hemodynamic mechanisms of antianginal action of calcium...

1887

Hemodynamic Mechanisms ofAntianginal Action of Calcium Channel

Blocker Nisoldipine in DynamicExercise-Induced Angina

Mitsuhiro Yokota, MD, Takashi Miyahara, MD, Mitsunori Iwase, MD,

Makoto Watanabe, MD, Tatsuyuki Matsunami, MD, Susumu Kamihara, MD,

Masafumi Koide, MD, Hidehiko Saito, MD, and Jun Takeuchi, MD

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipineand to determine the reproducibility of the clinical and hemodynamic events induced by supineleg exercise, 30 patients with stable effort angina pectoris were studied. They were divided intotwo groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and theother group of 11 patients received a single dose of placebo orally. Chest pain was induced inall of 30 patients during the control exercise test. After nisoldipine administration, chest painwas not induced in 13 of 19 patients and was of lessened severity in five patients with the same

work load as those performing control exercise. ST segment at peak exercise showed less severe

depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p<0.001) at restand 22% (p <0.001) at peak exercise, and coronary vascular resistance was reduced by 31%(p<0.01) at rest and 18% (p <0.01) at peak exercise. Pulmonary artery wedge pressure fell from6±1 to 3±1 mm Hg (p<0.001) at rest and from 28±3 to 11+2 mm Hg (p<0.001) at peakexercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and duringexercise was not modified by nisoldipine. However, coronary sinus flow at peak exerciseincreased significantly from 219±24 to 249±31 ml/min (p<0.01) after nisoldipine, andmyocardial oxygen uptake was not significantly changed despite decreased coronary vascularresistance. The clinical and hemodynamic events induced by the exercise during invasivestudies (except pulmonary artery wedge pressure at rest) were reproducible after placeboadministration. Our data demonstrate that increased coronary blood flow could be the majormechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.

(Circulation 1990;81:1887-1898)

C alcium channel blockers have obtained wideacceptance in the treatment of exercise-induced angina pectoris. Recently, much

interest has been focused on the mechanisms of theirantianginal actions and their effects on exercise per-formance in patients with angina. The exact mecha-nisms are multifactorial and complex and are relatedto a combination of effects on heart rate, myocardialcontractility,'-3 possibly myocardial oxygen supplythrough coronary vasodilation,4 and peripheral vascu-

From the Department of Clinical Laboratory, Nagoya Univer-sity Hospital, and the First Department of Internal Medicine,Nagoya University School of Medicine, Nagoya, Japan.Address for reprints: Mitsuhiro Yokota, MD, Department of

Clinical Laboratory, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan, 466.

Received July 27, 1988; revision accepted February 14, 1990.

lar resistance. The various calcium channel blockersare not equal in their systemic vascular, coronary vas-cular, electrophysiological, and myocardial effects.5-8Negative inotropic effect of the drug in intact humanis variable and controversial. Accordingly, it is rea-sonable to consider that these drugs might havedifferent effects on rest and exercise left ventricularperformance in patients with exercise-inducedangina pectoris.

Nisoldipine is a calcium channel blocker of thedihydropyridine class, similar in chemical structure tonifedipine,910 and exhibits greater smooth muscleselectivity than the parent compound, resulting inmore potency as a vasodilator with fewer myocardialdepressant effects.10 Oral administration of nisol-dipine has been shown to have antianginal effects inrecent clinical trials.1"12 However, it is still unclear

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1888 Circulation Vol 81, No 6, June 1990

TABLE 1. Summary of Pertinent Clinical and Angiographic Findings in 19 Patients Receiving Nisoldipine

Coronary angiogram (% diameterreduction) Left ventricular angiogram Exercise

Age (yr) Collateral durationPatient and sex LAD LCx RC filling EF (%) Wall motion (sec)

1 55 M 75 0 0 None 83 Normal 6002 45 M 0 100 90 Fair 75 Anterior hypokinesia 5403 66 M 95 0 0 None 74 Normal 6154 71 M 75 50 99 Good 79 Normal 5405 60 F 99 50 0 Fair 80 Anterior hypokinesia 255

6 38 M 95 99 100 Fair 62 Anterior hypokinesia 2707 55 M 0 100 0 Good 74 Normal 4058 55 M 99 0 0 Fair 66 Anterior hypokinesia 2709 71 M 50 100 0 Fair 72 Normal 540

10 63 M 75 50 100 Good 35 Anterior and inferior hypokinesia 36011 63 M 75 99 90 None 60 Inferior akinesia 285

12 60 M 0 99 50 None 72 Posterior hypokinesia 22013 52 M 99 90 90 Poor 74 Anterior hypokinesia 34514 49 M 95 95 90 None 50 Posterior hypokinesia 36015 68 M 100 0 100 Good 56 Inferior and anterior hypokinesia 42016 52 M 0 99 0 None 84 Normal 66017 56 M 75 0 0 None 84 Normal 66018 54 M 100 0 0 Good 73 Anterior hypokinesia 490

19 41 M 75 100 99 Good 64 Inferior hypokinesia 540

LAD, left anterior descending artery; LCx, left circumflex artery; RC, right coronary arterv; EF. ejection fraction; M, male; F, female.

