Acute Vasoreactivity Testing with Nicardipine in Patients with Pulmonary Arterial
Hypertension

Yukihiro Saito1, Kazufumi Nakamura1, Katsumasa Miyaji2, Satoshi Akagi1, Hiroki
Mizoguchi3, Aiko Ogawa3, Soichiro Fuke4, Hideki Fujio5, Takahiko Kiyooka6, Satoshi
Nagase1, Kunihisa Kohno1, Hiroshi Morita1, 7, Kengo F Kusano1, Hiromi Matsubara3, Tohru
Ohe1, and Hiroshi Ito1

From the 1Department of Cardiovascular Medicine, Okayama University Graduate School of
Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; 2 Department of
Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan;
3

Division of Cardiology, National Hospital Organization, Okayama Medical Center, Okayama,

Japan; 4Departmemt of Cardiology, Japanese Red Cross Okayama Hospital, Okayama, Japan;
5

Departmemt of Cardiology, Japanese Red Cross Society Himeji Hospital, Himeji, Japan;

6

Division of Cardiology, Tokai University Oiso Hospital, Oiso, Japan; 7Department of

Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry,
and Pharmaceutical Sciences, Okayama, Japan.

Corresponding Author/Reprints: Kazufumi Nakamura, MD, PhD
Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, 2-5-1 Kita-ku, Shikata-cho, Okayama 700-8558,
Japan.
Phone: +81-86-235-7351

Fax: +81-86-235-7353,
1

E-mail: ichibun@cc.okayama-u.ac.jp

Short running title:

Nicardipine Challenge in PAH

Disclosure: None.
The authors have no conflicts of interest to report.

2

Abstract:

Acute vasoreactivity testing for patients with pulmonary arterial hypertension(PAH) has been reported to be useful to identify patients with sustained beneficial response tooral calcium channel blockers (CCBs), but there is a risk of exacerbation during the testingwith oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine,
a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testingwith nicardipine in PAH patients.
performed in 65 PAH patients.

Acute vasoreactivity testing with nicardipine was

Nicardipine was administered by short-time continuous

infusion (1 μg/kg/min for 5 min and 2 μg/kg/min for 5 min) followed by bolus injection (5μg/kg). Hemodynamic responses were continuously measured using a right heart catheter.
Acute responders were defined as patients who showed a decrease in mean pulmonary arterypressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved orincreased cardiac output.

Two acute responders and sixty-three non-acute responders wereidentified. There was no hemodynamic instability requiring additional inotropic agents ordeath during the testing.

Acute responders had good responses to long-term oral CCBs.

The acute vasoreactivity testing with nicardipine is safe and might be useful for identifying
CCB responders in PAH patients.

Key words: calcium channel blockers, acute vasoreactivity testing, pulmonary arterial
hypertension
13Abbreviations
BP = blood pressure; BNP = brain natriuretic peptide; [Ca2+]cyt = free Ca2+ concentration in
the cytosol; CCB = calcium channel blocker; CO = cardiac output; CI = cardiac index;
GPCR = G protein-coupled receptors; HR = heart rate; iNO = inhaled nitric oxide; IP3R =inositol 1,4,5-trisphosphate receptors; NO = nitric oxide; PAH = pulmonary arterial
hypertension; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge
pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RHC = rightheart catheterization; ROC = receptor-operated Ca2+ channel; SaO2 = saturation of arterial
blood; SOC = store-operated Ca2+ channel; SPAO2 = saturation of pulmonary arterial blood;
SRAO2 = saturation of right atrial blood; SVR = systemic vascular resistance; TRPC =transient receptor potential cation channels; TPR = Total pulmonary resistance; TRPG =tricuspid regurgitation pressure gradient; VDCC = voltage-dependent calcium channel

4Introduction
Pulmonary arterial hypertension (PAH) is a condition characterized by elevatedmean pulmonary artery pressure, and the prognosis is poor in most cases (1, 2).

