Nifedipine in the treatment of prinzmetal's (variant) angina

Nifedipine in the Treatment of Prinzmetal’s (Variant) Angina

SHELDON NATHANIEL JOHN JOHN JAMES JOHN

GOLDBERG,

MD

REICHEK,

MD

WILSON, MD W. HIRSHFELD,

Jr.,

MULLER, A. KASTOR,

Philadelphia,

MD

MD’ MD,

FACC

Pennsylvania

The clinical response to therapy with the calcium-blocking agent nifedipine was assessed in 12 patients with variant angina pectoris who were 44 to 67 years old. Five patients had vasospasm of the left anterior descending coronary artery, and seven had spasm of a dominant right coronary artery. Before nifedipine therapy, the frequency of angina1 attacks per 24 hour period ranged from 1 to 12, with ventricular tachycardia accompanying ischemic episodes in 7 of 12 patients and high grade atrioventricular block occurring in 2 patients. After therapy with nifedipine, 11 of 12 patients had initial relief of symptoms, and 7 of the 11 had long-term relief. Withdrawal of nifedipine led to recurrence of angina on six occasions in four patients. Provocative testing in the cardiac catheterization laboratory by means of the cold pressor test in one patient and ergonovine maleate in another before and after nifedlpine administration showed that this agent can block both alpha adrenergic- and ergonovine-induced vasospasm. Nifedipine may have a significant role in the therapy of angina caused by coronary spasm.

Myocardial ischemia in man is now known to be caused by either or both of the following mechanisms: (1) a primary increase in myocardial oxygen demand that is not accompanied by an adequate increase in myocardial oxygen supply, as occurs in fixed obstructive coronary artery disease with exertional or pacing-induced angina’; or (2) a primary reduction in myocardial oxygen supply due to an abrupt reduction in coronary blood flow, as occurs in coronary arterial spasm.2-5 Because coronary spasm may be caused by a variety of stimuli that have as their final common pathway the calcium-mediated contraction of coronary arterial smooth muscle, we studied the effects of the calcium-blocking agent nifedipine in 12 patients with variant angina. The clinical response of these 12 patients, along with the effect of nifedipine on cold-pressor- and ergonovine-induced coronary vasospasm, forms the basis of this report. Methods From the Cardiac Catheterization Laboratory, Hospital of the University of Pennsylvania and the Cardiovascular Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the Cardiovascular Division, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts.* Manuscript received April 4, 1979; revised manuscript received June 12, 1979, accepted June 13, 1979. Address for reprints: Sheldon Goldberg, MD, Cardkwascular Section, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19 104.

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October 22, 1979

Patient selection: The criteria for inclusion of the patients in this study were: (1) a history of angina at rest associated with S-T segment alterations in the electrocardiogram; (2) coronary arterial spasm with or without fixed obstructive lesions demonstrated with selective coronary arteriography; (3) prior failure of conventional therapy ‘*withlong- and short-acting nitrates; and (4) informed consent for the administration of nifedipine. Catheterization: Cardiac catheterization and selective coronary arteriography were performed with the Judkins technique. Provocative testing for coronary spasm with ergonovine maleate was carried out in 8 patients as follows: Ergonovine maleate was given as a 0.05 mg bolus dose intravenously every 2 minutes until electrocardiographic changes and typical angina occurred; then a second angiogram of the coronary artery clinically thought to be affected by spasm was obtained. Nitroglycerin was then given sublingually or intravenously, or both,

The American Journal of CARDIOLOGY

Volume 44

NIFEDIPINE FOR VARIANT

I

Clinical

Characteristics

Case no.

Age (yr) & Sex

1

46F

2

67F

3

43M

4

62M

5

52M

6

46F

7

58M

8

52M

9

46M

10

53F

11

44F

12

56M

ET AL

Clinical characteristics of uatient population (Table I): Five women and seven men aged 44 to 67 years met the

until the electrocardiographic changes and the angina resolved. A third cineangiogram followed nitroglycerin administration. In one patient the cold pressor test was used to provoke spasm, and in three patients another spasm occurred spontaneously. Nifedipine administration: Forty to 120 mg of nifedipine was administered in divided doses every 4 to 6 hours (120 mg/day is the maximal dose recommended by the manufacturer). In each patient the dosage was gradually increased until relief of symptoms occurred or the maximal dose had been administered. Nitrate therapy was initially continued during nifedipine administration. Nitrates were administered in the maximal dose tolerated by the patient and consisted of a combination of isosorbide dinitrate and nitropaste in addition to sublingual nitroglycerin. In one patient (Patient 10) the efficacy of nifedipine therapy was further tested in the catheterization laboratory by a second application of the cold pressor test while the patient was receiving nifedipine. Another patient (Patient 12), who had ergonovine-induced vasospasm, was rechallenged with this agent after the acute administration of nifedipine.

