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Increase in plasma norepinephrine during prazosin therapy for chronic congestive heart failure
Increase in Plasma Norepinephrine During Prazosin Therapy for Chronic Congestive Heart Failure
LEON DAVID MYRON
STEIN,
M.D.
P. HENRY,
M.D.
H. WEINBERCER.
Indiunopolis,
M.D.
~ndiunu
From the Krannert Institute of Cardiology, the Department of Medicine, Indiana_ University School of Medicine, Lilly Laboratory for Clinical Research and Wishard Memorial Hospital, Indianapolis, Indiana. This study was supported in part by the Herman C. Krannert Fund, by USPHS Grants HL-06308, HL-07182 and HL14159, Specialized Center of Research (SCOR) Hypertension. from the National Heart, Lung and Blood Institute. Requests for reprints should be addressed to Dr. Leon Stein, Wishard Memorial Hospital, Indiana University Medical Center, 1001 West 10th Street, Indianapolis, IN 46202. Manuscript accepted September 11, 1980.
To investigate the mechanism of pharmacodynamic tolerance reported to occur during prazosin therapy of chronic congestive heart failure, we measured plasma norepinephrine, plasma epinephrine, plasma renin activity (PRA) and plasma aldosterone, as well as hemodynamics in eight patients with chronic congestive heart failure, functional class III and IV (NYHA), before and during 10 weeks of prazosin therapy. Initially, prazosin therapy produced significant hemodynamic improvement, but no significant changes were noted in norepinephrine, epinephrine, plasma renin activity or aldosterone. During ambulatory therapy, fluid retention developed in four patients, and three of them had symptoms or clinical evidence of congestive heart failure for which they required an increase in diuretic or prazosin therapy. Plasma norepinephrine levels for the whole group were signficantly higher after four weeks of therapy (p
April 1981 The American Journal of Medicine
Volume 79
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PRAZOSIN FOR CONGESTIVE HEART FAILURE-STEIN
TABLE I Patient
Patient Population Age (yr), Race andSex
1
ET AL.
Diagnosis
NYHAClass
2 3
54,B.F 55,B,M 62,B,F
Arteriosclerotic heart disease Idiopathic cardiomyopathy Arteriosclerotic heart disease
IV IV IV
4
57,B,F
Arteriosclerotic heart disease
Ill
65,C,F 52,B.M 64,B,F 57,C,M
Arteriosclerotic heart disease Alcoholic cardiomyopathy Arteriosclerotic heart disease Arteriosclerotic heart disease
IV IV IV III
mechanisms involved in this tolerance are not known. To investigate whether this pharmacodynamic tolerance was related to alterations in the sympathetic nervous system or in the renin-angiotensin system, we measured plasma norepinephrine, epinephrine, plasma renin activity, aldosterone and hemodynamic parameters during 10 weeks of prazosin therapy. We also compared the changes that occurred with those that occurred during infusion of sodium nitroprusside, a direct smooth muscle vasodilator with a similar balanced reduction in cardiac preload and afterload but devoid of direct action on the adrenergic receptors. MATERIAL
AND METHODS
Following informed consent, we studied eight patients, three male and five female, in functional class III or IV chronic congestive heart failure (NYHA), despite administration of digitalis and diuretics. Administration of these drugs was continued, and the patients were maintained on a 2 g sodium diet. Their clinical features are listed in Table I.
Study Design. Tbe study was divided into three phases [Table II]. An inpatient pretreatment evaluation and titration with prazosin (phase 1). an ambulatory treatment period lasting nine weeks (phase II) and a final inpatient evaluation (phase III]. Phase I. Following catheterization of the right side of the heart the patients entered the study if their pulmonary artery wedge pressure exceeded 15 torr and their cardiac index was less than 2.5 liters/min/m2. After blood sampling for plasma norepinephrine, epinephrine, plasma renin activity and aldosterone determinations, their response to an infusion of sodium ni-
TABiE
II
2 days Pretreatment evaluation
Therapy Digoxin. furosemide 120 mg Digitoxin, furosemide 80 mg Digoxin, furosemide 200 mg. procainamide hydrochloride 1,500 mg Digitoxin, dyazide 1 capsule, disopyramide phosphate 400 mg Digoxin, furosemide 160 mg Digoxin, furosemide 80 mg Digoxin, furosemide 80 mg Digoxin. furosemide 160 mg
troprusside was assessed. We started at 10 pg/min and increased by 10 pg every 10 minutes, until the pulmonary artery wedge pressure fell to 50 percent of control or the systolic blood pressure level fell to 90 torr. After 15 minutes of stabilization, hemodynamic measurements and blood sampling were repeated. The catheters were removed, and the patient was titrated with oral prazosin in increasing dosages three times a day until maximum clinical reduction in symptoms and signs of congestive heart failure was achieved. This took an average of six days. The mean dose of prazosin was 5 f 3 mg every 3 hours. Prazosin was withheld, and after a 34-hour washout period, hemodynamic measurements and blood samples were obtained. Prazosin was readministered at the last titrated dosage, the hemodynamics were determined hourly for 4 hours, and blood sampling was repeated at 2 hours. Peak hemodynamic effects of prazosin usually occurred between 1 and 2 hours; only peak effects are reported. Those patients who showed a beneficial clinical and hemodynamic response were discharged and followed weekly. During this period (phase II), prazosin and/or diuretic therapy was adjusted as needed. Plasma norepinephrine, epinephrine, plasma renin activity and aldosterone were measured again at one and four weeks. After nine weeks the patients were hospitalized (phase III). Following another 24-hour washout period, hemodynamic measurements and blood sampling were repeated before and after prazosin therapy as outlined.