Although

we and other investigators have reported that a small proportion of patients with PAH respondto long-term calcium channel blockers (CCBs) and have a better prognosis (3-6), the empiricuse of CCBs in PAH is not recommended because of the risk of exacerbation (7, 8).
Acute vasoreactivity testing is usually performed to predict a better prognosis andidentify acute responders who are more likely to have a sustained beneficial response to oral
CCBs and can be treated with these less-expensive drugs (6, 9).

Although acutevasoreactivity testing is most commonly performed using inhaled nitric oxide (iNO) (10),intravenous epoprostenol (11), or intravenous adenosine (12), there are uncertainties
regarding the choice of vasodilator (13).
In pulmonary arterial smooth muscle cells (PASMCs), the free Ca2+ concentration in
the cytosol ([Ca2+]cyt) is an important determinant of contraction, migration and proliferation.
[Ca2+]cyt in PASMCs can be increased by Ca2+ influx through voltage-dependent calcium
channels (VDCC), receptor-operated Ca2+ channels (ROC) and store-operated Ca2+ channels(SOC) and by Ca2+ release from intracellular stores via inositol 1,4,5-trisphosphate receptors(IP3Rs) and ryanodine receptors.

NO, epoprostenol and adenosine suppress elevation of[Ca2+]cyt through inhibition of ROC and SOC, which are associated with G protein-coupled
receptor (GPCR), IP3R and transient receptor potential cation channels (TRPCs); however,
CCBs suppress the elevation through inhibition of VDCCs (14).
Acute vasoreactivity testing using CCBs appears to be a reasonable method forpredicting response to long-term CCBs, however, the safety and efficacy of oral andintravenous CCBs for the testing have not been established in PAH patients.
5

Occurrence of

life-threatening hemodynamic compromise has often been documented in nifedipine andverapamil testing (7, 15, 16). Therefore, it is now accepted that CCBs should not be used for
acute testing (17, 18).
Since oral CCBs have a long half-life, there is a risk of exacerbation due toinstability of pharmacokinetics when they are used for testing (7, 16).

Therefore, thedevelopment of a testing method using a short-acting intravenous CCB is needed.
Nicardipine chloride, a hypotensor available in most countries in the world, isadministered to patients with hypertensive emergency, to those with acute heart failure
associated with hypertension, and to those with hypertension during an operation bycontinuous infusion at 0.5 to 6 μg/kg/min, at 0.5 to 2 μg/kg/min, and at 0.5 to 10 μg/kg/min orbolus injection at 10 to 30 μg/kg respectively, by reference to Japanese package insert.

The

half-life of nicardipine after intravenous injection at 10 μg/kg to a healthy adult is about 1 h,which is shorter than that of nifedipine at 10 mg per os (about 2.6 hours).

Therefore, wedeveloped a testing method using short-acting intravenous nicardipine and examined thesafety and usefulness of the test.

Materials and Methods
Subjects
We performed acute vasoreactivity testing using intravenous nicardipine for adultpatients diagnosed as having PAH without left heart disease who had been hospitalized in our
hospital from April 1999 to October 2011.
Pulmonary hypertension was defined by a resting mean pulmonary artery pressure(PAP) ≥25 mmHg during right heart catheterization (RHC) with a mean pulmonary capillarywedge pressure (PCWP) ≤15 mmHg (19).
6Exclusion criteria were as follows: thromboembolic pulmonary hypertension,
hemodynamic instability including cardiac index less than 2.2 L/min/m2 and systolic bloodpressure less than 80mmHg, or having symptoms associated with low cardiac output at rest.
All of the studies were approved by the Ethics Committee of Okayama University
Graduate School of Medicine, Density, and Pharmaceutical Sciences, and written informed
consent was obtained from all patients before the procedure. The investigation also
conformed to the principles outlined in the Declaration of Helsinki.

Baseline Evaluation
Baseline evaluation included medical history, WHO functional class, physicalexamination, 6-minute walk test and brain natriuretic peptide (BNP). Baseline
hemodynamic evaluations were performed in all patients with RHC as previously described (1,20).

Baseline hemodynamic measurements included heart rate (HR), blood pressure (BP),right atrial pressure (RAP), mean PAP, PCWP, and CO determined by the Fick method.
Cardiac index (CI) was calculated as CO/body surface area. Total pulmonary resistance(TPR) was calculated as (mean PAP/CO) × 80.

