Effects of Nisoldipine on Systemic and Leg Blood Flow, Oxygen Transport and Metabolism, and

Hemodynamics During Exercise in Effort Angina Pectoris

Jai Ram, MB, S. Ben Freedman, MB, PhD, Sadamasa Ogasawara, MD, Andrew Thomson, MB, and David T. Kelly, MB

The acute effects of 10 mg of oral nisoldipine on hemodynamics, oxygen transport and metabolism, and distribution of cardiac output, at rest and dur- ing semiupright bicycle exercise, were evaluated in 10 men with effort angina receiving long-term /31 blockade. Cardiac output and leg blood flow were measured using the thermodilution technique. At rest, nisoldipine decreased systemic resistance from 18.9 f 1.0 to 15.9 f 1.2 dynes l s l cmp5 l

102 (p <0.05) and cardiac output increased from 4.8 f 0.2 to 5.3 f 0.3 liters/min (p <O.OS) without changing leg blood flow. During maximal exercise with nisoldipine, systemic resistance was reduced (10.6 f 0.9 to 8.6 f 0.5 dynes l s l cm-5 l lo*, p <0.05) and cardiac output increased 18% (10.3 f 0.7 to 12.2 f 0.6 liters/min, p <0.05) when com- pared with control values. Exercise heart rate was higher with nisoldipine (113 f 4 vs 106 f 4 beats/ min, p <O.Ol), but the mean arterial pressure was not significantly changed, giving a higher rate-pres- sure product. The increase in mean pulmonary ar- tery wedge pressure was attenuated (26 f 3 vs 30 f 3 mm Hg during control exercise, p <O.OS), but ST depression was unaltered. Exercise leg flow was reduced by nisoldipine from 4.3 f 0.4 to 3.9 f 0.3 liters/min (p = 0.07) and the proportion of car- diac output distributed to the legs was reduced from 42 f 3 to 33 f 3% (p KO.01). Despite this, leg oxygen saturation and extraction, femoral ve- nous and arterial lactate concentration, femoral venoarterial lactate difference, leg lactate produc- tion and femoral venous pH did not change, indicat- ing no significant alteration in leg oxygen transport or oxidative metabolism. In keeping with its vasodi- lator action, nisoldipine altered rest and exercise hemodynamics. Although exercise cardiac output increased, flow was redistributed away from exer- cising muscle without changing oxygen transport or metabolism.

(Am J Cardiol 1989;63:802-806)

D uring exercise there is a marked increase in cardi- ac output, largely as a result of increased flow to exercising muscle. 1-3 Vasodilator drugs used

to treat effort angina may further augment cardiac out- put during exercise, but may alter adversely the regional distribution of blood flow to exercising muscles. We have previously shown that the dihydropyridine calcium antagonist, nifedipine, increased cardiac output at rest and during exercise in patients with effort angina, al- though the proportion of cardiac output going to exer- cising legs was reduced.4 Nisoldipine is a new, longer acting dihydropyridine drug, with more potent coronary and systemic vasodilator effects than nifedipine or dilti- azem,5,6 and has been shown to be an effective antiangi- nal agent when used alone7-9 or in combination with a /3 blocker.‘O The purpose of this study was to determine the effect of nisoldipine on systemic and regional blood flow, and oxygen transport and metabolism, as well as on hemodynamics during exercise in patients with effort angina receiving long-term ,f31 blockade.

METHODS Patients: Ten men ages 56 f 7 years (mean f stan-

dard deviation) (range 44 to 63) were studied within 3 weeks (mean 12 f 7 days) of coronary angiography. All patients had stable effort-related angina pectoris (func- tional class 2 to 3) and a positive result for ischemia on the exercise electrocardiogram. There was a history of prior myocardial infarction in 7 patients. Patients with unstable angina, recent (<8 weeks) myocardial infarc- tion and clinical congestive heart failure were excluded. Three patients had l-vessel disease (>70% lumen diam- eter reduction), 6 had 2-vessel and 1 had 3-vessel dis- ease. The mean left ventricular ejection fraction was 58 f 10% (range 43 to 7 1). No patient had significant val- vular heart disease or intermittent claudication, and all had good pedal pulses without femoral bruits.