Hemodynamics. All studies were performed in the postabsorptive state 1 hour after instrumentation between 11 a.m. and 3 p.m. Pulmonary artery, pulmonary artery wedge and right atria1 pressures were measured with a thermodilution balloon tipped
Study Protocol PhaseI lnpatlesf 70-24 hours 6 days Titration with PZ
Washout
O-4 Hours
PhaseII Outpatlertl 9 weeks
1 Day
PhaseIll Inpatient 10-24 Hours Washout
Control PZ
O-4 Hours Control PZ
I 4
4
Invasive Hemodynamics # 4 4 z Invasive Hemodynamics Plasma catecholamines, plasma renin activity and plasma aldcsterqne NOTE: T Indicates times of studies. NP = sodium nitroprusside: PZ = prazosin.
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I’RAZOSIN
FOR
CONGESTIVE
HEART
FAILIIRE-STEIN
ET AL.
Hemodynamic Effects of Sodium Nitroprusside and Prazosin
TABLE Ill
Parameter Heart rate (beatsimin) NP PZ I PZ III Mean arterial pressure (torr) NP PZ I PZ Ill Cardiac output (litersimin) NP PZ I PZ Ill Pulmonary artery wedge pressure (torr) NP PZ I PZ Ill Right atrial pressure (torr) NP PZ I PZ Ill Systemic vascular resistance (dynes-sec-cmp5) NP PZ I PZ Ill Pulmonary vascular resistance (dynepsec-cmW5) NP PZ I PZ Ill
Control
Treatment
P
91fll 93 f 6 82 f 14’”
87f 11 90 f 8 79% 15
NS NS NS
103 f 12 101 f 7 95f9’ 3.20 f 1.20 3.51 f 0.80 3.54 f 0.78 28 f 6 26 f 3 19f7”’
86f 89f 85f
14 11 10
4.53 f 1.29 4.46 f 1.60 3.83 f 0.59 15f6 19f5 13f6
<0.0005
15 f 8 11 f5 10f 3”
9f5 9f4 7f3
co.01 NS NS
2,513 f 1210 2,143 f 408 2,012 f 511’
1,397 f 293 1,555 f 364 1,661 f 482
<0.005 co.05 NS
393 f 388 f 380 f
192 187 199
283 f 315 f 321 f
149 151 147
NS NS NS
NOTE: Values = mean f standard deviation. NP = sodium nitroprusside; PZ I = prazosin, phase I study; PZ Ill = prazosin, phase Ill study. = p 0.005 comparing control during PZ Ill to pretreatment control. * = p 0.05; * = po.01. l
l
Swan-Ganz
catheter
l
l
and systemic arterial
pressure via a
Teflon@ catheter introduced into a femoral artery. Pressures and the electrocardiogram were recorded continuously on a six channel Gould Brush 260 recorder. Mean pressures were derived electronically. Cardiac output was measured with a computer (Edwards 5200), as the average of three determinations with a variation of !ess than 10 percent. Derived measurements included: SVR=AP-RAPXBO AP-PAWXBO and PVR = co co -where SVR = systemic vascular resistance, dynes - sec. cmm5; AP = mean arterial pressure. torr; RAP = right atria1 pressure, torr; CO = cardiac output, liters/min: and PVR = pulmonary vascular resistance, dynes - set - cm+; PAW = pulmonary artery wedge pressure, torr. Blood sampling. During the inpatient studies we obtained blood samples for determination of plasma renin activity and aldosterone assay from the femoral artery, and simultaneous femoral artery and pulmonary artery blood samples for norepinephrine and epinephrine assay to estimate their pulmonary extraction. Outpatient samples were obtained between 11 A.M. and 3 P.M. after a needle was inserted in an antecubital vein, and the patient had rested supine for 1 hour. Samples for norepinephrine, epinephrine, plasma renin activity and aldosterone determination were collected in heparinized or EDTA-containing tubes, stored in ice, centri-
April
fuged within 30 minutes and frozen. Catecholamines were quantified by radioenzymatic assay (18,191and plasma renin activity and aldosterone by radioimmunoassay [ZO]. Statistical Analysis. The inpatient data were analyzed by analysis of variance. The outpatient data at one and four weeks were analyzed using the Student’s paired t test. The null hypothesis was rejected with p <0.05. Results are expressed as mean f standard deviation (SD). RESULTS
Clinical Course. Initially, all patients experienced a reduction in dyspnea and fatigue. Later, during the ambulatory phase, four patients gained weight, associated with increased dyspnea in one and the development of pulmonary rales in two. These three patients responded to an increase in the diuretic and/or prazosin dose. After 10 weeks, the condition in all patients improved to a functional class II (NYHA). Their weight averaged 163 f 40 pounds before therapy and 162 f 34 pounds after 10 weeks (p not significant]. The daily dose of prazosin averaged 16.8 f 2.4 mg at 10 weeks compared to 15 f 4 mg after titration. Hemodynamics. The hemodynamic data are shown in Table III. Pretreatment measurements indicated an increased pulmonary artery wedge and right atria1 pressure as well as reduced cardiac output and in-
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PRAZOSIN
FOR CONGESTIVE
HEART
FAILURE-STEIN
ET AL.
TABLE IV
FINAL
Changes in Plasma Norepinephrine and Plasma Epinephrlne
PRAZOSIN Number
Plasma Plasma Norepinephrine Epinephrine (997mt) @g/ml)
Inpatient (measured in pulmonaryartery) Phase I
I-
10
2 L
PULMONARY
20 ARTERY
Pretreatment baseline 8 276 f 347 42 f 52 Sodium nitroprusside 7 243 f 322 45 f 55 Initial control 7 356 f 378 39 f 53 Initial prazosin 8 331 f 256 29 f 30 Phase Ill Final control 8 455 f 90 28 f 22 Final prazosin 7 521 f 130’ 30f 18 Outpatient (measured In antecubltal vein) 1 week 8 315 f 215 50 f 57 4 weeks 8 439 f 264’ 31 f36
30
WEDGE PRESSURE
(tort-)
l
NOTE: Values = mean f standard deviation. p CO.05 compared to pretreatment baseline and p <0.02 compared to sodium nitroprusside. p CO.01 compared to first week. l
l
1 \
i
I
2%
I I
1 !I
PULMONARY
ARTERY
INITIAL
PRAZOSIN
WEDGE PRESSURE
(tort-)
J
Figure 1. Ventricular function curves during the pratosin studies. A significant reduction in pulmonary artery wedge pressure occurs during both the initial and final administration of prazosin (p
creased systemic vascular resistance and pulmonary vascular resistance. After the administration of sodium nitroprusside and prazosin the heart rate was unchanged. Both drugs significantly reduced mean arterial pressure (p <0.0005 and p
828
April
1981
The American Journal of Medicine
Volume
l
70
!