Acute Vasoreactivity Testing
Acute vasoreactivity testing was performed at the time of absence of hemodynamic
instability. Acute pulmonary vasodilator responsiveness was assessed by administration ofnicardipine (Astellas Pharma Inc, Tokyo, Japan) with short-time continuous infusion (1μg/kg/min for 5 min and 2 μg/kg/min for 5 min) followed by bolus injection (5 μg/kg) (Figure
1).

We used continuous infusion at a low dose for a short time before bolus injection toensure PH patients’ safety.
7

Hemodynamic responses were continuously measured before, during and afteradministration of nicardipine using an RHC. SaO2 (saturation of arterial blood) and SPAO2(saturation of pulmonary arterial blood) were measured to calculate CO every 5 minutes.

A

significant acute response to nicardipine was defined as a reduction in mean PAP of at least
10 mmHg to an absolute mean PAP of less than 40 mmHg without a decrease in CO
according to the American College of Chest Physicians developed guidelines (21).
Discontinuance criteria were systemic BP less than 70 mmHg, HR elevation more than 50
bpm from baseline, and/or appearance of any other constitutional symptoms.

Chronic Treatment with CCB
Chronic oral CCB therapy was initiated in patients who showed significant acutepulmonary vasoreactivity as defined above.

Statistical Analysis
All values are expressed as mean ± standard deviation.

Results
Study group
Sixty-five patients met the criteria of PAH and were included in the analysis. The
clinical characteristics and baseline hemodynamic parameters of these 65 patients are shownin Table 1.

Responses to intravenous nicardipine and long-term CCB in acute responders
Hemodynamic changes during the testing are shown in Table 2. The values after8

administration shown in Table 2 were measured when maximum variation of mPAP was
detected. There was no hemodynamic instability requiring additional inotropic agents ordeath during the testing.

Two acute responders were identified.

Responder 1
A 26-year-old woman with idiopathic PAH was admitted to our hospital 4 years after
diagnosis at another hospital.

Beraprost sodium at a daily dose of 60 μg had been prescribedfor 2 years, but shortness of breath became exacerbated and recurrent episodes of syncope
during activity occurred.

She was therefore referred to our hospital for treatment.

Pretherapeutic hemodynamic data were as follows: HR, 65 bpm; systemic BP, 108/66/85
mmHg; PCWP, 7 mmHg; PAP, 84/35/55 mmHg; RAP, 5 mmHg; CO, 3.3 L/min; CI, 2.2
L/min/m2; systemic vascular resistance (SVR), 1939 dynes·sec·cm–5; pulmonary vascular
resistance (PVR), 1163 dynes·sec·cm–5; and TPR, 1333 dynes·sec·cm–5.
Unfortunately, her hemodynamic data were incomplete because the right heart
catheter tip had moved down to the right ventricle from the pulmonary artery and could not berecovered.

Systolic right ventricular pressure (sRVP) and saturation of right atrial blood(SRAO2) were therefore assessed as alternatives to systolic PAP and saturation of pulmonary
arterial blood (SPAO2), respectively.

Her sRVP decreased to 41 mmHg from 69 mmHg and

CO increased to 3.0 L/min from 2.0 L/min after administration of nicardipine, and she wastherefore considered to be an acute responder.
Treatment with oral nifedipine at a daily dose of 10 mg was started, and then thedaily dose was titrated up to 90 mg.

Two years after starting the drug treatment, her data

were as follows: HR, 64 bpm; systemic BP, 135/85/102 mmHg; PCWP, 5 mmHg; PAP,
35/10/22 mmHg; RAP, 0 mmHg; CO, 4.1 L/min; CI, 2.8 L/min/m2; SVR, 1990
9

dynes·sec·cm–5; PVR, 331 dynes·sec·cm–5; and TPR, 429 dynes·sec·cm–5. Figure 2 shows
improvement of right ventricular overload on an electrocardiogram and improvement inenlargement of cardiothoracic ratio and main pulmonary trunk on a chest X-ray. She has
now achieved remission without PAH.