All patients were receiving long-term fir selective blockade with either metoprolol (100 to 200 mg/day) or atenolol (50 to 100 mg/day) for angina pectoris. Con- From the Hallstrom Institute of Cardiology, University of Sydney, Royal Prince Alfred Hospital, Sydney, Australia. This study was sup- ported by a grant from Bayer AG, Sydney. Manuscript received Sep- tember 19, 1988; revised manuscript received and accepted January 3, 1989.

Address for reprints: S.B. Freedman, MD, Hallstrom Institute of Cardiology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia 2050.

802 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

TABLE I Effect of Nisoldipine on Systemic Hemodynamics and Oxygen Metabolism

HR MAP co PAWP SVR

(beats/mtn) (mm W (hters/min) (mm H&9 (dynes. s. crnm5. lo*) van (liters/min)

Control Rest 62dz3 113f3 4.8f0.2 5fl 18.9 f 1.0 0.26f 0.02 30*2 Submax 94f4 134f6 8.0 f 0.5 26f3 133fl.l 0.90 f 0.09 62f5

(30 watts) Max 106f4 138f7 10.3 f 0.7 30f3 10.6 f 0.9 1.27f0.11 66f4

(48 watts) Nisoldipine

Rest 69zk3* 104f2” 5.3 f 0.3t 4fl 15.9 i 1.2+ 0.29 zko.03 30f2 Submax lOOf 128f4 9.8 f 0.6t 22f4 10.2 f 5.67 1.06 f 0.08 58f3

(30 watts) Max 113f44 133f4 12.2 f 0.6t 26f3+ 8.6 f 0.5t 1.37 f0.12 594z3t

(48 watts)

Data are mea” * standard error of the mean * p <O 01. * p <O 05 nlsoldlplne “s correspondang level during control exercne CO = cardiac output, HR = heart rate: MAP = mean arterial pressure; 02 Ext = systemic oxygen extraction. PAWP = mean pulmonary artery wedge pressure, SIR = systenc vas-

cular resistance: VO2 = systemic oxygen consumptv3n

comitant calcium antagonist therapy (4 patients) was stopped for at least 48 hours and oral or cutaneous ni- trates (5 patients) for at least 24 hours before the study. Sublingual nitroglycerin was continued as required.

The protocol was approved by the institutional ethics review committee and all patients gave written informed consent.

Study protocol: The study was an open within-pa- tient evaluation of a single oral dose of nisoldipine. Methodology was similar to that of our nifedipine study.4 Briefly, a 7Fr Swan-Ganz thermodilution cathe- ter was inserted through the right antecubital vein and positioned in the right pulmonary artery. A 5Fr Swan- Ganz thermodilution catheter was inserted percutane- ously into the right femoral vein and advanced about 15 cm anterograde into the iliac vein, so that the tip was 1 cm distal to the pubic ramus. A short 21-gauge polyeth- ylene cannula was inserted into the right radial artery.

After instrumentation, patients were positioned on a semiupright (45’) bicycle ergometer. After 15 to 20 minutes, baseline hemodynamic measurements were made and blood samples obtained from the radial artery and femoral vein to measure lactate concentration, oxy- gen saturation and hemoglobin, and from the pulmo- nary artery to measure oxygen saturation and hemoglo- bin. Phasic and mean systemic arterial, pulmonary ar- tery, pulmonary artery wedge and right atria1 pressures were recorded at rest and during exercise.

Patients began exercising with an initial workload of 30 watts, which was increased by 20 watts every 4 min- utes until exercise was limited by chest pain, fatigue or breathlessness. Leg blood flow and cardiac output mea- surements were made during the second and third min- utes of each exercise level. Pressure measurements and samples were taken in the fourth minute.

After the first exercise test, patients were given 10 mg of nisoldipine orally. Two hours later, rest measure- ments were repeated and the exercise protocol was re- commenced, with measurements obtained at times iden- tical to those in the control study. Patients were exer- cised to an identical workload (mean 48 watts). One patient stopped after 30 watts and the remainder reached 50 watts.