PRAZOSIN
FOR CONGESTIVE
I4
-10
:
4 + 5 u %
tj -lOv) .
.
4
-20
w 5
-26
-.
.
x
.
L
l
-30
-30
I_-_&
-40
ET AL.
o-
0
l
.
FAILIIRE-STEIN
r .8Op<.O5
r .78PC.O5
0
HEART
200
400
-
.
-qo,L.4 600
1200
CONTROL
200
PLASMA
400
600
1200
NOREPINEPHRINE
(pg/ml)
Figure 2. Correlation between control plasma norepinephrine and the perter change in mean arterial pressure and systemic vascular resistance during phase I prazosin administration. @ = mean arterial pressure; percent A = percent change; SVR = systemic vascular resistance
Following prazosin administration, the norepinephrine level rose to 521 + 130 pg/ml and was significantly higher than during pretreatment baseline [p <0.05) as well as during the infusion of sodium nitroprusside (p CO.02). Pulmonary artery epinephrine averaged 42 f 52 pg/ml before therapy and did not change significantly throughout the inpatient study. Control norepinephrine correlated significantly with the decrease in mean arterial pressure and systemic vascular resistance after prazosin administration during
. . 1 . r .76
0
-10
phase I, r 0.78 and r 0.80 (p <0.05), (Figure 2) although largely due to the high values in one patient. No correlation was noted during the infusion of sodium nitroprusside or when prazosin was given during phase III. Pulmonary extraction of norepinephrine was 6 f 20 percent before therapy (normally it exceeds 25 percent [21]] and remained low throughout the study. No significant extraction of epinephrine was noted. During phase II, peripheral venous norepinephrine was 315 f 215 pg/ml one week after discharge; four
r .82
p-Z.05
p-z.05
-20
-30
-40 3
6
9
12
CONTROL
3
PLASMA (ng/ml/3
RENIN
6
9
12
ACTIVITY
hrs)
Figure 3. Correlation between control plasma renin activity and the percent change in mean arterial pressure and systemic vascular resistance during phase I prazosin administration. s = mean arterial pressure; percent A = percent change: SVR = systemic vascular resistance.
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70
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FOR CONGESTIVE
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FAILURE-STEIN
ET AL.
weeks later norepinephrine had increased to 439 f 264 pg/ml (p
tration of sodium nitroprusside or prazosin. Control plasma renin activity correlated with the reduction in mean arterial pressure and systemic vascular resistance following the administration of prazosin during phase I, r 0.76 and r 0.82 (p <0 05) (Figure 3). No correlation was noted during the infusion of sodium nitroprusside or after 10 weeks of therapy with prazosin. Plasma aldosterone averaged 14.2 f 8.8 ng/lOO ml (normal 5 to 30 ng/lOO ml) and did not change significantly during treatment with sodium nitroprusside or prazosin. During phase II, plasma renin activity averaged 9.4 f 10 ng/ml/3 hours one week after discharge. Four weeks later, plasma renin activity averaged 15.1 f 10 in the eight patients (p not significant). Plasma aldosterone averaged 11.2 f 8.8 ng/lOO ml during the first week and at four weeks averaged 17.7 f 15.1 ng/lOO ml (p not significant). Our results during the inpatient studies demonstrate a significant increase in plasma norepinephrine, but not in plasma renin activity or aldosterone, following 10 weeks of prazosin therapy (Figure 41. Similarly, only norepinephrine increased significantly during the ambulatory phase, after half the patients had manifested fluid retention and/or exacerbation of congestive heart failure. Of the four patients in whom pharmacodynamic tolerance developed, plasma renin activity increased in two, aldosterone increased in all and norepinephrine increased in three. COMMENTS The
B t---
NP PHASE
IC I __(
IPZ
FC
FPZ
M PHASE
III
Plasma norepinephrine. plasma renin activity ant gun, 4. aldosterone during phase I and Ill inpatient studies. After 10 weeks of prazosin therapy plasma norepinephrine is significantly higher than during sodium nitroprusside infusion (p <0.02) and pretreatment baseline (p <0.05). B = pretreatment baseline; FC = postwashout control during final study; FPZ = effect of prazosin during final study; IC = postwashout control during initial study; IPZ = effect of prazosin during initial study; NP = sodium nitroprusside.