Responder 2
A 37-year-old woman with IPAH was admitted to our hospital with the chiefcomplaint of shortness of breath.
Pretherapeutic hemodynamic data were as follows: HR, 65 bpm; systemic BP,
117/67/89 mmHg; PAP, 62/25/37 mmHg; RAP, 2 mmHg; CO, 6.1 L/min; CI, 3.6 L/min/m2;
SVR, 1135 dynes/sec/cm5; and TPR, 482 dynes/sec/cm5.
Hemodynamic changes in this acute responder were as follows: HR, 65 bpm;
systemic BP, 111/60/79 mmHg; PAP, 39/15/24 mmHg; RAP, 2 mmHg; CO, 6.7 L/min; CI,
4.0 L/min/m2; SVR, 923 dynes·sec·cm–5; TPR, 288 dynes·sec·cm–5; variation in mPAP, -13mmHg; and variation in CO: +0.6 L/min.
Treatment with oral amlodipine at a daily dose of 2.5 mg was started.

Four days

after starting the drug treatment, tricuspid regurgitation pressure gradient (TRPG) had
decreased to 41 mmHg from 70 mmHg as shown by ultrasonography. Now she takes
amlodipine at a daily dose of 5 mg and TRPG is 53 mmHg. Figure 3 shows improvement of
septal flattening during systole and TRPG by an echocardiogram.

Non-responders
Data for the 63 non-responders were as follows: baseline mPAP, 54±18 mmHg;
variation in mPAP, 0.9±4.4 mmHg; and variation in CO, 0.4±0.9 L/min.
10

Discussion
We performed acute vasoreactivity testing using intravenous nicardipine.

The test

was safe and two responders were identified in the 65 patients.
It has been demonstrated that long-term CCB responders have better prognosis thanthat of CCB non-responders, and CCBs are less expensive than other vasodilators (6, 22).
Therefore, vasoreactivity testing to find responders is important and is required in clinicalsettings.
According to the ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension (2009), vasodilator challenge should only be performed with short-acting, safe,and easy-to-administer drugs with no or limited systemic effects (23).

Acute vasoreactivity

testing is most commonly performed using inhaled nitric oxide (iNO) (10), intravenous
epoprostenol (11), or intravenous adenosine (12).

However, several investigators have also

pointed out a problem with these agents: it is important to consider that these agents havedifferent mechanisms of action and diverse hemodynamic effects, and their use may therefore
not be interchangeable (13, 24).

Since iNO vasodilates the pulmonary artery selectively andits half-life is very short (3 minutes) it has minimal systemic side effects (25). However, theduration of inhalation and the concentration for testing have not been standardized.
Although adverse effects of iNO are very rare, to prevent leakage of NO, a delivery system, agas cylinder and respiratory therapy are required.
Intravenous epoprostenol revealed the patients most likely to benefit from CCB
therapy; however, a favorable response to epoprostenol does not indicate that all patients will
have a long-term response to CCBs (22). Epoprostenol causes frequent adverse reactions,such as flushing, headache and hypotension (25).
expensive in Japan than in America.
11

In addition, this drug is ten-times more

Adenosine is an easily available, stable and inexpensive medication that has
pulmonary vasodilatory properties.

Its half-life is 5-10 seconds. When given intravenously,

the short half-life allows a relatively higher plasma concentration of the agent in thepulmonary circulation rather than the systemic circulation, thus reducing systemic side effects(26). Adverse effects are palpitation, bronchospasm, hypotension, bradycardia andatrioventricular block (27).
Acute vasoreactivity testing with the above-described drugs still fails to identify allof the patients who will have a long-term CCB response (6, 9), and it is unclear why somepatients have an initial positive vasoreactivity testing but do not respond to CCBs after sometime.
Furthermore, according to the ESC/ERS Guidelines for the diagnosis and treatmentof pulmonary hypertension (2009) , the use of CCBs given orally or i.v. as an acute test is
discouraged, due to the risk of potentially life-threatening complications, however, thestatement was based on the reports in which oral nifedipine, intravenous/oral verapamil, or
intravenous diltiazem was used for acute vasoreactivity testing (23, 28-31). We performed
acute vasoreactivity testing using intravenous nicardipine. The test was safe in the 65
patients.
Nicardipine is an intravenous CCB, available not only in Japan but also in othercountries, and is administrated as a hypotensor.