TABLE

ANGINA-GOLDBERG

criteria for inclusion in the study. Angina at rest was present in all patients, and an exertional component was present in two. The duration of angina at rest ranged from1 week to 72 months. Ventricular tachycardia occurred during ischemic episodes in 7 of 12 patients. High grade atrioventricular (A-V) block during ischemia occurred in two patients, both of whom had right coronary artery spasm. Spasm of the left anterior descending coronary artery occurred in five patients, and spasm of the right coronary artery recurred in the remaining seven patients. Fixed obstructive lesions of hemodynamic significance (narrowing of luminal diameter by at least 50 percent) were present in the coronary artery affected by spasm in 2 of 12 patients. Coronary spasm was provoked in 8 of 12 patients by means of ergonovine maleate in total doses ranging from 0.10 to 0.20 mg. Left ventricular function was normal in all patients except Patient 9. This patient, who had had an anterior myocardial infarction 3 weeks before the study, had an anterior ventricular aneurysm and reduced ejection fraction of 44 percent.

of 12 Patients Angina1 Pattern

Electrocardiographic Features

Catheterization Data

Initial Response to Nifedipine

Resting angina X 7 days; 4 attacks/day prior to cath Exertional angina X 7.5 yr; resting angina X 3 yr; 2 attacks/day prior to cath Resting angina X 2 mo; 4 attacks/day prior to cath Resting angina X 19 mo; 12 attacks/day prior to cath 2 yr of exertional and resting angina; 3 attacks/day prior to cath Resting angina X 6 mo; 1 attack/day prior to cath ResWg angina X 1 mo; 3 attacksidav_ prior to cath Resting and exertional angina X 6 yr; 6 attacks/day prior to cath Resting angina X 2 mo; 3 attacks/day prior to cath

S-T t II. Ill, aVF; VT

Normal LVF; normal CA’s; RCA spasm (E)

Pain-free, 60 mglday

S-T t II, Ill, aVF; VT

Normal LVF; 60% RCA lesion; RCA spasm (S)

Pain-free, 60 mglday

S-T t V,-Vs;

VT

Normal LVF; normal CA’s; LAD spasm (S)

Pain-free, 120 mg/day

S-T&Vs;

S-T 1 V,-

Normal LVF; 50% LAD lesion; 60% RCA lesion; LAD spasm (E) Normal LVF; 50% LAD lesion; RCA spasm (E)

Pain-free, 140 mg/day

Normal LVF; 30% LAD lesion; 30% RCA lesion; LAD spasm (E) Normal LVF; normal CAs; LAD spasm (E)

Pain-free, 60 mg/day

S-T t V,-V6

Normal LVF; normal CAs; LAD spasm (S)

Pain-free, 80 mg/day

Anterior scar; S-T t II, Ill, aVF; S-T 1 II, Ill, aVF; VT; A-V block

Pain-free, 120 mg/day

Resting angina X 3.5 yr; 3 attacks/day prior to cath Resting angina X 1 mo; 2 attacks/day prior to cath Resting angina X 8 mo; 1 attack/day prior to cath

S-T t II, Ill, aVF; S-T 1 II, Ill, aVF; A-V block

Anterior aneurysm; total occlusion; LAD; 50% LCx; normal dominant RCA; RCA spasm (E) Normal LVF; 70% LAD lesion; RCA spasm (CP)

S-T t II, Ill, aVF

Normal LVF; normal CAs; RCA spasm (E)

Pain-free, 40 mg/day

S-T t II. Ill, aVF

Normal LVF; normal CAs; RCA spasm (E)

Pain-free, 40 mglday

63

S-T t II, Ill. aVF; VT

S-T t V,-Vs;

VT

S-T t V,-Vs

Pain-free, 60 mg/day

No effect

Pain-free, 120 mg/day

A-V = atrioventricular; CAs = coronary arteries; cath = cardiac catheterization; (CP) = cold pressor-induced spasm; (E) = ergonovine-induced spasm; LAD = left anterior descending oronary artery; LCx = left circumflex coronary artery; LVF = left ventricular function; RCA = right coronary artery; (S) = spontar ous spasm; S-T ‘i and S-T 1 = S-T segment elevation and depression, respectively.