830
April 1981
The American Journal of Medicine
sympathetic nervous system may play an important role in the pathophysiology of chronic congestive heart failure. When the cardiac output is reduced, stimulation of arterial alpha receptors increases systemic vascular resistance and provides inotropic support through cardiac beta adrenergic receptors. In addition, systemic vascular resistance may be increased by altered vascular smooth muscle reactivity, structural alterations in the arterial wall or humorally delivered vasoconstrictors such as epinephrine and angiotensin. Norepinephrine levels as reported in this and other studies do not produce pressor effects [22]. There is now evidence for discrete alpha, and alpha2 subtypes of adrenergic receptors [23]. Alpha1 adrenergic receptors are the classic postsynaptic alpha receptors, mediating catecholaminergic constriction of smooth muscle. Alpha2 receptors are found in presynaptic nerve terminals in which they mediate feedback inhibition of depolarization-induced norepinephrine release. Another function recently described for alpha2 receptors is inhibition of renin release by the kidney [24]. Prazosin lowers systemic vascular resistance by acting as an alpha adrenergic receptor antagonist relatively specific for the alpha1 subset of receptors [25]. Chidsey et al. [l,3] reported that peripheral venous and urinary levels of norepinephrine were elevated in patients with congestive heart failure both at rest and during exercise, but the group was not clearly separated
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PRAZOSIN FOR CONGESTIVE
from normal subjects. No correlation between urinary excretion of norepinephrine and severity of heart failure was demonstrable. Curtis et al. [4] measured plasma norepinephrine in patients with congestive heart failure treated with the angiotensin converting enzyme inhibitor, teprotide. Plasma norepinephrine levels before therapy were high (620 pg/ml) in peripheral venous plasma. Sole et al. [2l] recently measured simultaneous pulmonary artery and aortic norepinephrine in 24 patients with and without pulmonary hypertension, nine of whom had congestive heart failure. Pulmonary artery norepinephrine was 314 f 13 pg/ml in those with normal pulmonary vascular resistance. These values compare favorably with those found in the current study. It is possible that the norepinephrine level was lower in the pulmonary artery than in an antecubital vein which carries the washout of skin and muscle, organs involved in the neurogenic vasoconstriction of congestive heart failure. However, we obtained simultaneous venous antecubital and pulmonary artery samples in five patients with congestive heart failure (unpublished observations) and found no consistent differences between them. In addition, pulmonary artery norepinephrine concentrations following prazosin administration during phase I of the present study were not significantly different from those obtained one week later from a peripheral vein. It would appear that plasma norepinephrine need not be increased in patients with severe congestive heart failure studied in a basal state. Plasma norepinephrine is a complex function of circulatory delivery, release, metabolism and washout, and does not simply represent neuronal sympathetic activity. The pulmonary vascular endothelium normally extracts over 25 percent of pulmonary artery norepinephrine, but it does not extract epinephrine. This function can be inhibited by alpha adrenergic blockade [26] and is reduced when pulmonary vascular resistance is high [21]. In this study norepinephrine extraction was reduced before and during vasodilator therapy, probably because pulmonary vascular resistance remained high. An intriguing and paradoxic result of our investigation was the increase in norepinephrine during prazosin therapy. During the ambulatory phase of our study, peripheral venous norepinephrine was significantly higher after four weeks of therapy [p
HEART FAILIJRE-STEIN
ET AL.
patients had a blunted hemodynamic response whereas norepinephrine increased further, to levels significantly higher than those before therapy (p
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ET AL.
PRAZOSIN FOR CONGESTIVE HEART FAILURE-STEIN
blockade independent of an increase in plasma renin activity. The present investigation does not show consistent changes in plasma renin activity and aldosterone, but this may reflect the complex control of this system. The increase in norepinephrine suggests that the sympathetic nervous system could contribute to pharmacodynamic tolerance during prazosin therapy of congestive heart failure. Because similar increases have been reported in hypertensive subjects treated with prazosin, without evidence of tolerance [29], and considering the
small number of patients in the present study, these conclusions can be only tentative. Further investigation is necessary to confirm whether elevations in plasma norepinephrine levels are relevant to the problem of tolerance during prazosin therapy of congestive heart failure. ACKNOWLEDGMENT
We wish to extend special thanks to Jean Statza, R.N. and Carol Robideau for their invaluable assistance during the conduct of the research.
REFERENCES 1. Chidsey
2.
3.
4. 5. 6.
7. 8
9. 10.
11.
12.
13.
14.
15.
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CA, Braunwald E, Morrow AG: Catecholamine excretion and cardiac stores of noreuineohrine in congestive heart failure. Am J Med 1965; ‘39:442-451. Kraner RS. Mason DT. Braunwald E: Augmented svmnathetic neurotransmitter activity in the peGpheral vascular bed of oatients with congestive heart failure and cardiac norepinephrinc depletion. Circulation 1968; 38: 629-634. Chidsev CA, Harrison DC, Braunwald E: Augmentation of the piasma norepinephrine response to exe&e in patients with congestive heart failure. N Engl J Med 1962; 267: 650-654. Curtiss C, Cohn JN. Vrobel T: Role of the renin-angiotensin svstem in the svstemic vasoconstriction of chronic congestive heart failure. Circulation 1978; 56: 763-776. Watkins L Jr, Burton JA. Haber E. Cant JR, Smith FW, Barger AC: The renin-aldosteronc system in congestive failure in conscious dogs. J Clin Invest 1976: 57: 1606-1617. Turini GA. Brunner HR. Ferruson RK. Rivier IL. Gavras H: Congestive heart failure i’l normotonsive man-hemodynamics. renin and aneiotensin II blockade. Br Heart 11976: 40: 1134-1142. Israili ZH: Correlation of pharmacological effects with plasma levels of antihypertensive drugs in man. Ann Rev Pharmacol Toxicoll979: 19: 25-52. Davis R, Ribner HS, Kcung E, Sonnenblick EH. LeJemtel TH: Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme. N Engl I Med 1979; 301: 117-121. Lowensiein J, Steele JM Jr: Prazosin: Mechanism of action and role in antihvpcrtensive therapy. . _ Cardiovasc Med 1979: 4: 865-891. -. Miller RR, Awan NA, Maxwell K, Mason DT: Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator prazosin. N Enall Med 1977: 297: 303-307. Awan NA, Mi‘ile’rRR, DoMaria AN, Maxwell K. Neumann A, Mason DT: Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic refractory heart failure. Concomitant relief of pulmonary congestion and elevation of pump output dcmonstratcd by improvements in symptomatology. exercise tolerance, hemodynamics and echocardiography. Circulation 1977; 56: 346-354. Arnold S, Ports T, Chatterjee K, Williams R. Rubin S, Parmley W: Rapid attentuation of prazosin mediated increase in cardiac output in patients with chronic heart failure (abstr). Circulation 1977; 56, 57 (suppl III): 111-222. Packer M, Meller J, Gorlin R, Herman MV: Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure. Circulation 1979: 59: 531-539. Desch CE, Magorien RD, Triffon DW, Blanford ME, Unverferth DV. Leier CV: Development of pharmacodynamic tolerance to prazosin in congestive heart failure. Am J Cardioll979; 44: 1178-1182. Elkavam II, Leiemtel TH. Mathur M. Ribner HS. Frishman WH. Strom J: Sonnenblick EH: Marked early attenuation of hcmodynamic effects of oral prazosin therapy in chronic congestive heart failure. Am J Cardiol1979: 44: 540-545.
