Hemodynamic effects of nifedipine in primary pulmonary hypertension

JACC Vol 2, No I July 1983 174- 9

174

CASE REPORTS

Hemodynamic Effects of Nifedipine in Primary Pulmonary Hypertension JOHN S, DOUGLAS , Jr., MD, FACC Atlanta , Georgia

Progressive dyspnea and syncope occurred in a young woman with primary pulmonary hypertension despite therapy with hydralazine. Abnormal pulmonary artery reactivity was documented by an additional increase in pulmonary artery pressure and pulmonary vascular resistance during exercise and after an episode of hydralazine-induced hypotension. Nifedipine reduced rest and exercise pulmonary artery pressure, pulmonary vascular resistance and right ventricular stroke work, and

Primary pulmonary hypertension is a rare disorder characterized by progressive dyspnea, syncope and right-sided heart failure, resulting in death within 3 to 5 years in the majority of patients (I), Although recognized as a clinical entity over 30 years ago (2), the etiology and pathogenesis of this disease remain obscure, Wood (3) suggested that a pulmonary vasoconstrictor factor was operative and others (4,5). as a result of pathologic studies, hypothesized that prolonged vasoconstriction of the pulmonary arteries of unknown cause is the primary pathophysiologic event. Subsequent development of medial hypertrophy of the muscular pulmonary arteries and finally intimal fibrosis occur. Symptoms are not specific in this disorder and in many patients the diagnosis is made late in the course of the disease, Until recently, attempts at therapy had been discouraging. The most promising therapeutic effort in this disease has been the use of vasodilator agents. In certain patients. presumably still in the early phases of the disease. vasodilators have proved effective in reducing pulmonary artery resistance and. in many cases. ameliorating symptoms to a variable degree (6-13) , In many patients, however. the reduction in pulmonary vascular resistance was accompanied by an increase in pulmonary blood flow but no decrease in From thc Departments of Medicine and Radiolo gy. Emory Uruversuy School of Medicine. Woodruff Medical Center. Atlanta. Georgia. Manuscript received December 7. 1982. revised manuscnpt received January 17. 1983. accepted January 19, 1983 Addre s~ for repnnts: John S Douglas. Jr , MD, Cardiovascular Laboratory. Emory University Clinic, 1365 Clifton Road N.E , Atlanta. Georgia 30322. (l~ 1983

by the Arnencan College of Cardiology

increased cardiac output and markedly improved exercise capacity. Reevaluation after 6 months showed persistence of the favorable hemodynamic and clinical effects. Vasodilator therapy, potentially hazardous because of effects on systemic vascular resistance, can be evaluated safely only with hemodynamic monitoring. Nifedipine may be a useful drug in selected patients with primary pulmonary hypertension.

pulmonary artery pressure. This combination of high pulmonary blood flow and pressure is theoretically undesirable and the long-term effects on the right ventricle and pulmonary vascular bed are unknown. In addition. powerful vasodilating agents may signifi cantly lower systemic arterial pressure and resistance with undesired consequences. Serious hypotensive reactions and death have been reported with the use of vasodilator therapy in primary pulmonary hypertension (14-16). This report describes a patient with primary pulmonary hypertension whose condition worsened with hydralazine therapy and who experienced a hypotensive reaction to this agent while under hemodynamic observation. The hemodynamic changes and clinical response with nifedipine are also reported.

Case Report Clinical features. A 33 year old white woman was admitted to Emory University Hospital with a 10month history of progressive dyspnea on effort and three episodes of syncope. Dyspnea was gradual in onset, occurring initially with vigorous bicycle exercise; dyspnea subsequently occurred with walking at a moderate pace and limited the patient to climbing only one flight of stairs. Syncope occurred during or after exertion. The patient had been otherwise healthy. did not smoke or use appetite-suppressing drugs and was free of known pulmonary disease. Because of the progressive symptoms and findings of an enlarged main pulmonary 0735-1097/83/$3 DO