Methodologic studies: Femoral vein flow was mea- sured with a 5Fr Swan-Ganz thermodilution catheter and 2.5-ml bolus injections of iced 5% dextrose. Flow measurements using this technique correlate closely with directly measured flow in vitro (r = 0.99, standard error of the estimate = 0.17 liter/min), as we have pre- viously repork14 Total leg blood flow was calculated as twice the flow measured in 1 leg. Rest and exercise leg flow measurements were similar to previous studies us- ing this technique or other methods.4J-14

Measured variables: Oxygen tension and saturation, hemoglobin concentration, pH, carbon dioxide tension and bicarbonate were measured in each blood sample. Blood oxygen content was calculated as the product of hemoglobin concentration, 1.39 ml oxygen/g hemoglo- bin, and oxygen saturation. Cardiac output was mea- sured by thermodilution and iced dextrose. Blood for lactate measurement was collected in perchloric acid and assayed by a spectrophotometric technique.

Twelve-lead electrocardiograms plus bipolar leads CM4 through CM6 were continuously monitored during and after exercise on a Marquette Case-2 recorder with automated measurements of ST-segment deviations.

Statistical methods: Data are presented as mean f standard error. Differences between measurements at rest and at each exercise level before and after nisoldi- pine were compared using paired t tests. Measurements for these comparisons were made at identical workloads and times. A p value <0.05 was considered significant. For technical reasons, lactate measurements were not available in 1 patient, and oxygen saturation measure- ments were not available in another. No statistical tech- niques were used to interpolate missing data values for these 2 patients.

RESULTS Systemic hemodynamic and metabolic measure-

ments: CONTROL: At rest, cardiac output and mean pul- monary artery wedge pressure were normal and the mean heart rate was 62 beats/min, consistent with nor- mal left ventricular function and p blockade. Systemic oxygen extraction was 30% and total oxygen consump- tion was 0.26 f 0.02 liter/min (Table I, Figure 1).

THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1, 1989 803

NIBOLDIPINE AND EXERCISE BLOOD FLOW

TABLE II Effect of Nisoldipine on Leg Flow

Leg Flow (liters/min)

Leg Flow/CO rytes-s-cm-5. lo*) (%)

Control Rest 0.54zt 0.06 357f31 llfl Submax 4.1 f 0.3 48f4 51f2

(30 watts) Max 4.3 f 0.4 53h6 42f3

(48 watts) Nisoldipine

Rest 0.56 f0.05 314&30 llfl Submax 3.5 f 0.3” 54f5 38h4f

(30 watts) MS 3.9 f 0.3% 57 f 5 33%3+

(48 watts)

Data are mean *standard error of the mean. *p=Ocr3,~p<ool,*

exe&e test p = 0 07. nmldipme vs correspondmg level durmg control

CO = cardm output, FVR = ilmfemoral vascular resistance.

Patients exercised for an average of 8 minutes until stopped by chest pain (6 patients), fatigue (2) or short- ness of breath (2), at a mean maximal workload of 48 watts. Maximal oxygen consumption increased to 1.27 f 0.11 liters/min. Cardiac output reached a peak of 10.3 f 0.7 liters/min with a large increase in mean pul- monary artery wedge pressure to 30.2 f 2.5 mm Hg. Systemic oxygen extraction increased to 66% and arteri- al lactate increased from 0.6 f 0.2 to 4.7 f 1.0 mmol/ liter.

EFFECTS OF NISOLDIPINE: Administration of nisoldipine caused a 10% increase in resting cardiac output without change in systemic oxygen extraction, Nisoldipine de- creased resting systolic, diastolic and mean arterial pres- sures and increased heart rate, with a reduction in sys-

FIGURE 1. Effect ef nisoldipine on hemodynamico at rest and duing submaximal (30 watts) and maximal (48 watts) exer- cise. Nisoldipine values are indiited by the open &c/es and job& by broken hes, control values by crosses and so/id linea Error bars represent standard error of the mean. *p <O.OS, * *p <O.Ol nisoldipine versus corresponding level during control exercise test. MAP = mean arterial pressure; PAWP = mean pulmonary artery wedge pressure; RA mean = mean right atrial pressure.

804 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

temic resistance, in keeping with its known vasodilator action.

At maximal exercise, duration and workload (mean 48 watts) were identical to control values in each pa- tient. Exercise was limited by the same symptom, al- though in 1 patient angina was less severe and in anoth- er more severe after nisoldipine. Maximal ST-segment depression was unchanged by nisoldipine (2.2 f 0.2 mm for both control and nisoldipine), and all patients had positive results on the exercise electrocardiograms be- fore and after nisoldipine.