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16. Awan NA, Miller RR, Maxwell S, Mason DT: Development of svstemic vasodilator tolerance to urazosin with chronic useof the agent in ambulatory therapy of severe congestive heart failure (abstrl. Am 1Cardiol 1978; 41: 367. 17. Harper R. Claxton H. Mid&brook K, Anderson S. Pitt A: Acute and chronic effects of prazosin in severe congestive cardiac failure (abstr]. Circulation 1979; 59. 60 (suppl): II129. 18. Boren KR. Henry DP. Selkurt EE. Wcinbergcr MH: Renal modulation of urinary catccholamine excretion during volume expansion in the clog. Hypertension 1980; 2: 383-389. 39. Coyle JT, Henry DP: Catecholamincs in fetal and newborn rat brain. J Neurochem 1973; 21: 61-67. 20. Weinberger MH, Kern DC, Gomez-Sanchez NJ, Kramer BT. Martin BT. Nuaent CA: The effect of dexamethasone on the control’of pGsma aldostcrone concentration in normal recumbent man. J Lab Clin Med 1975; 85: 957-967. 21. Sole MJ, Drobac M, Schwartz L, Hussein MN, Vaughan-Neil El? The extraction of circulating catecholamines by the lungs in normal man and in patients with pulmonary hypertension. Circulation 1979; 60: 160-163. 22. Silverberg AB, Shah SD, Haymond MW. Cryer PE: Norepinephrine: hormone and neurotransmitter in man. Am J Phvsiol1978: 234: E252-E256. 23. Berthelsen S. Pettinger WA: A functional basis for classification of a-adrenergic receptors. Life Sci 1977: 21: 595606. 24. Pettinger WA, Keeton TK. Campbell WB. Harper DC: Evidence for a renal a-adrenerrric recentor inhibiting renin release. Circ Res 1976; 38: 338-346. ’ 25. Davey MJ, Massingham R: A review of the biological effects of prazosin including recent pharmacological findings. Curr Med Res Opin 1976; 4: 47-60. 26. Iwasawa Y, Gillis CN: Pharmacological analysis of norepinephrine and 5.hydroxytryptamine removal from the pulmonary circulation. J Pharmacol Exper Therap 1974; 188: 386-393. 27. Koshv MC: Phvsiolonic evaluation of a new antihvnertensive agent: prazosin HCL. Circulation 1977; 55: 533-537. 28. Haves lM: Experience with prazosin in the treatment of patients with-severe hypertension. Med J Aust 1976; 1: 562-564. 29. Wilson-Mulvihill J. Graham RM, Pettinger W. ct al.: Comparative effects of prazosin and phenoxybenzamine on arterial blood pressure, heart rate, and plasma catecholamines in essential hypertension. J Cardiov Pharmac 1979: 1 (suppl): Sl. 30. Colucci WS, Wynne J. Holman BL, Braunwald E: Long term therapy of heart failure with prazosin: a randomized double blind trial. Am J Cardiol 1980; 45:337-344. 31. Weil JV. Chidsey CA: Plasma volume expansion resulting from interference with adrenergic function in man. Circulation 1968: 37: 54-61. 32. Ibsen H: Changes in plasma volume and extracellular fluid volume after addition of prazosin to propranolol treatment in patients with hypertension. Stand J Clin Lab Invest 1978; 38: 425-429.
Volume 70
LEON DAVID MYRON
STEIN,
M.D.
P. HENRY,
M.D.
H. WEINBERCER.
Indiunopolis,
M.D.
~ndiunu
From the Krannert Institute of Cardiology, the Department of Medicine, Indiana_ University School of Medicine, Lilly Laboratory for Clinical Research and Wishard Memorial Hospital, Indianapolis, Indiana. This study was supported in part by the Herman C. Krannert Fund, by USPHS Grants HL-06308, HL-07182 and HL14159, Specialized Center of Research (SCOR) Hypertension. from the National Heart, Lung and Blood Institute. Requests for reprints should be addressed to Dr. Leon Stein, Wishard Memorial Hospital, Indiana University Medical Center, 1001 West 10th Street, Indianapolis, IN 46202. Manuscript accepted September 11, 1980.
To investigate the mechanism of pharmacodynamic tolerance reported to occur during prazosin therapy of chronic congestive heart failure, we measured plasma norepinephrine, plasma epinephrine, plasma renin activity (PRA) and plasma aldosterone, as well as hemodynamics in eight patients with chronic congestive heart failure, functional class III and IV (NYHA), before and during 10 weeks of prazosin therapy. Initially, prazosin therapy produced significant hemodynamic improvement, but no significant changes were noted in norepinephrine, epinephrine, plasma renin activity or aldosterone. During ambulatory therapy, fluid retention developed in four patients, and three of them had symptoms or clinical evidence of congestive heart failure for which they required an increase in diuretic or prazosin therapy. Plasma norepinephrine levels for the whole group were signficantly higher after four weeks of therapy (p
April 1981 The American Journal of Medicine
Volume 79
825
PRAZOSIN FOR CONGESTIVE HEART FAILURE-STEIN
TABLE I Patient
Patient Population Age (yr), Race andSex
1
ET AL.
Diagnosis
NYHAClass
2 3
54,B.F 55,B,M 62,B,F
Arteriosclerotic heart disease Idiopathic cardiomyopathy Arteriosclerotic heart disease
IV IV IV
4
57,B,F
Arteriosclerotic heart disease
Ill
65,C,F 52,B.M 64,B,F 57,C,M
Arteriosclerotic heart disease Alcoholic cardiomyopathy Arteriosclerotic heart disease Arteriosclerotic heart disease
IV IV IV III
mechanisms involved in this tolerance are not known. To investigate whether this pharmacodynamic tolerance was related to alterations in the sympathetic nervous system or in the renin-angiotensin system, we measured plasma norepinephrine, epinephrine, plasma renin activity, aldosterone and hemodynamic parameters during 10 weeks of prazosin therapy. We also compared the changes that occurred with those that occurred during infusion of sodium nitroprusside, a direct smooth muscle vasodilator with a similar balanced reduction in cardiac preload and afterload but devoid of direct action on the adrenergic receptors. MATERIAL
AND METHODS
Following informed consent, we studied eight patients, three male and five female, in functional class III or IV chronic congestive heart failure (NYHA), despite administration of digitalis and diuretics. Administration of these drugs was continued, and the patients were maintained on a 2 g sodium diet. Their clinical features are listed in Table I.