DOUGLAS NIFEDIPINE IN PRIMARY PULMONARY HYPERTENSION

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July 1983 174-9

artery on chest X-ray study, the patient was referred for cardiac evaluation. On physical examination, the patient appeared healthy and had no dyspnea or cyanosis at rest. Blood pressure was 115/72 mm Hg. Heart rate was 68 beats/min and regular. Jugular venous pressure and contour were normal and carotid pulsations were normal. The chest was clear. The first heart sound was normal; the second heart sound split widely on inspiration with an accentuated pulmonary component. An early systolic click and soft early diastolic blowing murmur were heard along the left sternal border. There were no gallop sounds. Chest X-ray films showed normal heart size on the anteroposterior projection and right ventricular prominence on the lateral projection. The main pulmonary artery was enlarged. The peripheral pulmonary vasculature was normal, The electrocardiogram revealed normal sinus rhythm and right axis deviation. and the echocardiogram showed a reduced a dip of the pulmonary valve suggesting pulmonary hypertension. Arterial blood gases were normal at rest and pulmonary function studies were normal. The ventilationperfusion lung scan was normal, Tests for antinuclear antibody and rheumatoid factor were negative. Cardiac catheterization revealed moderate pulmonary hypertension with normal pulmonary capillary wedge pressure: pulmonary artery pressure 51/20 (mean 32). right ventricular pressure 55/6, right atrial pressure 3 and pulmonary capillary wedge pressure 6 mm Hg. Oximetry revealed no intracardiac shunts. Pulmonary angiography, left ventnculography and supravalvular aortography were normal. On the basis of these studies, a diagnosis of primary pulmonary hypertension was made. The patient was placed on coumadin empirically and hydralazine therapy was begun at 10 mg four times a day and increased to 50 mg four times a day over a 3 week period. Symptoms of dyspnea on effort continued to worsen over a 5 month period. with the development of mild dyspnea at rest and marked dyspnea on climbing less than half a flight of stairs. The patient experienced syncope once after disciplining a child and twice after effort, and was referred for reevaluation. Physical findings, electrocardiogram, chest X-ray films and blood gases were unchanged. Methods of hemodynamic measurements. To measure hemodynamic changes with exercise and evaluate the response to vasodilator therapy, a Swan-Ganz catheter was placed in the pulmonary artery and the left radial artery was cannulated for direct blood pressure recording. Measurement of cardiac output was performed by thermodilution (mean of three determinations). Derived hemodynamic variables were calculated using the following formulas:

PYR

PA - PCW - - - - x 80 CO

SYR

RYSWI

175

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- - - - x 80 CO

SY(PA-RA) (0.0136) Body surface area '

where PYR is pulmonary vascular resistance, PA is mean pulmonary artery pressure, PCW is mean pulmonary capillary wedge pressure, CO is cardiac output, SA is mean systemic arterial pressure, RA is mean right atrial pressure, SY is stroke volume and RYSWI is right ventricular stroke work index. After receiving no medicanons for 2 weeks, the patient underwent pulmonary artery and systemic arterial pressure recordings and cardiac output measurements while resting in the supine position. She was then exercised at 50 watts on an upnght bicycle after the gauges were readjusted to atrial level, and the measurements of pressure and flow were repeated at frequent intervals during exercise. A bicycle training session had been conducted the previous day. On day I. measurements of rest and exercise cardiac output and pulmonary and systemic pressures were made before and after nifedipine. 10 mg orally. On day 2, these recordings were made before and sequentially for 9 hours after nifedipine , 20 mg orally. On day 3, recordings were made before and for 9 hours after nifedipine , 30 mg orally, and on day 4, the response to oral hydralazine was tested. After 6 months of nifedipine therapy, the patient was rehospitalized and repeat measurements of pulmonary artery pressure and flow were performed. Data were collected at rest and during bicycle exercise at 50 and 100 watts. The nifedipine dose schedule at that time was 10 mg orally every 2.5 hours for a total of 60 mg during the day and 20 mg at bedtime. Hemodynamic measurements at rest were made hourly for 24 hours. Response to exercise was recorded 2 hours after the second dose of the day. Hemodynamic response to exercise and vasodilator therapy. Before treatment with nifedipine, pulmonary artery pressure at rest was moderately elevated (69/27 mm Hg, mean 47). This was an increase of 50% from that recorded at catheterization 5 months previously. Pulmonary vascular resistance was elevated at rest to 654 dynes-s-cm - 5 (normal = 67 ± 30). Systemic arterial pressure and cardiac output were normal (Table I). With mild bicycle exercise (50 watts), the patient became dyspneic and fatigued easily, completmg only 4.5 minutes of exercise. During exercise, pulmonary artery pressure increased sharply to 118/54 mm Hg (mean 76). Pulmonary vascular resistance, which was markedly elevated at rest, increased by 50% during exercise and the pulmonary vascular resistance/systemic vascular resistance ratio increased to 0.85. Cardiac output increased 20o/c and systemic vascular resistance decreased 11%. These