October 22, 1979

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805

COLD

PRESSOR

1

I

I

---_-

+ NIFEDIPINE ,.*a II

COLD

_~_____

PRESSOR

OfllmHp

-.

---

Ommnp

FIGURE 1. Patient 10. Upper left, lead II electrocardiogram, aortic pressure tracing and right coronary angiogram raKen under baseline conditions. Upper right, the same recordings after the cold pressor test. Lead II shows S-T segment depression; there is a decrease in aortic pressure from the control level; and the right coronary angiogram shows severe spasm. Lower left, 1 minute later. Lead II now shows S-T segment elevation, and there is severe hypotension. These changes reverted to baseline levels after nitroglycerin administration. Lower right, after nifedipine administration a repeat cold pressor test was carried out. Lead II shows only mild S-T segment depression; the aortic pressure is stable; and the right coronary arterial angiogram is unchanged from the control study.

CONTROL

NIFEDIPINE FOR VARIANT ANGINA-GOLDBERG

Results Initial clinical response to nifedipine administration (Table I): Before nifedipine therapy, the frequency of angina1 episodes for the entire group of 12 patients ranged from 1 to 12lday. Within 24 to 48 hours of selection of the optimal nifedipine dose, pain at rest disappeared in 11 of 12 subjects. Clinically adverse hypotension or tachycardia was not observed, and no acute side effects were observed. After the administration of the optimal nifedipine dose, concomitant nitrate therapy was withdrawn in four patients. Provocative invasive testing before and after nifedipine: In Patient 10 the efficacy of nifedipine was further evaluated with the cold pressor test in the catheterization laboratory. With the patient asymptomatic at the beginning of the test, results of hemodynamic and angiographic studies were normal (Fig. 1, upper left). After immersion of the patient’s hand in ice

ET AL.

water for 63 seconds (Fig. 1, upper right), marked S-T segment depression in lead II, hypotension and crushing retrosternal pain developed; a repeat right coronary angiogram taken a few seconds later showed severe spasm. Approximately 1 minute later (Fig. 1, lower left) S-T segment elevation had replaced depression in lead II, and aortic pressure had decreased to 50/40 mm Hg. Relief was obtained after sublingual administration of five 0.3 mg nitroglycerin tablets. The patient, who was having three episodes of angina per day, was then given 120 mg of nifedipine per day in addition to nitrates, and was rechallenged with the cold pressor test (Fig. 1, lower right). At this time angina did not develop, the lead II electrocardiogram showed only minor S-T segment depression, the aortic pressure was normal, and no spasm was seen in the right coronary artery. In Patient 12, the ability of nifedipine to block ergonovine-induced vasospasm was demonstrated: Two cardiac catheterization procedures were performed. The

FIGURE 2. Patient12. Top left, normal right coronary angiogram performed with the patient at rest. Top right, after administration of 0.2 mg of ergonovine there is severe spasm. This was accompanied by angina and S-T elevation in lead III. Bottom, after pretreatment with nifedipine, 20 mg (buccal absorption), coronary hemodynamics were modified (as shown in Table II). Rechallenge with ergonovine results in only mild diffuse narrowing. There were no electrocardiographic changes and the patient did not have angina.