Study Design. Tbe study was divided into three phases [Table II]. An inpatient pretreatment evaluation and titration with prazosin (phase 1). an ambulatory treatment period lasting nine weeks (phase II) and a final inpatient evaluation (phase III]. Phase I. Following catheterization of the right side of the heart the patients entered the study if their pulmonary artery wedge pressure exceeded 15 torr and their cardiac index was less than 2.5 liters/min/m2. After blood sampling for plasma norepinephrine, epinephrine, plasma renin activity and aldosterone determinations, their response to an infusion of sodium ni-
TABiE
II
2 days Pretreatment evaluation
Therapy Digoxin. furosemide 120 mg Digitoxin, furosemide 80 mg Digoxin, furosemide 200 mg. procainamide hydrochloride 1,500 mg Digitoxin, dyazide 1 capsule, disopyramide phosphate 400 mg Digoxin, furosemide 160 mg Digoxin, furosemide 80 mg Digoxin, furosemide 80 mg Digoxin. furosemide 160 mg
troprusside was assessed. We started at 10 pg/min and increased by 10 pg every 10 minutes, until the pulmonary artery wedge pressure fell to 50 percent of control or the systolic blood pressure level fell to 90 torr. After 15 minutes of stabilization, hemodynamic measurements and blood sampling were repeated. The catheters were removed, and the patient was titrated with oral prazosin in increasing dosages three times a day until maximum clinical reduction in symptoms and signs of congestive heart failure was achieved. This took an average of six days. The mean dose of prazosin was 5 f 3 mg every 3 hours. Prazosin was withheld, and after a 34-hour washout period, hemodynamic measurements and blood samples were obtained. Prazosin was readministered at the last titrated dosage, the hemodynamics were determined hourly for 4 hours, and blood sampling was repeated at 2 hours. Peak hemodynamic effects of prazosin usually occurred between 1 and 2 hours; only peak effects are reported. Those patients who showed a beneficial clinical and hemodynamic response were discharged and followed weekly. During this period (phase II), prazosin and/or diuretic therapy was adjusted as needed. Plasma norepinephrine, epinephrine, plasma renin activity and aldosterone were measured again at one and four weeks. After nine weeks the patients were hospitalized (phase III). Following another 24-hour washout period, hemodynamic measurements and blood sampling were repeated before and after prazosin therapy as outlined.
Hemodynamics. All studies were performed in the postabsorptive state 1 hour after instrumentation between 11 a.m. and 3 p.m. Pulmonary artery, pulmonary artery wedge and right atria1 pressures were measured with a thermodilution balloon tipped
Study Protocol PhaseI lnpatlesf 70-24 hours 6 days Titration with PZ
Washout
O-4 Hours
PhaseII Outpatlertl 9 weeks
1 Day
PhaseIll Inpatient 10-24 Hours Washout
Control PZ
O-4 Hours Control PZ
I 4
4
Invasive Hemodynamics # 4 4 z Invasive Hemodynamics Plasma catecholamines, plasma renin activity and plasma aldcsterqne NOTE: T Indicates times of studies. NP = sodium nitroprusside: PZ = prazosin.
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4
I’RAZOSIN
FOR
CONGESTIVE
HEART
FAILIIRE-STEIN
ET AL.
Hemodynamic Effects of Sodium Nitroprusside and Prazosin
TABLE Ill
Parameter Heart rate (beatsimin) NP PZ I PZ III Mean arterial pressure (torr) NP PZ I PZ Ill Cardiac output (litersimin) NP PZ I PZ Ill Pulmonary artery wedge pressure (torr) NP PZ I PZ Ill Right atrial pressure (torr) NP PZ I PZ Ill Systemic vascular resistance (dynes-sec-cmp5) NP PZ I PZ Ill Pulmonary vascular resistance (dynepsec-cmW5) NP PZ I PZ Ill
Control
Treatment
P
91fll 93 f 6 82 f 14’”
87f 11 90 f 8 79% 15
NS NS NS
103 f 12 101 f 7 95f9’ 3.20 f 1.20 3.51 f 0.80 3.54 f 0.78 28 f 6 26 f 3 19f7”’
86f 89f 85f
14 11 10
4.53 f 1.29 4.46 f 1.60 3.83 f 0.59 15f6 19f5 13f6
<0.0005
15 f 8 11 f5 10f 3”
9f5 9f4 7f3
co.01 NS NS
2,513 f 1210 2,143 f 408 2,012 f 511’
1,397 f 293 1,555 f 364 1,661 f 482
<0.005 co.05 NS
393 f 388 f 380 f
192 187 199
283 f 315 f 321 f
149 151 147
NS NS NS
NOTE: Values = mean f standard deviation. NP = sodium nitroprusside; PZ I = prazosin, phase I study; PZ Ill = prazosin, phase Ill study. = p 0.005 comparing control during PZ Ill to pretreatment control. * = p 0.05; * = po.01. l
l
Swan-Ganz
catheter
l
l
and systemic arterial
pressure via a
Teflon@ catheter introduced into a femoral artery. Pressures and the electrocardiogram were recorded continuously on a six channel Gould Brush 260 recorder. Mean pressures were derived electronically. Cardiac output was measured with a computer (Edwards 5200), as the average of three determinations with a variation of !ess than 10 percent. Derived measurements included: SVR=AP-RAPXBO AP-PAWXBO and PVR = co co -where SVR = systemic vascular resistance, dynes - sec. cmm5; AP = mean arterial pressure. torr; RAP = right atria1 pressure, torr; CO = cardiac output, liters/min: and PVR = pulmonary vascular resistance, dynes - set - cm+; PAW = pulmonary artery wedge pressure, torr. Blood sampling. During the inpatient studies we obtained blood samples for determination of plasma renin activity and aldosterone assay from the femoral artery, and simultaneous femoral artery and pulmonary artery blood samples for norepinephrine and epinephrine assay to estimate their pulmonary extraction. Outpatient samples were obtained between 11 A.M. and 3 P.M. after a needle was inserted in an antecubital vein, and the patient had rested supine for 1 hour. Samples for norepinephrine, epinephrine, plasma renin activity and aldosterone determination were collected in heparinized or EDTA-containing tubes, stored in ice, centri-