This drug inhibits uptake of Ca2+ to vascularsmooth muscle cells to dilate blood vessels (32).

It has been reported that nicardipine has

more powerful antagonism in vascular smooth muscle cells than in cardiomyocytes and ismore vasoselective than other CCBs (nifedipine, verapamil, diltiazem) (33).

Nicardipine,

an intravenous CCB, is short-acting compared to oral CCBs. Therefore, it appeared that
acute vasoreactivity testing using nicardipine could be carried out safely and might be useful12for identifying long-term CCB responders more specifically than other vasodilators. Since ourstudy was carried out in a small population, further controlled studies in larger populations areneeded to confirm our results of testing including safety.
Since nicardipine was reported to induce reflex tachycardia and palpitation, we used
low dosage by reference to that for patients with acute heart failure (34-36), and marked
elevation in HR during testing was not observed in our study (Table 2).

Fortunately, there

were no critical hypotensive effects, and the testing could be carried out safely. However, it
is often difficult to restore a patient’s condition, when the condition has deteriorated.
Therefore, PAH patients should be closely monitored in the intensive care unit during acutevasoreactivity testing.
We did not compare this testing with other conventional vasodilator approaches andan active control group.

Therefore, appropriate dosage for testing and usefulness were notadequately established.

However, the mechanisms by which elevation of [Ca2+]cyt aresuppressed by nicardipine and by other drugs (NO, epoprostenol and adenosine) are different,
and addition of nicardipine testing with other vasodilator approaches might therefore raise theprecision of acute vasoreactivity testing.
A positive test is observed in about 10-15% of patients with IPAH.
half of these patients will experience long-term benefits of CCBs (24).

Approximately

As stated above,nonly a small number of patients benefit from CCBs. However, survival rate of long-term
CCB responders was 97% in an average follow-up period of 7 years in a large retrospective
study (n=557) in which IPAH patients were treated with CCBs after demonstrating acutepulmonary vasoreactivity (6).

Therefore, treatment with a CCB is one of the favorable andpossible treatment options.
In conclusion, acute vasoreactivity testing with nicardipine is safe for PAH patients13and might be useful for identifying long-term CCB responders in PAH patients.

Acknowledgments
We thank Kaoru Akazawa, Aya Miura, Miyuki Fujiwara and Masayo Ohmori for
their excellent technical assistance.

14

References

1.

Akagi S, Nakamura K, Miyaji K, Ogawa A, Kusano KF, Ito H, et al.
Marked hemodynamic improvements by high-dose epoprostenol therapy
in patients with idiopathic pulmonary arterial hypertension. Circ J.
2010;74:2200-5.

2.

Ohkita M, Tawa M, Kitada K, Matsumura Y. Pathophysiological Roles ofEndothelin Receptors in Cardiovascular Diseases. J Pharmacol Sci.
2012;119:302-13.

3.

De Feyter PJ, Kerkkamp HJ, de Jong JP. Sustained beneficial effect of
nifedipine

inprimary

pulmonary

hypertension.

Am

Heart

J.

1983;105:333-4.
4.

Saito D, Haraoka S, Yoshida H, Kusachi S, Yasuhara K, Nishihara M, etal. Primary pulmonary hypertension improved by long-term oral
administration of nifedipine. Am Heart J. 1983;105:1041-2.

5.

Rich S, Kaufmann E, Levy PS. The effect of high doses ofcalcium-channel blockers on survival in primary pulmonary hypertension.
N Engl J Med. 1992;327:76-81.

6.

Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al.
Long-term response to calcium channel blockers in idiopathic pulmonary
arterial hypertension. Circulation. 2005;111:3105-11.

7.

Partanen J, Nieminen MS, Luomanmaki K. Death in a patient withprimary pulmonary hypertension after 20 mg of nifedipine. N Engl J Med.
1993;329:812; author reply -3.