whether the beneficial effects of the drug areachieved by a decrease in myocardial oxygen demandat any level of exertional stress or if they are a resultof an increase in myocardial oxygen supply inhumans.Dynamic exercise is the most common physiological

stress in a human and can bring out cardiac abnormal-ities not present at rest. For this reason, dynamicexercise can be considered the most practical test toprovoke chest pain in patients with effort anginapectoris, to evaluate the efficacy of antianginal agents,and to elucidate the antianginal mechanism.The main purposes of the present study was to

evaluate the effect of nisoldipine on systemic andcoronary hemodynamics in dynamic exercise-inducedangina pectoris and to elucidate its antianginal mech-anisms in patients with stable effort angina pectorissubjected to supine leg exercise before and after oraladministration of a single dose of 10 mg nisoldipine.The study was also designed to determine whetherthe clinical and hemodynamic events induced bysupine leg exercise during invasive studies are repro-ducible after placebo administration in patients withstable effort angina pectoris.

MethodsPatientsThe study group consisted of 30 patients (29 men

and one woman) with stable effort angina pectoris(age, 38-71 years; mean age, 54 years). They wereadmitted to the Nagoya University Hospital for inves-tigation of suspected coronary artery disease. They

were randomly (in a nonblinded manner) divided intotwo groups -one group of 19 patients who received asingle 10 mg dose of nisoldipine orally (Table 1), andanother group of 11 patients who received a singledose of identical placebo orally (Table 2). The groupswere unequal in size because of the inability to obtainsatisfactory coronary sinus blood flow measurementsin some patients. Each patient had previous positiveexercise tests with chest pain and significant ischemicST-segment depression on angina-limited supine mul-tistage bicycle ergometer exercise tests on at least 2different days before the definitive study. These testswere done to familiarize patients with supine legexercise and to avoid poor reproducibility of theexercise test results. This study was approved by anappropriate institutional review committee, and eachpatient gave informed consent.

Hemodynamic StudiesA triple-lumen thermistor Swan-Ganz catheter

was positioned in the pulmonary artery percutane-ously through the brachial vein to measure cardiacoutput and pulmonary artery wedge pressure. Ther-modilution technique was used to determine cardiacoutput. The thermodilution curve, recorded with thethermodilution cardiac output computer (model Ri-5DCP, General Scanning Inc., Los Angeles, Califor-nia), was checked for consistency before the resultswere accepted as reflecting cardiac output. Irregular(not smooth and not characterized by a rapid peak)curves, especially during exercise, were excludedfrom the study. A double-thermistor catheter (model


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Yokota et al Antianginal Action of Nisoldipine 1889

TABLE 2. Summary of Pertinent Clinical and Angiographic Findings in 11 Patients Receiving Placebo

Coronary angiogram (% diameterreduction) Left ventricular angiogram Exercise

Age (yr) Collateral durationPatient and sex LAD LCx RC filling EF (%) Wall motion (sec)

1 38 M 99 0 0 Poor 70 Anterior akinesia 6202 44 M 99 0 25 Good 70 Anterior hypokinesia 5603 47 M 99 90 0 None 40 Anterior and inferior akinesia 3504 47 M 100 0 0 Fair 35 Anterior askinesia 3405 62 M 50 0 75 None 79 Normal 4806 41 M 100 0 25 None 35 Anterior akinesia 5207 45 M 90 0 25 None 59 Anterior akinesia 3608 58 M 100 0 25 Fair 37 Anterior akinesia 3509 57 M 90 75 0 None 28 Anterior dyskinesia 240

10 57 M 90 75 50 Fair 74 Anterior hypokinesia 44011 42 M 99 0 90 None 50 Anterior and posterior hypokinesia 340

LAD, left anterior descending artery; LCx, left circumflex artery; RC, right coronary artery; EF, ejection fraction; M, male; F, female.

CCS/TU-GOK, Wilton-Webster Laboratories, LosAngeles, California) was placed percutaneously inthe coronary sinus through the brachial vein. Thedistal external thermistor was advanced to the greatcardiac vein, and the proximal external thermistorwas positioned in the coronary sinus between theostium and the termination of the middle cardiacvein under fluoroscopic guidance. Coronary sinusand great cardiac vein flows were calculated accord-ing to the method of Ganz et a113 using a computersystem (Thermo Flow, Goodman Co., Ltd., Nagoya,Japan). The injectate was normal saline solution atroom temperature delivered by a Harvard pump at aflow rate of 40 ml/min. Coronary sinus flow and greatcardiac vein flow were recorded on a six-channelrecorder (Unicorder, Nippon Denshi Kagaku Co.,Ltd., Kyoto, Japan) at a paper speed of 100cm/min. ATeflon catheter was also cannulated in the brachialartery for direct measurement of arterial pressure.Pulmonary artery wedge pressure and arterial pres-sure were measured by a Siemens pressure trans-ducer (model 746, Solna, Sweden) from a zero ref-erence midchest level.