The cardiac output at maximal exercise was signifi- cantly increased by nisoldipine, from 10.3 f 0.7 to 12.2 f 0.6 liters/min (p <0.05), and systemic vascular resis- tance was correspondingly reduced. Oxygen extraction decreased from 66 to 59%, consistent with the increased cardiac output, but maximal oxygen consumption was unchanged. The maximal heart rate increased signifi- cantly with nisoldipine, from 106 to 113 beats/min, without significant change in systolic, diastolic or mean arterial pressures, so there was a significant increase in rate-pressure product from 20.6 f 1.5 to 22.1 f 1.2 beats/min X mm Hg/lOO (p <0.05). The increase in mean pulmonary artery wedge pressure was slightly but significantly attenuated (30 f 3 vs 26 f 3 mm Hg, p <0.05) and the mean right atria1 pressure was signifi- cantly lowered. Peak arterial lactate did not change sig- nificantly with nisoldipine.

Leg blood flow and metabolism: CONTROL: At rest, leg blood flow was 0.54 f 0.06 liter/min, which repre- sented 11% of the cardiac output. Leg oxygen extrac- tion was 49% and leg oxygen consumption was 46 f 6 ml/min (Tables II and III, Figure 2).

With exercise, there was an g-fold increase in leg blood flow and a decrease in femoral vascular resis- tance. Leg oxygen consumption’increased to 609 f 53 ml/min and oxygen extraction increased to 78%. There was a 6-fold increase in femoral lactate, with a concom-

FIGURE 2. Effect of nisoldipine on cardiac output, systemic vascular resistance (SVR), leg flow and distribution of cardiac output to legs (LEG FLOWX.0.). Symbols as in Figure 1.

TABLE III Effect of Nisoldipine on Leg Oxygen Transport and Metabolism

Control Rest Submax

(30 watts) Max

(48 watts) Nisoldipine

Rest Submax

(30 watts) Max

(48 watts)

Leg

g$

50f4 22f3

21f3

48f3 23f2

23f3

Leg 02

(;

49ic4 78zk3

78f4

50f3 76f2

77f3

Leg w? (ml/mm)

46zk6 582 f 42

609 f 53

5Of5 490 f 44*

539 f 42

Femoral Lactate

(mmol/liter)

0.7 f 0.2 3.7 f 0.6

6.0 f 1.0

0.7 f 0.4 3.3 f 0.7

5.8f 1.0

V-A Lactate

Difference (mmol/liter)

0.05 f 0.07 1.1 f 0.3

1.1 eo.3

0.19 f 0.2 0.7 f 0.4

0.7 f 0.6

Lactate Productlon Femoral

(mmol/min) PH

0.02 f 0.04 7.36 f 0.05 4.9 f 1.6 7.24* 0.17

4.9 f 1.6 7.19 f 0 02

0.15 f0.15 7 37 f 0.01 21f1.5 7.27 f 0.16

2.0 f 2.2 7.21 f 0 02

Data are mean f standard error of the mean. * p <0.05 nisoldlpine vs corresponding level during control exwxe test Leg 02 Ext = illofemoral oxygen extraction; Leg SO2 = iliofemoral venous oxygen saturatvw Leg V02 = leg oxygen consumptKn V-A = lllofemoral venous-arterial

itant increase in venoarterial lactate gradient, lactate decrease in that study. This difference may be due to production and decrease in leg pH. the more potent vasodilator action of nisoldipine.

EFFECTS OF NISOLDIPINE: Administration of nisoldipine did not produce any change in resting leg blood flow or iliofemoral vascular resistance. Leg oxygen consump- tion and oxygen extraction were also unchanged.

During exercise, leg blood flow was reduced by ni- soldipine at both submaximal and maximal work levels from 4.30 f 0.4 to 3.86 f 0.3 liters/min (at maximal work), although this just failed to reach statistical sig- nificance (p = 0.07). The iliofemoral vascular resistance was not further reduced by nisoldipine. Oxygen extrac- tion and consumption also remained unchanged at max- imal work.

Nisoldipine did not alter the increase in femoral lac- tate levels seen during control exercise. There were no differences in venous-arterial lactate gradient or leg lac- tate production from the control exercise and there was an identical decrease to 7.21 in leg pH.