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NIFEDIPINE FOR VARIANT ANGINA-GOLDBERG ET AL

baseline right coronary angiogram with the patient asymptomatic and at rest was normal (Fig. 2, top left). After the administration of a total of 0.2 mg of ergonovine (four 0.05 mg bolus injections), the patient’s typical angina developed along with S-T segment elevation seen in leads II, III and aVF and a decrease in blood pressure from 150/80 to 90/60 mm Hg. At this time the coronary angiogram showed severe right coronary arterial spasm (Fig. 2, top right). These changes were reversed by sublingual administration of nitroglycerin. At the second catheterization procedure coronary hemodynamic values were measured before and after administration of 20 mg of nifedipine (buccal absorption) (Table II). Resting mean arterial pressure was 120 mm Hg and coronary blood flow (measured with the thermodilution technique) was 117 ml/min. Twenty minutes after: nifedipine administration, mean arterial pressure decreased to 100 mm Hg and coronary blood flow increased to 164 ml/min. Concomitantly, the myocardial arteriovenous oxygen difference narrowed from a control value of 63 to 50 percent. At this point, repeat challenge with ergonovine was carried out at the same 0.2 mg dose that had previously produced spasm. The patient remained asymptomatic, there were no electrocardiographic changes and the repeat coronary aniiogram (Fig. 2, bottom) showed only mild, diffuse harrowing, that is, the normal angiographic response to ergonovine.5 Long-term follow-up study (Table III): The long-term follow-up results varied in the 11 patients who had shown an excellent initial response to tiifedipine. Seven of these 11 patients continued to have an excellent response and were either asymptomatic or had only infrequent angina1 episodes easily relieved by nitroglycerin. The follow-up period for the seven patients ranged from 2 to 17 months, and the dose of nifedipine ranged from 40 to 120 mg/day. The effects of nifedipine therapy are dramatically demonstrated by Patient 4 (Fig. 3). Before the administration of nifedipine, this patient had 12 attacks daily for approximately 1 week, with ventricular tachycardia accompanying the ischemic episodes. Coronary arteriography revealed a fixed 50 percent stenosis of the proximal left anterior descending coronary artery. After ergonovine administration, transient total occlusion of this artery was produced, starting at

the fixed lesion. The patient continued to have attacks despite therapy with long- and short-acting nitrates. After administration of 40 mglday of nifedipine, the patient’s angina1 syndrome was completely abolished for a period of 4 months. However, headache and digital dysesthesizis developed during therapy and the patient decided to discontinue nifedipine therapy. Within 3 days, severe episodes of the typical angina recurred at a frequency of 4lday and a total of 8 episodes in 48 hours. Nifedipine was administered, and the patient became asymptomatic for 2 months. He again chose to discontinue use of nifedipine because of side effects and became severely symptomatic, having four attacks of angina a day. He again resumed therapy with nifedipine and has now been symptom-free for 9 months. Concomitant administration of 80 mg/day of propranolol has decreased the severity of the headaches. Follow-up history, physical examination and chest X-ray films in this patient have shown no evidence of heart failure despite simultaneous administration of a calcium antagonist and a beta adrenergic blocking agent. The remaining four patients included one patient (Patient 3) with normal coronary arteries who had an acute myocardial infarction after nitrate withdrawal during nifedipine therapy. The second patient (Patient 8) died suddenly after 1 month of nifedipine therapy. This patient had recurrence of variant angina and associated ventricular arrhythmias despite nifedipine therapy. Two attempts to discontinue nifedipine led to worsening of his symptoms. In a third patient (Patient

TABLE Ill Long-Term Follow-Up Study of 12 Patients Case no.

Nifedipine .’ Dose (mgjday)

Follow-Up Period (mo)

:

:8

3

120

4

40

15

5

120

2

6

120

13

7

No response to initial

9”

120 60

1 314

10

120

2

11

60

5

12

40

5

1;

Clinical Status No angina No angina Myocardial infarction after nitrate withdrawal No angina; headache, digital dysesthesias on drug Occasional resting angina; 8 nitroglycerin/m0 Occasional resting angina; 5 nitroglycerin/m0

nifedipine ‘TABLE II Patient 12. Coronary Hemodynamic Effects of Acute Nifedipine Administration Prior to Ergonovine Rechallenge

MAP (mm Hg) CBF (ml/min) CVR (mm Hg/ml per min) a-v O* A (%)

Control

Nifedipine

120 117 1.03

100 164 0.61

63

50

a-v Oz A = myocardial arteriovenous oxygen difference; CBF = coronary blood flow: CVR = coronary vascular resistance; MAP = mean arterial pressure.

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Oied suddenly Recurrence of attacks on nifedipine: required surgery on nondiseased coronary artery (ligation and bypass) Angina-free on drug; leg cramps and headache required drugwithdrawal; angina recurred No angina; mild fatigue, headache, perspiration on drug Pain-free