176

DOUGLAS NIFEDIPINE IN PRIMARY PULMONARY HYPERTENSION

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Table 1. Hemodyn amic Data at Rest and During the Fifth Minute of Bicycle Exercise Before and After Therapy With Nifedip ine 3h After Nifedipine (20 mg orally)

Control

PA pressure (mm Hg) Systolic Diastolic Mean SA pressure (mm Hg) Systolic Diastolic Mean Cardiac output (liters/min) PVR SVR Heart rate (beats/min) Stroke volume (ml) PCW pressure (mm Hg) RA pressure (rnrn Hg) Arterial O2 sat (%) Pa0 2 (rnrn Hg) PVR/SVR RVSWI (gm/beat per m2)

After 6 Mo. Nifedipine (10 mg orally every 2.5 h)

Rest

50 W

Rest

50 W

Rest

50 W

100 W

69 27 47

11 8 54 76

52 24 37

79 28 50

42 23 29

60 25 39

72 26 44

114 60 83 4.9

117 64 84 5.9

115 56 74 6.7

120 48 74 8.5

123 62 82 5.7

128 62 87 8.3

125 61 84 10.5

654 1322 62 79 7 2 97 103 0.49 29

995 1170 11 0 53 5

335 838 74 90 9 4 98 11 4 0.40 24

423 677 11 0 77 5 2 96 78 0.62 29

350 987 72 79 4 3

342 840 11 0 75 4 2

322 642 125 84 2 0

035 17

04 1 22

0.50 29

I

96 81 0.85 32

PA = pulmonary artery; Pa0 2 = arterial oxygen pressure; PCW = pulmonary capillary wedge: PVR = pulmonaryvascular resistance (dynes-s-cm - 5) . RA = nght atrium; RVSWI = right ventricular stroke work index: SA = systemic artery: sat = saturation: SVR = systemic vascular resistance (dynes-s-cm- 5) .

findin gs confi rmed the presence of abnormal pulmonary vascular reactivity. Vasoconstriction occurred, whereas the normal response to exercise is passive dilation of the pulmonary vascular bed. After administration of nifedipine in doses of 10, 20 and 30 mg orally, a decrease in mean pulmonary artery pressure at rest occurred to 43, 37 and 34 mm Hg, respectively, when measured 3 hours after ingestion. Pulmonary vascular resistance at rest was reduced 36 to 44% by nifedipine in the preceding doses, while signifi cant increases in exercise tolerance occurred with all doses. Flushing, considered unpleasant to the patient, was experienced with the 30 mg dose of nifedipine; 20 mg was the maximal dose that was well tolerated. Hemodynamic responses to exercise before and 3 hours after 20 mg of nifedipine are reported in Table I. (Data recorded at I and 2 hours after ingestion were incomplete because of technical factors, but pulmonary artery pressure and cardiac output were quite similar to those recorded at 3 hours after ingestion.) Nifedipine blunted the pulmonary vasoconstrictive response noted with exercise and produced a greater pulmonary blood flow at reduced pulmonary artery pressure. Cardiac output rose to 8.5 liters/ min during bicycle exercise at 50 watts. This exercise level was accomplished at a mean pulmonary artery pressure of 50 mm Hg compared with an exercise pulmonary artery pressure of 76 mm Hg before nifedipine. Whereas pulmonary vascular resistance at rest had been 654 dynes-s-cm :" before nifedipine and increased by more than 50% with