8.

Barst RJ, Gibbs JSR, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin
15

LJ, et al. Updated Evidence-Based Treatment Algorithm in Pulmonary
Arterial Hypertension. Journal of the American College of Cardiology.
2009;54:S78-S84.
9.

Morales-Blanhir J, Santos S, de Jover L, Sala E, Pare C, Roca J, et al.
Clinical value of vasodilator test with inhaled nitric oxide for predicting
long-term response to oral vasodilators in pulmonary hypertension. Respir
Med. 2004;98:225-34.

10.

Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J.
Inhaled nitric oxide as a cause of selective pulmonary vasodilatation inpulmonary hypertension. Lancet. 1991;338:1173-4.

11.

Rubin LJ, Groves BM, Reeves JT, Frosolono M, Handel F, Cato AE.
Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary
hypertension. Circulation. 1982;66:334-8.

12.

Schrader BJ, Inbar S, Kaufmann L, Vestal RE, Rich S. Comparison of theeffects of adenosine and nifedipine in pulmonary hypertension. J Am Coll
Cardiol. 1992;19:1060-4.

13.

Ghofrani HA, Wilkins MW, Rich S. Uncertainties in the diagnosis andtreatmentofpulmonaryarterial

hypertension.

Circulation.

2008;118:1195-201.
14.

Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, et al.
Cellular and molecular basis of pulmonary arterial hypertension. J Am
Coll Cardiol. 2009;54:S20-31.

15.

Landmark K, Refsum AM, Simonsen S, Storstein O. Verapamil andpulmonary hypertension. Acta Med Scand. 1978;204:299-302.
16

16.

Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, et al.
Inhaled nitric oxide as a screening agent for safely identifying responders
to oral calcium-channel blockers in primary pulmonary hypertension.
European Respiratory Journal. 1998;12:265-70.

17.

Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial
hypertension. N Engl J Med. 2004;351:1425-36.

18.

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA,
et al. Guidelines for the diagnosis and treatment of pulmonary
hypertension: The Task Force for the Diagnosis and Treatment of
Pulmonary Hypertension of the European Society of Cardiology (ESC)
and the European Respiratory Society (ERS), endorsed by theInternational Society of Heart and Lung Transplantation (ISHLT).
European Heart Journal. 2009;30:2493-537.

19.

Satoh T, Saji T, Watanabe H, Ogawa S, Takehara K, Tanabe N, et al. A
phase III, multicenter, collaborative, open-label clinical trial of sildenafil
in Japanese patients with pulmonary arterial hypertension. Circ J.
2011;75:677-82.

20.

Hashimoto K, Nakamura K, Fujio H, Miyaji K, Morita H, Kusano K, et al.
Epoprostenol therapy decreases elevated circulating levels of monocyte
chemoattractant

protein-1

inpatients

withprimary

pulmonary

hypertension. Circ J. 2004;68:227-31.
21.

Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV.
Medical therapy for pulmonary arterial hypertension: updated ACCP
evidence-based clinical practice guidelines. Chest. 2007;131:1917-28.
17

22.

Montani D, Savale L, Natali D, Jais X, Herve P, Garcia G, et al.
Long-term response to calcium-channel blockers in non-idiopathic
pulmonaryarterial

hypertension.

European

Heart

Journal.

2010;31:1898-907.
23.

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA,
et al. Guidelines for the diagnosis and treatment of pulmonary
hypertension: the Task Force for the Diagnosis and Treatment of
Pulmonary Hypertension of the European Society of Cardiology (ESC)
and the European Respiratory Society (ERS), endorsed by theInternational Society of Heart and Lung Transplantation (ISHLT). Eur
Heart J. 2009;30:2493-537.

24.

Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing anduse of calcium channel blockers in pulmonary arterial hypertension.
Respiratory Medicine. 2010;104:481-96.

25.

Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F, Azarian R, et al.
Inhaled nitric oxide as a screening vasodilator agent in primary
pulmonary hypertension. A dose-response study and comparison withprostacyclin. Am J Respir Crit Care Med. 1995;151:384-9.