NIFEDIPINE FOR VARIANT

9), who had had a prior anterior myocardial infarction, right coronary arterial spasm developed. This patient had an initially encouraging response to nifedipine, but he had recurrence of one episode of angina a day accompanied by ventricular tachycardia while he was receiving the drug. An attempt to change to perhexiline therapy resulted in recurrence of more frequent and severe episodes when nifedipine was withdrawn. This patient was finally treated by ligation of the nondiseased right coronary artery proximally and saphenous vein bypass grafting into the distal right coronary artery, past the point of angiographically demonstrated focal spasm. Another patient (Patient 10) discontinued nifedipine therapy because of headache, leg cramps and flushing-symptoms possibly related to the peripheral vasodilatory effects of the drug. These symptoms antedated nifedipine therapy but became more severe during administration of the drug. This patient has had recurrence of resting angina after withdrawal of nifedipine, and subsequently died during coronary bypass surgery at another institution. Discussion The main findings of this study are (1) The addition of nifedipine to nitrates is efficacious in the initial therapy of refractory variant angina. (2) There were no major initial side effects due to nifedipine administration; specifically, clinically adverse hypotension or tachycardia was not observed and, in addition, none of the patients had symptoms of congestive heart failure, a possible side effect of therapy with calcium-blocking agents. (3) Nifedipine withdrawal is associated with recurrence of angina, an effect that was demonstrated on six occasions in four patients. (4) Nifedipine not only can suppress spontaneous symptoms, but it also can block cold pressor- and ergonovine-induced coronary vasospasm. The cold pressor test is an alpha adrenergic stimulus that has been shown to increase coronary vascular resistance6y7 and to induce coronary vasospasm,8 whereas ergonovine is a specific and sensitive agent for provocation of spasm in patients with variant angina.5 Previous investigations on treatment of coronary spasm: The renewed interest in coronary vasospasm as a possible etiologic factor in unstable anginagJO and acute myocardial infarctionll-l3 had led investigators to use various agents in an attempt to block smooth muscle contraction of the epicardial coronary arteries. The rationale for the use of calcium antagonistic agents in the therapy of coronary spasm is based on their ability to impede movement of calcium ions during excitation-contraction coupling in vascular smooth muscle.14J5 For example, coronary spasm was induced in a series of 10 patients by increasing pH via hyperventilation and Tris buffer infusion.‘6 These maneuvers cause a decrease in local hydrogen ion concentration, which presumably leads to less competition with calcium ions and hence promotes coronary arterial smooth muscle spasm. Diltiazem, a calcium antagonist, was demonstrated to suppress coronary vasospasm in five patients who received the drug.16 Encouraging clinical

ANGINA-GOLDBERG

ET AL.

results were also reported in preliminary investigations utilizing the calcium-blocking agents verapamil,17 perhexiline18 and nifedipine.lg Therapeutic implications: The use of calciumblocking agents in the therapy of coronary vasospasm offers a new therapeutic approach to this problem. Previous studies have suggested that a primary decrease in coronary blood flow and increase in coronary vascular resistance, accompanied by a widening of the myocardial arteriovenous oxygen difference, contribute to both cold-induced6,7 and ergonovine-induced5 angina. Nifedipine has the opposite effects: It increases coronary blood flow, reduces coronary vascular resistance and narrows the myocardial arteriovenous oxygen difference.20 These effects were dramatically demonstrated in Patient 12 (Table II) before rechallenge with ergonovine. The observation that S-T segment depression may precede S-T segment elevation early in the course of spasm lends further support to the concept that coronary vasospasm may cause unstable angina with S-T segment depression in patients with severe fixed coronary disease. Thus, it is possible that calcium-blocking vasodilators will prove useful in a var.iety of clinical settings, including variant angina with or without coexistent atherosclerotic disease, unstable angina with S-T segment depression, and acute myocardial infarction. Although initial drug efficacy is dramatic, long-term results are less clear-cut. We have observed the long-

Priorlo Treatment 12 -

IO

-

8-

2-

O4 months

2 months

9 months

FIGURE 3. Clinical course of Patient 4. Each episode of nifedipine (N) withdrawal resulted in recurrence of ischemic symptoms. Reinstitution of nifedipine therapy promptly prevented angina1 episodes.

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NIFEDIPINE FOR VARIANT ANGINA-GOLDBERG

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term side effects of headache, digital dysesthesias, leg cramps and flushing. These effects may be caused by the systemic vasodilatory effect of the drug. In addition, because nifedipine interferes with excitation-contraction coupling in cardiac as well as smooth muscle, the potential for a deleterious effect on myocardial performance needs to be assessed. Although we did not observe symptoms of heart failure, either in a patient with a recent anterior infarction or in a patient siinultaneously receiving a beta adrenergic blocking agent, the hemodynamic effects of this new agent need to be studied in a variety of patients. No attempt was made in the present study to compare prospectively the efficacy of long-term acting nitrates with that of nifedipine. Rather, nitrate therapy was initially continued simultaneously with nifedipine administration. Gradual reduction of nitrates was associated with a myocardial