exercise, pulmonary vascular resistance after nifedipine decreased to 335 dynes-s-cm- 5 at rest and increased only 25% during exercise at 50 watts. Three hours after ingestion of nifedipine, 20 mg, the patient could exercise for 30 minutes at 50 watts compared with an exercise tolerance of less than 5 minutes before treatment. Nine hours after ingestion of nifedipine, 20 mg, exercise tolerance was reduced to less than 5 minutes at 50 watts. Figure I shows the hemodynamic measurements performed during the bicycle exercise (50 watts) before and after three different doses of nifedipine. Because symptoms were experienced primarily during exercise, the therapeutic effect of greatest interest is that on exercise hemodynamics. A significant therapeutic effect occurred after the 10 mg dose and a greater effect occurred after the 20 mg dose. At 3 hours after 20 mg of nifedipine, there was a 33% decrease in exercise pulmonary artery pressure. This effect appeared to be waning at 7 hours and was gone by 9 hours after oral ingestion. With the 30 mg dose, the magnitude of change at 3 hours was comparable with that of the 20 mg dose. At 9 hours after the 30 mg dose, a mild vasodilator effect persisted, as evidenced by lower pulmonary artery pressure and resistance and higher cardiac output compared with pretreatment levels. Figure 2 depicts changes in hemodynamics at rest that occurred after oral administration of two 25 mg doses of hydralazine. After the initial dose, there was a decrease in pulmonary artery pressure from 75/42 to 60/25 mm Hg, an

DOUGLAS NIFEDIPINE IN PRIMARY PULMONARY HYPERTENSION

JACC Vol 2. No 1 July 1983 174-9

l

N 10mg Q!

Figure 1. Hemodynamic measurements dunng exercise before and after nifedipme. 10, 20 and 30 109 orally. Data were collected dunng the fifth minute of bicycle exercise (5~att,) CO = cardiac output; N = nifedipine; PA = mean pulmonary artery pressure; PAS = pulmonary artery systolic pressure; PYR = pulmonary vascular resistance.

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increase in cardiac output from 5 to 5.4 liters/min and a small decrease in pulmonary vascular resistance. One hour after the second dose of hydralazine, the patient was allowed to sit up to urinate. At that point, she became nauseated, presyncopal and developed tachycardia. Blood pressure decreased to 50 mm Hg systolic; it returned to pretreatment levels when the patient was allowed to resume a supine posture and the feet were elevated. Subsequently. pulmonary artery pressure increased significantly to 99/43 mm Hg and chest discomfort occurred. Marked increase In pulmonary vascular resistance was noted (533 to 886 dynes-scm After a period of observation during which pulmonary vascular resistance remained stable. sublingual nifedipine, 10 rng, was administered. The chest discomfort promptly dissipated and there was a significant and abrupt decrease in pulmonary artery pressure ( 100/38 to 60/26 mm Hg). Cardiac output increased and a 60% decrease in pulmonary vascular resistance occurred. On outpatient therapy. exercise tolerance improved dramatically on nifedipine, 20 mg orally 4 times a day. An improved quality of life resulted as activity levels returned to near normal. Because of Hushing with a 20 mg dose of nifedipine , the dosing schedule was adjusted to 10 mg orally every 2 Y2 hours for a total of 60 mg during waking hours and 20 mg at bedtime. After 6 months of therapy, pulmonary artery pressure and How were measured again (Table I). Mean pulmonary artery pressure and pulmonary vascular resistance at rest were comparable with levels recorded 3 hours after 20 mg of nifedipine orally during the evaluation, 6 months previously. During 24 hours of observation, mean pulmonary artery pressures and resistance at rest were virtually constant on the frequent dosing schedule. However, during bicycle exercise at 50 watts, mean pulmonary artery pressure increased only to 39 mm Hg as compared with 76 mm Hg before any therapy and 50 mm Hg after 20 mg of nifedipine. Pulmonary vascular resistance, which had increased dramatically before treatment, decreased slightly at 50 watts and decreased further at 100 watts (Fig. 3). At 100 watts of bicycle exercise, which could be maintained easily for 30 minutes, cardiac output rose to 10.5 liters/min and the mean pulmonary artery pressure was 44 mm Hg. r

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Discussion Since the imtial characterization of primary pulmonary hypertension as a clinical entity by Dresdale et al. (2), attention has been focused increasingly on pulmonary arteriolar constriction as an important or primary pathophysiologic factor in this rare disorder. Early workers (2,3) observed transient reductions in pulmonary artery pressure and resistance with injections of vasodilator agents such as acetylcholine and tolazoline. leading to a search for an effective therapeutic agent. Subsequently, long-term benefit was reported in a small number of patients with phentolamine (7), diazoxide (9). isoproterenol (6) and hydralazine (8),

Figure 2. Hemodynamic changes after two 25 109 doses of hydralazinc orally (po) Systemic hypotension and presyncope occurrcd when the head was elevated. Chest discomfort occurred in association with increased pulmonary artery pressure and pulmonary vascular resistance. and promptly abated after nifedipine. 10 109 sublmgually (sl). t:!ydralazme 25mg po