26.

Nootens M, Schrader B, Kaufmann E, Vestal R, Long W, Rich S.
Comparative acute effects of adenosine and prostacyclin in primary
pulmonary hypertension. Chest. 1995;107:54-7.

27.

Oliveira EC, Ribeiro AL, Amaral CF. Adenosine for vasoreactivity testingin pulmonary hypertension: a head-to-head comparison with inhaled nitricoxide. Respir Med. 2010;104:606-11.
18

28.

Packer M, Medina N, Yushak M, Wiener I. Detrimental effects ofverapamil in patients with primary pulmonary hypertension. Br Heart J.
1984;52:106-11.

29.

Crevey BJ, Dantzker DR, Bower JS, Popat KD, Walker SD.
Hemodynamic and gas exchange effects of intravenous diltiazem inpatients with pulmonary hypertension. Am J Cardiol. 1982;49:578-83.

30.

Young TE, Lundquist LJ, Chesler E, Weir EK. Comparative effects ofnifedipine, verapamil, and diltiazem on experimental pulmonary
hypertension. Am J Cardiol. 1983;51:195-200.

31.

Packer M, Medina N, Yushak M. Adverse hemodynamic and clinicaleffects of calcium channel blockade in pulmonary hypertension secondary
to obliterative pulmonary vascular disease. J Am Coll Cardiol.
1984;4:890-901.

32.

Terai M, Takenaka T, Maeno H. Inhibition of calcium influx in rabbit
aorta by nicardipine hydrochloride (YC-93). Biochemical Pharmacology.
1981;30:375-8.

33.

Bristow MR, Ginsburg R, Laser JA, McAuley BJ, Minobe W. Tissue
response selectivity of calcium antagonists is not due to heterogeneity of[3H]-nitrendipine binding sites. Br J Pharmacol. 1984;82:309-20.

34.

Kumada T, Kawai C, Sasayama S, Kinoshita M, Kawamura K, Kusukawa
R, et al. Clinical Efficacy of Nicardipine by Intravenaous Infusion in
Patients with Acute Heart Failure
Double-blind

Placebo-controlled

1995;23:375-98.
19- A Multicenter Randomized

Trial

-.

Jpn

Pharmacol

Ther.

35.

Kinoshita M, Kawai C, Kumada T, Kawamura K, Kusukawa R. Acute
Effects of a Single Dose of Intravenous Administration of Nicardipine
Hydrochloride in Patients with Acute Heart Failure -Early Phase II study-.
Jpn Pharmacol Ther. 1995;23:345-56.

36.

Hirota Y, Kawai C, Hori R, Okumura K, Kinoshita M, Kumada T, et al.
Intravenous Nicardipine Infusion for the Treatment of Acute Heart Failure- A Double Blind Study for the Optimal Dose Determination (Late Phase
II Study) -. Jpn Pharmacol Ther. 1995;23:357-73.

20

Figure Legends
Figure 1: Protocol of acute vasoreactivity testing with nicardipine.
Figure 2:

Improvements in electrocardiogram and chest X-ray of responder 1.

before administration of nifedipine in April 1999.

(A) is(B) is at three years after starting

administration, March 2003.
Figure 3:

Improvement in transthoracic echocardiogram of responder 2.

Upper panels areparasternal short-axis view images in diastole and end-systole, and lower panels are tricuspid
regurgitation velocity images.

(A) Before administration of amlodipine in October 2009,septal flattening at end-systole was observed (upper panel). Tricuspid regurgitation (TR)velocity was 422 cm/s (lower panel) and TR pressure gradient (TRPG) , which is used for
estimation of systolic PAP, was 71 mmHg.

(B) At six days after starting administration of

amlodipine at 2.5 mg in November 2009, septal flattening at end-systole was improved (upper
panel). TR velocity was 319.4 cm/s (lower panel) and TRPG was 41 mmHg.

(C) Withadministration of amlodipine at 5 mg in January 2011, septal flattening at end-systole was
improved (upper panel).

TR velocity was 364.3 cm/s (lower panel) and TRPG was 53

mmHg.

21