infarction in one patient (Patient 3), but had no ill effects in three other patients in whom the drug was withdrawn (Patients 4,11 and 12). In addition, because the frequency of angina1 attacks varies and the frequency of coronary spasm may spontaneously resolve, further prospective studies utilizing clinical response and provocative testing in the catheterization laboratory will be needed to assess the true efficacy of nifedipine in patients with variant angina and in other clinical settings where coronary vasospasm may be an important etiologic factor. Acknowledgment We are indebted to Richard Johnson, Blanche Douglas, Marge Rokus, Linda Branco, Ion Bazgan, Pam Cahill, and Janet Urbanek for technical assistance and to Geri Del Vecchio for secretarial assistance.

References 1. Braunwald E: Thirteenth Bowditch lecture: the determinants of myocardial oxygen consumption. Physiologist 12:65-95, 1969 2. Meller J, Pichard A, Dack S: Coronary arterial spasm in Prinzmetal’s angina: a proved hypothesis. Am J Cardiol 37: 938940, 1976 3. MacAlpin RN, Kattus AA, Alvaro AB: Angina pectoris at rest with preservation of exercise capacity: Prinzmetal’s variant angina. Circulation 47:946-958. 1973 4. Ollva PB, Potts DE, Pluas G: Coronary arterial spasm in Prinzmetal’s angina: documentation by coronary arteriography. N Engl J Med 288:745-75 1, 1973 5. Goldberg S, Lam W, Mudge OH, Hlrshfeld JW, Kastor JA: Coronary hemodynamic and myocardial metabolic alterations accompanying coronary artery spasm. Am J Cardlol 43:481-487, 1979 6. Mudge GH, Grossman W, Mills R, Lesch M, Braunwald E: Reflex increase in coronary vascular resistance in patients with ischemic heart disease. N Engl J Med 295:1333-1337, 1976 7. Mudge GH, Goldberg S, Mann T, Gunther S, Grossman W: Comparison of metabolic and vasoconstrictor stimuli on coronary vascular resistance in man. Circulation 59544-550, 1979 8. Raizner AE, lshimori T, Chahlne RA, Jamal N: Coronary artery spasm induced by the cold pressor test (abstr). Am J Cardiol 41: 385, 1978 9. Maseri A, Mlmmo R, Chierchia S: Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest 68:625-633, 1975 10. Maseri A, L’Abbate A, Pesola A: Coronary vasospasm in angina pectoris. Lancet 1: 713-717, 1977 11. Olfva P, Breckenrldge JC: Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 56:

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366-374, 1977 12. Maseri A, LAbbate A, Baroldi G, Chlerchia S, Marzilli M, Balleatia AM, Severi S, Parodl 0, Blagfnl A, Dlstaute A, Pesota A: Coronary vasospasm as a possible cause of myocardial infarctioh. N Engl J Med 299:1271-1277. 1978 13. Braunwald E: Coronary spasm and acute myocardial infarction-new possibility for treatment and prevention. N Engl J Med 299:1301-1303, 1978 14. Somlyo AP, Somlyo AV: Vascular smooth muscle. II. Pharmacology of normal and hypertensive vessels. Pharmacol Rev 22: 249-252, 1970 15. Bohr DF: Vascular smooth muscle updated. Circ Res 32:665-672, 1973 16. Yasue H, Nagao M, Ornate S, Takizawa A, Mlwa K, Tanaka S: Coronary arterial spasm and Prinzmetal’s variant form induced by hyperventilatioh and Tris buffer infusion. Circulation 5856-62, 1978 17. Solberg LE, Nissen RG, Vliestra RE: Prinzmetal’s variant angina-response to verapamil. Mayo Clin Proc 53:256-259, 1978 18. Curry RC, Pepine CJ, Conti R: Refractory variant angina treated with perhexilene maleafe: results in 14 patients (abstr). Circulation 58:Suppl ll:ll-693, 1978 19. Muller J, Gunther S: Nifedipine therapy for Prinzmetal’s angina. Circulation 57:137-139, 1978 20. Vater W, Kroneberg G, Hoffmeister F, Kaller H, Meng K, Dberdorf A, Puls W, Schlossman K, Stolpek K: Zur Pharmakologie von 4 (2’nitrophenyl)-2.6 dimethyl-1.4 dihydropyridine-3,5, dicarbonscuredlmethylester (Nifedipine. ‘Bay a 1040). Arzneim Forsch 22: l-23. 1972

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