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DOUGLAS NIFEDIPINE IN PRIMARY PULMONARY HYPERTENSION

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JACC Vol 2. No I July 1983 174-9

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Figure 3. Comparison of rest andexercise pulmonary artery pressure, resistance and flow before nifedipine and after 6 months of therapy . Nifedipine, 10 mg orally, was administered 2 hours and 4.5 hours before therestandexercisemeasurements at the6 month evaluation. Data were recorded during the fifth minute of exercise. Abbreviations as in Figure I .

but each agent had disadvantages or limited effectiveness, or both. Hydralazine has been the most widely applied vasodilator since Rubin and Peter (8) reported reductions in pulmonary arteriolar resistance, increased cardiac output and symptomatic improvement in four patients with primary pulmonary hypertension. However, this agent has not been shown to lower pulmonary artery pressure. Therefore, by increasing pulmonary blood flow without reducing pulmonary artery pressure, hydralazine imposes an additional burden on the right ventricle, and long-term effects of increased flow and pressure on the pulmonary vascular bed are assumed to be undesirable. In addition, adverse hemodynamic reactions and death were reported (15,16) with the use of hydralazine in primary pulmonary hypertension. Recent preliminary reports ( II , 17) indicate effective pulmonary arteriolar dilation can be achieved with calcium blocking agents. These agents, by inhibiting slow-inward calcium movement in vascular smooth muscle, have been shown to impede excitationcontraction coupling producing relaxation of vascular smooth muscle. Effects of nifedip ine. Our study patient had experienced progressive exercise limitation and her pulmonary artery pressure had increased since the initial evaluation only 5 months previously. Hydralazine was of no symptomatic benefit and its use produced an episode of signifi cant systemic arterial hypotension accompanied by chest discomfort, reduced cardiac output and increased pulmonary vascular resistance. This type of pulmonary vasospastic response to sympathetic stimulation has been previously described in a patient with primary pulmonary hypertension (18). Pulmonary vascular tone in our patient was increased at rest and was influenced by physical activity. Pulmonary artery pressure and pulmonary vascular resistance increased by

more than 50% with light bicycle exercise, and exercise tolerance was markedly restricted. This response is similar to that reported by Ruskin and Hutter (7 ) in a patient who had pulmonary vasoconstriction at rest that increased with exercise. Nifedipine had beneficial effects on rest and exercise hemodynamics in our patient when tested acute ly and these effects were present on reevaluation 6 months later. This favorable long-term effect is significant in view of the tachyphylaxis reported with some vasodilators. Cardiac output increased with nifedipine, leading to improved tissue oxygenation and exercise tolerance. The increase in pulmonary vascular resistance noted during exercise before treatment with nifedipine was diminished by acute administration of nifedipine and, after 6 months of therapy, pulmonary vascular resistance decreased during exercise. Although the resistance in both systemic and pulmonary circuits was reduced by nifedipine, a reduction in the ratio of pulmonary to systemic vascular resistance indicates greater pharmacologic responsiveness in the pulmonary circulation. Rest and exercise pulmonary artery pressures were reduced by nifedipine. Although Rubin et al. (19) have shown that the failing right ventricle might benefit from a vasodilator that does not reduce pulmonary artery pressure, the long-term impact of an increased pulmonary artery blood flow at persisting high pulmonary artery pressure remains to be determined, but will probably be negative. Mecha nism of nifedipine's effects. Of particular interest was the abilityof nifedipineto reverse thepulmonaryvasoconstriction that occurred after hydralazine-induced systemic arterial hypotension and was presumably mediated by circulating catecholamines. The capacity to block catecholamine-induced vasoconstriction was one of the earliest observations made of the effects of calcium antagonists on vascular smooth muscle (20). The increase in cardiac output experienced with nifedipine at rest and during exercise does not appear to be due to opening of intrapulmonary shunts because no change in arterial oxygen tension occurred. The factor limiting cardiac output appeared to be high pulmonary vascular resistance. Increasing cardiac output with nifedipine is believed to be due to a direct effect on pulmonary arterial smooth muscle, producing vasodilation, reduced right ventricular afterload, reduced right ventricular work and increased pulmonary and systemic blood flow . The net result in our patient was greatly improved exercise tolerance. Predicting the response to vasodilator therapy. The success of vasodilator therapy in primary pulmonary hypertension is dependent on the tone present in the pulmonary vascular bed, the responsiveness of the pulmonary arterioles to the vasodilating agent and the magnitude of fixed pathologic changes. As suggested by Ruskin and Hutter (7), the relative lability of the pulmonary artery pressure and resistance may serve as a useful marker for predicting the response to vasodilator therapy. Patients with long-standing,