Bicycle Ergometer Exercise TestingAll drugs (except sublingual nitroglycerin) admin-

istered for relief of chest pain were withdrawn by 3days before the study. The method of invasive hemo-dynamic exercise testing has been reportedelsewhere.14-16 Angina-limited bicycle ergometer(electronically braked ergometer) exercise testingwas performed in patients in the supine positionbefore administration of nisoldipine or placebo toobtain control values. The exercise end point in thecontrol study was chest pain. The work load wasbegun at 150 kpm/min (25 W) and increased by 150kpm/min at 3-minute intervals. A single oral dose of10 mg nisoldipine or placebo was administered at theend of the control exercise test, and exercise testingusing the same method, duration, and work load wasperformed 1.5 hours after the administration of

nisoldipine or placebo. During exercise testing, amultilead electrocardiogram (modified 12 leads17 andFrank X, Y, and Z leads) was recorded continuously.Pulmonary artery wedge pressure, arterial pressure,cardiac output, and coronary sinus flow were mea-sured at rest and every 3 minutes during exercise, atpeak exercise, and 3 and 6 minutes after exercise. Wecould not obtain a measurement of coronary sinusflow in four patients either at rest or during exercisein the nisoldipine group.

Blood SamplingSamples of blood for oxygen saturation were simul-

taneously obtained in the brachial artery, the pulmo-nary artery, and the coronary sinus at rest, at peakexercise, and 6 minutes after exercise in 11 of 19patients in the nisoldipine group. Blood oxygen satura-tion was determined with a hemoximeter (modelABL3, Radiometer, Copenhagen, Denmark). Someparts of the sample were packed in dry ice for laterdetermination of norepinephrine levels by a modifica-tion of a method described by de Champlain et al.18Samples of blood for nisoldipine plasma levels wereobtained at 0.5, 1, 1.5, 2, 3, and 5 hours after nisoldipineadministration. The total plasma concentration ofnisoldipine and its active metabolites (as nisoldipineequivalent) were measured by radioreceptor assay.19

Angiographic Assessment of Coronary StenosisSelective coronary arteriography and left ventricu-

lography were performed in all patients studied usingthe Sones technique in the same day after the nisol-dipine or the placebo study. Left ventricular volume ineach patient was calculated by the use of biplanecineangiography. Each coronary artery was viewed inmultiple projections. Coronary cineangiograms,recorded on 35-mm films, were reviewed on a Tagarnoprojector. Collateral filling of the coronary arterialbranch was judged angiographically. Good filling wasdefined as opacification of the collaterally filled branchequal to that of vessels directly filled; poor filling was


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defined as just detectable opacification; and fair fillingwas defined as between good and poor.

CalculationsThe baseline from which observed electrocardio-

graphic changes were measured was taken from aline joining two consecutive P-Q junctions. The mag-nitude of ST-segment depression was measured usinga x7 magnifying glass calibrated in lOths of a milli-meter. Test results were reviewed by a secondobserver, and differences were resolved by joint studyof the record. The use of a calibrated magnifyingglass substantially increased agreement betweenreaders. Each exercise test was interpreted withoutknowledge of the results during control study orduring nisoldipine study. The electrocardiographiccriteria for a positive test in any lead were horizontalor downsloping ST-segment depression .1 mm for0.08 seconds or a slow upsloping ST-segment depres-sion .2 mm 0.08 seconds after the J point in at leastthree consecutive complexes. The degree of STchanges was expressed by the maximal value ofischemic ST-segment depression in any of the 15leads recorded.Hemodynamic variables were calculated as fol-

lows: (rate-pressure product) = (systolic bloodpressure) x (heart rate); (cardiac index [1/min/M2]) =(cardiac output/body surface area); (strokevolume index [ml/m2])=(cardiac index/heart rate);(mean arterial pressure)=[systolic arterial pressure+2xdiastolic arterial pressure)/3]; (systemic vascularresistance [dynes-sec-cm-5) =(mean arterial pressure/cardiac outputx80); (stroke work index [g/beats/m2]) =(stroke volume indexx [mean arterial pressure-mean pulmonary artery wedge pressure])xO.0136 (aconversion factor from mm Hg* cm3 to g. m, havingunits of g m/mm Hg. cm3); (coronary vascular resis-tance [mm Hg/ml/min])= (mean arterial pressure/coronary sinus flow); {(oxygen content [vol%])=(oxy-gen saturation[%] x hemoglobin concentration values[g/dl]x 1.34) (a conversion factor to get from percentsaturation to oxygen content)/100l; (myocardial oxygenuptake [ml/min])=(arterial oxygen content-coronarysinus oxygen content)x(coronary sinus flow/100).

StatisticsHemodynamic variables at rest and at peak exer-

cise were compared between the control period andthe nisoldipine period or the placebo period, respec-tively, using a paired t test. Pulmonary artery wedgepressure, systemic vascular resistance, coronary sinusflow, and coronary vascular resistance measured dur-ing the exercise test in the control period werecompared with those in the nisoldipine period usinga paired t test; a p value of less than 0.05 wasconsidered statistically significant. Linear regressionanalysis was made using myocardial oxygen uptakeduring the exercise test before nisoldipine as anindependent variable and after nisoldipine as adependent one. The test of regression coefficient andthe test of regression constant were made in the

obtained regression equation. All values in the text,figures, and tables are mean+SEM.

