M, Koesmer J Hypotensive responses to com- plethysmography J Am Gertatr Soc 1991,39 53--59
mon daily acnvmes m msntuttonahzed elderly Arch Intern Med 1990,150 7. Lambert CR, Grady T, Hashoni W, Blakely M, Panayroutou H Hemedynanuc
1518-1524 and anglograph~c comparison of intravenous mtroglycenn and mcardlpme mainly
2. Llpsttz LA. Jonsson PV, Marks BL, Parker JA, Royal HD, Wet JY Reduced m subjects without coronary artery disease Am J Cardiol 1993,71 420-423
supine cardiac volumes and diastohc filhng rates m elderly patients with chromc 8. Jansen RWMM, vanlaer HH, Hoefnagels WIlL Effect of mtrendtpme and
medmal conditions implications for postural blood pressure homeostasis J Am hydrochlorothtazlde on postprandml blood pressure reduction and carbohydrate
Genatr Soc 1990,38 103-107 metabolism m hypertensive panents over 70 years of age J Cardiovasc Pharma-
3 Lahln A. Rodngues EA, Carboni GP, Raftery EB Effects of long-term treat- col 1988,12(suppl 4) $59-$63

Response of High-Density Lipoprotoins to

Hypollpldemlc Drugs Accord,ng to Their Initial Level
Genovefa D Kolovou, MD, Yannis P. Fostinis, Helen I. Bilianou, MD, and Dennis V. Cokkinos, MD

high level of total cholesterol (>200 mg/dl) is a is seen with this diet; m paUents with mitial HDL cho-
A well- known risk factor for development of early
athe~osclerosls. 1 However, low levels of lugh-denslty
lesterol levels <39 mg/dl, an increase is seen. 7 We decid-
ed to investigate whether the response to some of the
hpoprotem (HDL) cholesterol2,3 are even more strongly most commonly used hpid-lowering drugs is also depen-
associated with early coronary artery disease and plaque dent on the iniual level of this hpoprotein.
progression These 2 unfavorable traits possibly have a e • •

synergistic effect.4'5 It has previously been shown that This study included 933 patients with dyshpidenua
the HDL cholesterol response to the European Athero- who were consecutively examined at the lipid clinic The
sclerosis Socmty first-step hpld-lowermg diet6 depends result of hypollp~demm treatment on HDL cholesterol
on basehne HDL cholesterol plasma levels: In patients according to baselme levels was prospectwely evaluat-
with imnal HDL cholesterol levels >39 mg/dl, a decrease ed. Dyslipidemia was diagnosed if the total cholesterol
was >200 mg/dl and the low-densay lipoprotem (LDL)
From the Department of Cardiology and the Department of B~o- cholesterol >130 mg/dl. 6 All patients were mmally treat-
chemistry, Onassls Cardiac Surgery Center, Athens, and the Um- ed for 3 months with the first-step hpid-lowenng diet as
verslty of Athens, Athens, Greece Dr Kolovou's address ts 51,
Aglon Anarglron, 151 24 Maroussl, Athens, Greece Manuscnpt suggested by the European Atheroscleros]s Society.6
receqvedJuly 5, 1994, rewsed manuscnpt received and accepted Dunng this stage, constant dietetic counseling was pro-
September 27, ] 994 vlded. After this interval, plasma samples for lipid analy-