The changes in distribution of cardiac output and leg blood flow found-in this study did not adversely affect leg oxygen transport or metabolism, as leg oxygen ex- traction and arteriovenous oxygen difference were un- changed from control values. In addition, because lac- tate levels and venoarterial lactate gradients were un- changed, lactate production and leg pH were not significantly altered. The majority of our patients had a reduced maximal exercise capacity during the control stage (mean maximal work level of 48 watts) and were limited mainly by significant angina or dyspnea. This suggests thdt;limitation of exercise was due to myocar- dial ischemia rather than leg muscle fatigue, so our re- sults cannot necessarily be extrapolated to patients, with lesser degrees of ischemia and greater exercise capaci$, who are limited instead by fatigue. :

The antiischemic effects of ‘nisoldipine have been REGIONAL DISTRIBUTION 0~ CARDIAC OUTPUT: Resting

leg blood flow before the administration of nisoldipine represented 11 f 1% of cardiac output. This did not change after nisoldipine (Table II, Figure 2). At sub- maximal and maximal exercise, the proportion of cardi- ac output going to the legs was reduced from 51 to 38% (p <O.Ol) and from 42 to 33% (p <O.Ol), respectively.

DISCUSSION Through its vasodilator action, nisoldipine decreased

systemic resistance and increased cardiac output both at rest and during exercise, but leg blood flow did not in- crease. Although at peak exercise the cardiac output in- creased by 18% after nisoldipine, this effect was not dis- tributed to exercising muscle, as leg flow decreased slightly. Therefore, the proportion of cardiac output supplying exercising muscle decreased significantly, from 42 to 33%. The normal or-adrenergic vasoconstric- tor control of blood flow to nonexercising vascular bedsly was probably overcome by nisoldipine-induced vasodilation to redistribute cardiac output away from exercising muscle. Similar changes were observed in a previous study using nifedipine,4 but leg flow did not

confirmed in a number of studies of angina1 patients&r0 that show’increases in exercise time, time to angina and time to l-mm ST depression,. The postulated ,mecha- nisms of action are reduced afterload15-*7 and coronary vasodilation.6J6J8 This is partially offset by the reflex increase in heart rate that is attenuated after longterm dosage8>9 or by concomitant /?-blockade.1°J7 Although our exercise test protocol was no# designed to measure antianginal efficacy, we found no significant reduction of exercise angina and no change in maximal ST de- pression at peak exercise. The increase in wedge pres- sure during exercise-induced ischemia was mildly atten- uated by nisoldipine, suggesting some antiischemic ef- fect.

The hemodynamic changes after nisoldipine docu- mented in this study confirm the vasodilator actions seen in previous studies. 15-i7 Although systemic resis- tance was reduced both at rest and during exercise, ar- terial pressure was reduced significantly only at rest. Reflex increases in heart rate after nisoldipine were seen both at rest and during exercise’despite /z? blockade, as noted previously.17 Thus, the rate-pressure product dur- ing exercise increased slightly in our study and may ac-

THE AMERICAN JOURNAL OF CARDIOLOGY APRIL I;‘1989 805

NISOLDIPINE AND MERCISE BLOOD FLOW

count for the limited antianginal efficacy during acute administration of nisoldipine.

Limitations of study: In this study, femoral venous thermodilution flow measurements were combined with sampling of femoral venous effluent to investigate the effects of nisoldipine on perfusion, oxygen availability and metabolism of working muscle. Thermodilution techniques for measuring leg flow have been validated in our and other laboratories,4J2J4 but have a basic lim- itation of measuring flow from nonexercising tissue in addition to exercising muscle. Although nonmuscular flow makes up a significant proportion of femoral flow at rest, the contribution is much smaller during exercise and is unlikely to have influenced the results.

This was a single-dose of study of nisoldipine, where the drug was always given after the control exercise. We were aware of the possible order effect of this study design, but given the long half-life of nisoldipine it was not possible to reverse the order of exercise tests. All studies were performed during ,&blocker therapy with a pr selective drug. This should not have interfered with the results, as ,6 blockade has not been found to alter leg blood flow or exercise-induced vasodilation. lg Combina- tions of fl blocker and vasodilators such as nifedipine have been shown effective in treating angina pectoris.20 This is also the case for nisoldipine,1°J5 and it is likely that this combination will be used clinically.

Acknowledgment: We would like to acknowledge the expert technical assistance of Leena Mitra-Duncan, BSc, and the cooperation of cardiologists and research personnel at the Hallstrom Institute.

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