ResultsClinical and Angiographic FindingsAmong 30 patients studied, 13 had three-vessel

disease, nine had two-vessel disease, and eight hadone-vessel involvement. Left ventricular ejection frac-tion ranged from 28% to 84% (mean, 63±3%) in allpatients studied, from 35% to 84% (mean, 69±3%) inthe nisoldipine group, and from 28% to 79% (mean,53±6%) in the placebo group. The ejection fractionshowed a significant difference between the twogroups (p<O.O1). Exercise duration ranged from 220to 660 seconds (mean, 433±24 seconds) in all patientsstudied, from 220 to 660 seconds (mean, 441±34seconds) in the nisoldipine group, and from 240 to 620seconds (mean, 418±35 seconds) in the placebogroup. The exercise duration did not show a significantdifference between the two groups.

Effects of Nisoldipine on Exercise-Induced Chest Painand Ischemic ST-Segment DepressionThe symptom-limited bicycle ergometer exercise

duration of the subjects in nisoldipine group of 19patients ranged from 220 to 660 seconds (mean,440±34 seconds) (Table 1). Chest pain was inducedin all 19 patients studied during the control exercisetest, but after nisoldipine administration, chest painwas not induced in 13 patients. In five patients, it wasof lessened severity, and only one patient (8) showedthe same severity of chest pain before and afternisoldipine administration.

Comparative analysis of exercise-induced ischemicST-segment depression before and after nisoldipineadministration was possible in all of 19 patients(Figure 1). Exercise-induced ST-segment depressionwas lessened in severity in all 19 patients afternisoldipine administration. Mean ST-segmentdepression was 0.18±0.03 mV in the control periodand was significantly reduced to 0.10±0.02 mV afternisoldipine administration (p <0.001).

Effects of Placebo on Exercise-Induced Chest Painand Ischemic ST-Segment DepressionThe symptom-limited bicycle ergometer exercise

duration of the placebo group of 11 patients rangedfrom 240 to 620 seconds (mean, 418+35 seconds)Table 2). Chest pain was induced in all of 11 patientsduring the control exercise test and in 10 patientsafter placebo administration chest pain. In only onepatient was pain of lessened severity. Comparativeanalysis of exercise-induced ischemic ST-segmentdepression before and after placebo administrationwas possible in all 11 patients. Exercise-induced ST-segment depression was 0.17±0.02 mV in the controlperiod and 0.16+0.03 mV in the placebo period;these changes were not significant.


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TABLE 3. Changes in Left Ventricular and Systemic Hemodynamic and Metabolic Responses to Supine BicycleErgometer Exercise Before and After Nisoldipine Administration in 19 Patients With Stable Effort Angina Pectoris

Control period

Baseline Peak exercise

Nisoldipine period


Heart rate (beats/min)Systolic arterial pressure (mm Hg)Diastolic arterial pressure (mm Hg)Mean arterial pressure (mm Hg)Rate-pressure product (x102)Pulmonary artery wedge pressure (mm Hg)Cardiac index (I/min/m2)Stroke volume index (ml/m2)Stroke work index (g im/beat/m2)Systemic vascular resistance (dynes/sec/cm-5)Epinephrine (pg/ml)Norepinephrine (pg/ml)

64±2159+685-+-3110+496-+-86+1

2.5 ±0.139±155+3

118 +4196±+893±3127+4220+2028+35.3±0.445+262±5

79+3*130+4*71±+2*91±+2*97+73±1*

3.2±0.1*42±249±2t

2,204+ 143 1,218±81 1,368-+70*

128+5*174+5*84±3t114±3*212± 1711±2*5.9±0.3t46±265±3

946 +43*26.9±7.5 89.2±20.6 38.5+9.3 106.2±22.9133.1±15.9 502.3±97.0 170.8±24.0 610.8+72.9

n=13 patients.*p<0.001, tp<0.01, :p<0.05 vs. control.

Effects of Nisoldipine on Systemic andCardiac Hemodynamics

Heart rate increased from 64±2 to 79+3 beats/min(p<0.001) at rest and from 118±4 to 128±5 beats/min(p<0.001) at peak exercise, whereas systolic arterialpressure decreased from 159±6 to 130±4 mm Hg(p<0.001) at rest and from 196±8 to 174±5 mm Hg(p<0.001) at peak exercise. As a result, rate-pressureproduct during exercise testing was not significantlymodified by nisoldipine administration. Cardiac indexincreased from 2.5 ±0.1 to 3.2± 0.1 1/min/m2 (p<0.001)at rest and from 5.3 ±0.4 to 5.9 ±0.3 1/min/m2 (p<0.05)

ST depression(mV)

0 -__

-0.1

-0.2 -

-0.3

-0.4

-0.5

I P <0.001 i

Control NisoldipineFIGURE 1. Plots of effects of nisoldipine on exercise-inducedmaximal ST-segment depression. Ischemic ST-segment depres-sion induced by supine bicycle ergometer exercise was improvedfrom 0.18±0.03 to 0.10+0.02 mV (p<0.001) by oral adminis-tration of nisoldipine in all of the 19 patients evaluated.

at peak exercise after nisoldipine administration. Inthe control exercise test, a marked elevation of pul-monary artery wedge pressure with an increase inwork load was observed, whereas after nisoldipineadministration the pressure decreased significantlythroughout the exercise test (Figure 2). Pulmonaryartery wedge pressure fell from 6 + 1 to 3 + 1 mm Hg(p<0.001) at rest and from 28+3 to 11+2 mmHg(p<O.001) at peak exercise after nisoldipine adminis-tration. Systemic vascular resistance decreased signif-icantly throughout the exercise test after nisoldipineadministration (Figure 3).