DOUGLAS NIFEDIPINE IN PRIMARY PULMONARY HYPERTENSION

JACC Vol 2. No July 1983 174-9

severe, fixed pathologic changes would be expected to benefit less from vasodilator therapy than would patients with vasoconstriction and little pathologic change. Our experience with this patient suggests that nifedipine may be a useful drug in treating patients with primary pulmonary hypertension in whom pharmacologically responsive vasoconstriction is documented.

References I. Gupta BD. Moodie DS. Hodgman JR Pnrnary pulmonary hyperten-

,IOn in adults. Clcv Clin 1980:47.275-84 2. Drcsdalc DT. Schultz M. Michtom RJ. Primary pulmonary hypertension Am J Mcd 1951.11686-705 . 3. Wood P. Pulmonary hypertension WIth special reference to the vasoconstrictive factor. Br Heart J 1958;20'557-70 . 4. Wagcnvoort CA. Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels In 156 chrucally diagnosed cases Circulation 1970:42:1163- 84 5 Edward, WD. Edwards JE Cluneal primary pulmonary hypertension. Three pathologic types, Circulation 1977.56:884-8. 6 Shetngar UR. Hultgren HN. Specter M. Martin R. Davres DII PrI' mary pulmonary hypertension: favorable effect of isoproterenol N Engl J Mcd 1976:295.1414- 15. 7. Ruskin IN. Hutter AM Jr Primary pulmonary hypertension treated WIth oral phentolamine. Ann Intern Med 1979:90772 -4 8. Rubin LJ . Peter RH Oral hydralazine for primary pulmonary hypertension. N Engl J Mcd 1980,302 69- 73.

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9 Honey M. Cotter L. Davies N. DCIlI>on D. Chrucal and hacmodynarruc effects of diazoxide In primary pulmonary hypertension. Thorax 1980.35 269-76 10 Horowitz JD. Brennan JB. Ohver LE. Harding D. Goble AJ. Louis WJ Effect.. of captopnl (SQ 14.225) In a pauent with primary pulmonary hypertension Postgrad Med J 1981.57.115-6 I I Carncnm F. Alberti E. Klugmann S. SalVI A Primary pulmonary hypertension effects of mfedipme Br Heart J 1980:44:352-6 12 Mcl.eod AA. Wise JR Jr. Daly K. Jewitt DE Nrfedipme m primary and -econdarypulmonaryhypertension (abst r) Circulanon 1981 :64(suppl IV) IV·180 13 MoluuddmSM. Evtcrbrook- D. Saenz A. et al. Hemodynamic ctfcctv of mtcdipmc In severe primary pulmonary hypertension (ubstr). Chest 1981.80.387 14 Buch J. Wennevold A. Hazards 01 drazoxide In pulmonary hypertcn'Ion Br Heart J 1981:46'401- 3. 15. Packer M. Greenberg B, Massie B. Dash H. Deleterious effects of hydralazme m patients with pulmonary hypertension. N Engl J Mcd 1982;306.1326-3 1. 16 Kronzon I. Cohen M. Winer HE Adverse effects 01 hvdrulazme In patients with primary pulmonary hypcrten-ron JAMA 1 9~2 .247 ·3112­ 4

17 Kumbara H. FUjimoto K. Wakabayaslu A. Kawai C Primary pulmonary hypertension. beneficial therapy 01 drluazcm Am Heart J 1981:\0 \ 230-1 18 Gorlm R. Clare FH. Zuska JJ. EVidence lor pulmonary vavoconstncnon In man Br Heart J 1958:20'346-50 19 Rubin LJ. Handel F. Peter RH. The eflectv of oral hydralazine on right ventricular cnd-diastuhc pressure In patients with right ventricular tailure Circulauon 1982.65.1369- 73 20 Godframd T. Kaba A. The role of calcium In the actions of drug, on vascular vrnooth muscle Arch Int Pharrnocodvn Ther 1972. . I96(<'u ppll.35- 49