April
fuged within 30 minutes and frozen. Catecholamines were quantified by radioenzymatic assay (18,191and plasma renin activity and aldosterone by radioimmunoassay [ZO]. Statistical Analysis. The inpatient data were analyzed by analysis of variance. The outpatient data at one and four weeks were analyzed using the Student’s paired t test. The null hypothesis was rejected with p <0.05. Results are expressed as mean f standard deviation (SD). RESULTS
Clinical Course. Initially, all patients experienced a reduction in dyspnea and fatigue. Later, during the ambulatory phase, four patients gained weight, associated with increased dyspnea in one and the development of pulmonary rales in two. These three patients responded to an increase in the diuretic and/or prazosin dose. After 10 weeks, the condition in all patients improved to a functional class II (NYHA). Their weight averaged 163 f 40 pounds before therapy and 162 f 34 pounds after 10 weeks (p not significant]. The daily dose of prazosin averaged 16.8 f 2.4 mg at 10 weeks compared to 15 f 4 mg after titration. Hemodynamics. The hemodynamic data are shown in Table III. Pretreatment measurements indicated an increased pulmonary artery wedge and right atria1 pressure as well as reduced cardiac output and in-
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FAILURE-STEIN
ET AL.
TABLE IV
FINAL
Changes in Plasma Norepinephrine and Plasma Epinephrlne
PRAZOSIN Number
Plasma Plasma Norepinephrine Epinephrine (997mt) @g/ml)
Inpatient (measured in pulmonaryartery) Phase I
I-
10
2 L
PULMONARY
20 ARTERY
Pretreatment baseline 8 276 f 347 42 f 52 Sodium nitroprusside 7 243 f 322 45 f 55 Initial control 7 356 f 378 39 f 53 Initial prazosin 8 331 f 256 29 f 30 Phase Ill Final control 8 455 f 90 28 f 22 Final prazosin 7 521 f 130’ 30f 18 Outpatient (measured In antecubltal vein) 1 week 8 315 f 215 50 f 57 4 weeks 8 439 f 264’ 31 f36
30
WEDGE PRESSURE
(tort-)
l
NOTE: Values = mean f standard deviation. p CO.05 compared to pretreatment baseline and p <0.02 compared to sodium nitroprusside. p CO.01 compared to first week. l
l
1 \
i
I
2%
I I
1 !I
PULMONARY
ARTERY
INITIAL
PRAZOSIN
WEDGE PRESSURE
(tort-)
J
Figure 1. Ventricular function curves during the pratosin studies. A significant reduction in pulmonary artery wedge pressure occurs during both the initial and final administration of prazosin (p
creased systemic vascular resistance and pulmonary vascular resistance. After the administration of sodium nitroprusside and prazosin the heart rate was unchanged. Both drugs significantly reduced mean arterial pressure (p <0.0005 and p
828
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1981
The American Journal of Medicine
Volume
l
70
!
PRAZOSIN
FOR CONGESTIVE
I4
-10
:
4 + 5 u %
tj -lOv) .
.
4
-20
w 5
-26
-.
.
x
.
L
l
-30
-30
I_-_&
-40
ET AL.
o-
0
l
.
FAILIIRE-STEIN
r .8Op<.O5
r .78PC.O5
0
HEART
200
400
-
.
-qo,L.4 600
1200
CONTROL
200
PLASMA
400
600
1200
NOREPINEPHRINE
(pg/ml)
Figure 2. Correlation between control plasma norepinephrine and the perter change in mean arterial pressure and systemic vascular resistance during phase I prazosin administration. @ = mean arterial pressure; percent A = percent change; SVR = systemic vascular resistance
Following prazosin administration, the norepinephrine level rose to 521 + 130 pg/ml and was significantly higher than during pretreatment baseline [p <0.05) as well as during the infusion of sodium nitroprusside (p CO.02). Pulmonary artery epinephrine averaged 42 f 52 pg/ml before therapy and did not change significantly throughout the inpatient study. Control norepinephrine correlated significantly with the decrease in mean arterial pressure and systemic vascular resistance after prazosin administration during
. . 1 . r .76
0
-10
phase I, r 0.78 and r 0.80 (p <0.05), (Figure 2) although largely due to the high values in one patient. No correlation was noted during the infusion of sodium nitroprusside or when prazosin was given during phase III. Pulmonary extraction of norepinephrine was 6 f 20 percent before therapy (normally it exceeds 25 percent [21]] and remained low throughout the study. No significant extraction of epinephrine was noted. During phase II, peripheral venous norepinephrine was 315 f 215 pg/ml one week after discharge; four
r .82
p-Z.05
p-z.05
-20
-30
-40 3
6
9
12
CONTROL
3
PLASMA (ng/ml/3
RENIN
6
9
12
ACTIVITY
hrs)
Figure 3. Correlation between control plasma renin activity and the percent change in mean arterial pressure and systemic vascular resistance during phase I prazosin administration. s = mean arterial pressure; percent A = percent change: SVR = systemic vascular resistance.