Effects of Nisoldipine on Coronary HemodynamicsComparative analysis of coronary blood flow was

permitted in 15 of 19 patients studied during bicycleergometer exercise testings (Tables 4 and 5). In thecontrol study, exercise induced an increase in coro-nary sinus flow and a decrease in coronary vascularresistance. After administration of nisoldipine, coro-nary sinus flow significantly increased from 219 to 249ml/min (p<0.01) at peak exercise (Figure 4). Coro-nary vascular resistance decreased from 1.30+±0.10 to0.90+±0.09 mm Hg/ml/min (p<0.01) at rest and from0.71+0.08 to 0.58±0.07 mm Hg/ml/min (p<0.01) atpeak exercise after nisoldipine administration (Fig-ure 5). Arteriocoronary sinus oxygen differenceshowed no significant difference at rest or at peakexercise. Myocardial oxygen uptake showed no sig-nificant difference throughout the exercise test afternisoldipine administration (Figure 6).

Effects of Placebo on Systemic, Cardiac, andCoronary Hemodynamics

Systemic, cardiac, and coronary hemodynamicmeasurements including heart rate, rate-pressureproduct, cardiac index, and coronary sinus flowshowed no significant changes at rest and at peakexercise after placebo administration (Table 6). Only


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o Control* Nisoldipine

(mean±SEM** P<0.01***P <0.001 FIGURE 2. Plots of effects of nisoldipine on pulmonary

artery wedge pressure (PA WP) during supine bicycle ergo-

meter exercise testing. Marked elevation of PAWP withincrease in work load was observed in the control exercisetesting, but after nisoldipine administration a significantdecrease in the pressure was noted throughout the exercisetesting.

Rest 3min Peak 1min 3min 6min

Exercise Recovery

pulmonary artery wedge pressure at rest fell signifi-cantly from 7±1 to 5±1 mm Hg (p<0.05).

Arterial Cathecholamine LevelsArterial norepinephrine levels tended to increase

at rest and at peak exercise in nisoldipine period(Table 3). However, this increase was not significant.

Plasma Concentration of NisoldipineThe total plasma concentration-time data of nisol-

dipine and its active metabolites after a single oraldose of 10 mg were fit to a one-compartment modelfor seven patients. Nisoldipine was rapidly absorbed

with Tma, (time to reach peak plasma concentration)of 1.6±0.2 hours, and elimination half-life (T1/2) was1.3±0.4 hours. Cm,, (peak plasma concentration) was17.6±5.1 ng/ml, and mean AUC (areas under plasmaconcentration-time curves) was 50.8±11.7 ng. hr/ml.

DiscussionThe present study has demonstrated a clear-cut

effect of nisoldipine on dynamic exercise-inducedangina pectoris in terms of disappearance or lessen-ing of chest pain and marked alleviation of ischemicST-segment depression after nisoldipine administra-tion; these effects are consistent with other recent

TABLE 4. Coronary Hemodynamic and Metabolic Effects of Nisoldipine at Rest

CSF CVR AV(mi/min) (mm Hg/ml/min) difference (ml/di) MVo2 (mi/min)

Patient C N C N C N C N

1 148 176 0.92 0.57 ... ... ... ...

2 117 150 0.79 0.61 ... ...

3 132 129 0.95 0.83 13.2 11.1 17.4 14.34 180 150 0.74 0.68 12.8 11.8 15.8 12.05 122 71 0.99 1.30 8.6 9.3 10.4 6.66 121 103 0.83 0.87 11.0 14.7 13.3 15.17 ... ... ... ... ... ... .....8 77 63 1.34 1.46 ... ... ... ...

9 75 68 1.83 1.56 13.3 11.9 9.9 8.110 110 149 1.44 0.70 11.3 11.9 12.4 18.111 ... ... ... ...........12 47 63 2.72 1.84 11.2 11.0 5.3 7.013 ... .. ....... ... ... ...

14 63 114 1.67 0.72 ... ... ... ...

15 ... ... ..... ... ... ... ...

16 94 85 1.26 1.10 10.2 9.8 9.6 8.317 64 102 1.77 0.80 8.5 6.6 5.4 6.718 54 75 2.02 1.31 9.4 7.9 5.1 5.919 57 134 1.81 0.75 13.2 11.1 7.5 14.9Mean 97 109 1.30 0.90 11.2 10.7 10.2 10.6+SEM 9 9 0.10 0.09 0.6 0.7 1.0 1.4p NS <0.01 NS NS

CSF, coronary sinus blood flow; CVR, coronary vascular resistance; AV difference, myocardial arteriovenous oxygendifference; MVo2, myocardial oxygen uptake; C, control; N, nisoldipine.

mmHg30-

20-

PAWP

10-

O-L


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FIGURE 3. Plots of effects of nisoldipine on systemicvascular resistance (SVR) during supine bicycle ergometerexercise testing. After nisoldipine administration, a signif-icant decrease in SVR was noted throughout the exercisetesting.

.

Rest 3min Peak 1 m'i 3min 6min- Exercise Recovery

clinical studies with nisoldipine.1112,20,21 To explainthese improvements, both direct cardiac effects andthe influence of nisoldipine on the systemic andcoronary circulations must be considered. Possiblemechanisms of action of nisoldipine for angina reliefare discussed on the basis of myocardial oxygen

demand and supply relation in dynamic exercise-induced angina.The routine daily dose of nisoldipine for patients

with effort angina pectoris was 10-20 mg in theclinical studies reported.1'12'20 We examined theexercise tolerance of 10 patients with stable effortangina pectoris using treadmill exercise at 2, 4, 7, and

24 hours after a single oral dose of 10 mg nisoldipinein a placebo-controlled study.21 Significant prolonga-tion of treadmill exercise duration was observed inthis group for 24 hours after nisoldipine administra-tion. Crean et a120 also reported that treadmill exer-

cise duration increased significantly after 5- and20-mg nisoldipine administration. Accordingly, the10-mg oral dose of nisoldipine used in the presentstudy seems to be appropriate for a single-dose study.

Systemic Hemodynamic Effects of NisoldipineMajor changes in the systemic hemodynamic

response after a single oral dose of nisoldipine

TABLE 5. Coronary Hemodynamic and Metabolic Effects of Nisoldipine at Peak Exercise

CSF CVR AV(mi/min) (mm Hg/m1/min) difference (mi/di) MVO2 (mi/min)

Patient C N C N C N C N

1 327 372 0.48 0.33 ... ...

2 251 294 0.48 0.40 ...3 332 361 0.44 0.36 14.7 13.9 48.6 53.44 371 451 0.42 0.29 12.2 13.4 32.7 41.15 168 147 0.68 0.75 8.1 9.1 13.7 13.46 169 144 0.60 0.80 15.6 15.4 26.3 22.27 ... ... ... ...........8 109 104 1.12 1.11 ...

9 193 186 0.82 0.78 14.4 12.1 27.8 22.410 161 202 1.02 0.68 14.5 14.5 23.3 29.211 ... ... ... ... ........12 89 131 1.52 1.13 12.7 13.3 11.3 17.513 ... ... ... ...........14 150 137 0.97 0.82 ... ... ...

15 ... ... ... ... ........16 209 234 0.69 0.50 14.7 13.2 30.6 30.817 379 506 0.35 0.24 8.0 8.1 30.3 40.918 108 179 1.23 0.72 9.7 8.4 10.7 15.119 265 294 0.56 0.47 14.6 13.9 38.7 40.7Mean 219 249 0.71 0.58 12.7 12.3 26.7 29.7

+SEM 24 31 0.08 0.07 0.9 0.8 3.9 4.3

p <0.01 <0.01 NS NS

CSF, coronary sinus blood flow; CVR, coronary vascular resistance; AV difference, myocardial arteriovenous oxygendifference; MVO2, myocardial oxygen uptake; C, control; N, nisoldipine.

dynes sec cm`3000

2000-

SVR

1000


(mean±SEM)

***P<0.001

0


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mi/min300-I


(mean±SEM)** P< 0.01

FIGURE 4. Plots ofeffects ofnisoldipine on coronary

sinus flow (CSF) during supine bicycle ergometer exer-

cise testing. A significant increase in CSF was noted atpeak exercise after nisoldipine administration.

0

Rest 3min PeakExercise

3min 6min

Recovery

observed at rest and during exercise in the presentstudy were a marked decrease in systemic vascularresistance and a decrease in arterial blood pressureassociated with an increase in cardiac index. Theinhibition of the transmembrane flux of calcium ionsin smooth muscle causes vasodilation, resulting in a

decrease in total peripheral resistance and ventricu-lar afterload.1022 Nisoldipine has been reported tohave a significant effect on vascular smooth musclerelative to cardiac muscle.10

Myocardial ischemia induced by dynamic exerciseis associated with abnormal ventricular functioncharacterized by a marked increase in left ventricularfilling pressure.23,24 The mechanism of this increase isstill controversial. Abnormal left ventricular com-pliance25-27 or impairment of left ventricular contrac-

tility due to acute myocardial ischemia28,29 are possiblemechanisms. In the present study, a marked decrease inpulmonary artery wedge pressure was observed duringsupine leg exercise testing after nisoldipine administra-tion; this is probably caused by an alleviation of myo-cardial ischemia or a decrease in its severity. Pulmonaryartery wedge pressure reflects left ventricular end-diastolic pressure in most clinical settings30 and evenduring dynamic exercise.31 Nisoldipine-induceddecrease in pulmonary artery wedge pressure could beassumed to reflect a similar fall in left ventricularend-diastolic pressure, which would induce a decreasein left ventricular wall tension.Heart rate increased both at rest and at peak

exercise after nisoldipine administration, but therate-pressure product, which is believed to reflect

mmHg/mi/min1.5-1

1.0"

CVR

0.5

0

o Control* Nisoldipine(mean±SEM)

* P<0.05** P <0.01

FIGURE 5. Plots of effects of nisoldipineon coronary vascular resistance (CVR) dur-ing supine bicycle ergometer exercise testing.After nisoldipine administration, a signifi-cant decrease in CVR was noted throughoutthe exercise testing.

Rest 3min Peak 3mn 6minExercise Recovery

200-

CSF

100-


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mlJmin601

X~ 40-'

14 30N

> 20-

10-

Y=0.99 X + 0.52(n=66)

r = 0.93r2 =0.87P< 0.001

50 60 milminMVO2 (Control)

FIGURE 6. Myocardial oxygen uptake (AMo2) during supinebicycle ergometer exercise testing before and after oral admin-istration of nisoldipine. MVo2 was not significantly modified bynisoldipine administration during the exercise. Relation betweennisoldipine and control period for myocardial oxygen uptake isgiven by the equation: MVo2 (nisoldipine)=0.99xMVo2(control) +0. 52. The correlation coefficient is 0. 93 (p<O. 001).From the test of regression coefficient and the test of regressionconstant, this regression equation is not significantly differentfrom the equation: AMVKo2 (nisoldipine) =MVo2 (control).

myocardial oxygen uptake,32 was not modified at allby nisoldipine administration. An increase in heartrate would be caused by a reflex sympathetic stimu-lating action originating from marked dilation ofsystemic vascular vessels as in the case of othercalcium channel blockers based on dihydropyridinederivatives.33

Arterial norepinephrine levels in the present studytended to increase at rest and at peak exercise afternisoldipine administration; this is considered to be aresult of a reflex increase in sympathetic activity.33The precise mechanism, however, remains unclear.Increased sympathetic activity may produce an

oxygen-wasting effect by increasing inotropic state.

Coronary Hemodynamic Effects of NisoldipineMyocardial oxygen uptake during supine leg exer-

cise testings was not significantly modified by nisol-dipine administration. Coronary vascular resistancewas markedly reduced after nisoldipine administra-tion, which did not result in an increased coronary

sinus flow at rest because of nisoldipine-inducedhypotension and the associated decrease in coronary

perfusion pressure. However, coronary sinus flow atpeak exercise showed a significant increase afternisoldipine administration. This increase in coronary

blood flow may play an important role in the mech-anism of antianginal action of nisoldipine. Tumas eta134 have reported no effects of nisoldipine on myo-cardial blood flow. There are several reports in whichnisoldipine increased coronary blood flow despite adecrease in systemic blood pressure at rest.35,36 Thereare very few reports, however, about the effects ofnisoldipine on coronary blood flow during dynamicexercise in patients with effort angina pectoris.

Previous investigators have suggested that exercisemay induce positional catheter changes, therebyincreasing variability among repeated thermodilutionmeasurements of coronary sinus flow.3738 However,Magorien et a139 found a highly significant correlationbetween the measurement obtained during exercise.In the present study, we displayed the thermodilutioncurves on a multichannel recorder. Irregular curveswere discarded to keep reliability of the data and toavoid contamination by right atrial blood.

Antianginal Mechanism of NisoldipineThe mechanisms of antianginal action of calcium

channel blockers have been considered to involve adecrease in myocardial oxygen uptake, an increase incoronary blood flow, improvement in the distributionof coronary blood flow, an increase in collateralblood flow, and protective action on the myocardium.

In the present study, nisoldipine administrationinduced no evident changes in myocardial oxygen

TABLE 6. Changes in Left Ventricular, Systemic, and Coronary Hemodynamic Responses to Supine Bicycle ErgometerExercise Before and After Placebo Administration in 11 Patients With Stable Effort Angina Pectoris

Control period


Placebo period


Heart rate (beats/min) 72+3 112±3 75±4 115±4Systolic arterial pressure (mm Hg) 143+7 186±9 137±5 182±9Diastolic arterial pressure (mm Hg) 81±3 92±3 82±3 92±5Mean arterial pressure (mm Hg) 102-4 123±5 100+3 122±6Rate-pressure product (x102) 102±8 208+11 102±7 209±12Pulmonary artery wedge pressure (mm Hg) 7+1 17+2 5±1* 16+2Cardiac index (1/min/m2) 2.7±0.2 5.0+0.2 2.7+0.1 5.1+0.1Stroke volume index (ml/m2) 38+3 45+3 37±4 45±4Stroke work index (g m/beat/m2) 50+6 66+5 48+8 67+7Systemic vascular resistance (dynes/sec/cm-5) 1,835+68 1,197+81 1,797+72 1,177+100Coronary sinus flow (ml/min) 109±10 190+ 17 118±25 213±31Coronary vascular resistance (mm Hg/ml/min) 1.00±0.10 0.71±0.08 1.07+0.12 0.67+0.07

*p<0.05 vs. control.


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uptake. Rate-pressure product also showed no signif-icant changes after nisoldipine administration. As theresult, a reduction in myocardial oxygen uptake couldnot be a major factor of the antianginal action ofnisoldipine. Coronary blood flow is one of the prin-cipal factors regulating myocardial oxygen supply.Because approximately 85% of coronary sinus bloodflow arises from the left ventricle, measurements ofcoronary sinus flow reflect left ventricular coronaryblood flow. The present study suggests that themechanism of protection by nisoldipine is mainly theresult of an increase in coronary blood flow.The calcium channel blockers nifedipine and dil-

tiazem have been found to inhibit ischemia-inducedvasodilation of the resistance vessels after the acutedilation has resolved.4041 In the presence of a proxi-mal coronary stenosis, ischemic vasodilation of thecoronary resistance vessels causes a decrease inperfusion pressure distal to the stenosis and loss ofthe ability for local autoregulation. These effects mayresult in redistribution of coronary blood flow awayfrom the subendocardium.42A3 Nifedipine has beenfound to attenuate this redistribution of coronaryblood flow and to increase subendocardial flow,41possibly by blunting the intense vasodilator responseto ischemia.44 Heusch et a145 have demonstrated thepresence of significant coronary vasodilator reserveduring exercise-induced myocardial ischemia in con-scious dogs and that nifedipine can recruit this reserveand induce an improvement of ischemic regionalmyocardial blood flow and function without majoreffects on systemic hemodynamics. One of the possibleantianginal mechanisms of nisoldipine would be animprovement in the distribution of coronary bloodflow to the subendocardium. The improved myocar-dial relaxation and diastolic compliance produced bynisoldipine like nifedipine46 could have been a possi-ble contributing factor to the increase in myocardialblood flow by increasing the perfusion pressure gradi-ent to the subendocardium.47

Waltier et a148 have reported that nisoldipineincrease coronary collateral blood flow to the isch-emic zone with equal distribution to the subendocar-dium and epicardium in dogs with acutely occludedleft anterior descending arteries. In the presentstudy, seven of 19 patients did not show collateralfilling, whereas their exercise-induced ischemic ST-segment depression improved and their exercise-induced chest pain was not induced or was of less-ened severity after nisoldipine administration. Theseresults may suggest that an increase in collateralblood flow could not be a principal mechanism ofantianginal action of nisoldipine in humans.

In addition to modulating coronary blood flow,nisoldipine could be involved in a variety of calcium-dependent processes to protect myocardium fromischemia including reduction of nucleotidebreakdown,49 stabilization of membrane perme-ability,50 protection of the integrity of sarcolemmalmembranes,51 and inhibition of leukotriene actions.52Any combination of these or other factors may play

an important role in the mechanism of protection bynisoldipine from acute myocardial ischemia, but wecould not distinguish among any of these mechanismsin the present study.

Reproducibility of Exercise Test ResultsWhen the symptom-limited bicycle ergometer exer-

cise test was performed in patients with stable effortangina pectoris, the exercise time, heart rate, and leftventricular end-diastolic pressure for evaluation of leftventricular function have been generally said to bereproducible.53,54 In the present study, the clinical andhemodynamic events induced by supine leg exerciseduring invasive studies were reproducible after placeboadministration in patients with stable effort anginapectoris. Excellent reproducibility was demonstrated inheart rate, rate-pressure product, and cardiac output aswell as coronary sinus flow and coronary vascularresistance both at rest and at peak exercise. Onlypulmonary artery wedge pressure at rest dropped sig-nificantly, compared with control study, after placeboadministration. However, this pressure at peak exercisewas not affected at all by placebo administration.Accordingly, the hemodynamic effects of nisoldipine,except pulmonary artery wedge pressure at rest,observed in this study should be reliable.

Pharmacokinetics of NisoldipineIn the present study the total plasma concentration

of nisoldipine and its active metabolites reached apeak 1.6 hours after administration, and the elimina-tion half-life was 1.3 hours. The bicycle ergometerexercise test was performed 1.5 hours after nisoldipineadministration, and it should be possible to obtainsufficient effects of nisoldipine at this time. Despitethis short half-life the pharmacodynamic effect ofnisoldipine was shown to persist for a much longerperiod.12,21 This discrepancy may be due to tissuebinding or to formation of an active metabolite.Recently it has been elucidated that nisoldipine hasthree active metabolites and exhibits dose-proportionalpharmacokinetics at oral dose from 2.5 to 20 mg.54

Limitation of StudyDynamic exercise tests with invasive hemodynamic

studies may be the most important practical test toelucidate the mechanism of antianginal drugs inpatients with effort angina pectoris. However, thisinvasive study may have some limitations. In thisstudy nisoldipine or placebo was always given afterthe control exercise. A possible order effect of thisstudy design cannot be denied. However, as nisol-dipine has a long pharmacodynamic effect, it was notpossible to reverse the order of exercise tests withinvasive hemodynamic monitoring. For the samereason, this was a study of only a single dose ofnisoldipine since repeated invasive studies could notbe justified. An oral dose of 10 mg nisoldipine used inthis study has been reported to be significantlyeffective11,12,20 and is a frequently used dose in clini-cal practice. Although a double-blinded design may


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be recommended for the evaluation of drug effects,the present study was a single-blinded design, andthis may be an important limitation of this study.Invasive hemodynamic measurements, including cor-onary sinus flow, which is a very important parameterin this study, are not always easy to be obtainedduring exercise in humans. The number of thepatients whose coronary sinus flows could not bemeasured led to unequal group sizes, which isanother potential limitation, but the placebo groupwas used only to demonstrate the reproducibility ofthe exercise protocol.

AcknowledgmentsWe thank Professor Sadayuki Sakuma (Director

of the Central Radiology Laboratory) for hisencouragement in accomplishing this study. Wealso thank Drs. Fumio Saito, Ryozo Kato, YasuhiroKodama, Kozo Nagata, Hitoshi Ishihara, and Masa-hiko Maeda for their cooperation in this study andMayumi Mori, Michiyo Hioki, and Tomoko Shibatafor their secretarial assistance.

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KEY WORDS * oxygen uptake * oxygen supply * coronary flow* wall tension * exercise tests


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and J TakeuchiM Yokota, T Miyahara, M Iwase, M Watanabe, T Matsunami, S Kamihara, M Koide, H Saito

in dynamic exercise-induced angina.Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine

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