April 1981 The American Journal of Medicine
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70
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PRAZOSIN
FOR CONGESTIVE
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FAILURE-STEIN
ET AL.
weeks later norepinephrine had increased to 439 f 264 pg/ml (p
tration of sodium nitroprusside or prazosin. Control plasma renin activity correlated with the reduction in mean arterial pressure and systemic vascular resistance following the administration of prazosin during phase I, r 0.76 and r 0.82 (p <0 05) (Figure 3). No correlation was noted during the infusion of sodium nitroprusside or after 10 weeks of therapy with prazosin. Plasma aldosterone averaged 14.2 f 8.8 ng/lOO ml (normal 5 to 30 ng/lOO ml) and did not change significantly during treatment with sodium nitroprusside or prazosin. During phase II, plasma renin activity averaged 9.4 f 10 ng/ml/3 hours one week after discharge. Four weeks later, plasma renin activity averaged 15.1 f 10 in the eight patients (p not significant). Plasma aldosterone averaged 11.2 f 8.8 ng/lOO ml during the first week and at four weeks averaged 17.7 f 15.1 ng/lOO ml (p not significant). Our results during the inpatient studies demonstrate a significant increase in plasma norepinephrine, but not in plasma renin activity or aldosterone, following 10 weeks of prazosin therapy (Figure 41. Similarly, only norepinephrine increased significantly during the ambulatory phase, after half the patients had manifested fluid retention and/or exacerbation of congestive heart failure. Of the four patients in whom pharmacodynamic tolerance developed, plasma renin activity increased in two, aldosterone increased in all and norepinephrine increased in three. COMMENTS The
B t---
NP PHASE
IC I __(
IPZ
FC
FPZ
M PHASE
III
Plasma norepinephrine. plasma renin activity ant gun, 4. aldosterone during phase I and Ill inpatient studies. After 10 weeks of prazosin therapy plasma norepinephrine is significantly higher than during sodium nitroprusside infusion (p <0.02) and pretreatment baseline (p <0.05). B = pretreatment baseline; FC = postwashout control during final study; FPZ = effect of prazosin during final study; IC = postwashout control during initial study; IPZ = effect of prazosin during initial study; NP = sodium nitroprusside.
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April 1981
The American Journal of Medicine
sympathetic nervous system may play an important role in the pathophysiology of chronic congestive heart failure. When the cardiac output is reduced, stimulation of arterial alpha receptors increases systemic vascular resistance and provides inotropic support through cardiac beta adrenergic receptors. In addition, systemic vascular resistance may be increased by altered vascular smooth muscle reactivity, structural alterations in the arterial wall or humorally delivered vasoconstrictors such as epinephrine and angiotensin. Norepinephrine levels as reported in this and other studies do not produce pressor effects [22]. There is now evidence for discrete alpha, and alpha2 subtypes of adrenergic receptors [23]. Alpha1 adrenergic receptors are the classic postsynaptic alpha receptors, mediating catecholaminergic constriction of smooth muscle. Alpha2 receptors are found in presynaptic nerve terminals in which they mediate feedback inhibition of depolarization-induced norepinephrine release. Another function recently described for alpha2 receptors is inhibition of renin release by the kidney [24]. Prazosin lowers systemic vascular resistance by acting as an alpha adrenergic receptor antagonist relatively specific for the alpha1 subset of receptors [25]. Chidsey et al. [l,3] reported that peripheral venous and urinary levels of norepinephrine were elevated in patients with congestive heart failure both at rest and during exercise, but the group was not clearly separated
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PRAZOSIN FOR CONGESTIVE
from normal subjects. No correlation between urinary excretion of norepinephrine and severity of heart failure was demonstrable. Curtis et al. [4] measured plasma norepinephrine in patients with congestive heart failure treated with the angiotensin converting enzyme inhibitor, teprotide. Plasma norepinephrine levels before therapy were high (620 pg/ml) in peripheral venous plasma. Sole et al. [2l] recently measured simultaneous pulmonary artery and aortic norepinephrine in 24 patients with and without pulmonary hypertension, nine of whom had congestive heart failure. Pulmonary artery norepinephrine was 314 f 13 pg/ml in those with normal pulmonary vascular resistance. These values compare favorably with those found in the current study. It is possible that the norepinephrine level was lower in the pulmonary artery than in an antecubital vein which carries the washout of skin and muscle, organs involved in the neurogenic vasoconstriction of congestive heart failure. However, we obtained simultaneous venous antecubital and pulmonary artery samples in five patients with congestive heart failure (unpublished observations) and found no consistent differences between them. In addition, pulmonary artery norepinephrine concentrations following prazosin administration during phase I of the present study were not significantly different from those obtained one week later from a peripheral vein. It would appear that plasma norepinephrine need not be increased in patients with severe congestive heart failure studied in a basal state. Plasma norepinephrine is a complex function of circulatory delivery, release, metabolism and washout, and does not simply represent neuronal sympathetic activity. The pulmonary vascular endothelium normally extracts over 25 percent of pulmonary artery norepinephrine, but it does not extract epinephrine. This function can be inhibited by alpha adrenergic blockade [26] and is reduced when pulmonary vascular resistance is high [21]. In this study norepinephrine extraction was reduced before and during vasodilator therapy, probably because pulmonary vascular resistance remained high. An intriguing and paradoxic result of our investigation was the increase in norepinephrine during prazosin therapy. During the ambulatory phase of our study, peripheral venous norepinephrine was significantly higher after four weeks of therapy [p
HEART FAILIJRE-STEIN
ET AL.
patients had a blunted hemodynamic response whereas norepinephrine increased further, to levels significantly higher than those before therapy (p
April 1981
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ET AL.
PRAZOSIN FOR CONGESTIVE HEART FAILURE-STEIN
blockade independent of an increase in plasma renin activity. The present investigation does not show consistent changes in plasma renin activity and aldosterone, but this may reflect the complex control of this system. The increase in norepinephrine suggests that the sympathetic nervous system could contribute to pharmacodynamic tolerance during prazosin therapy of congestive heart failure. Because similar increases have been reported in hypertensive subjects treated with prazosin, without evidence of tolerance [29], and considering the
small number of patients in the present study, these conclusions can be only tentative. Further investigation is necessary to confirm whether elevations in plasma norepinephrine levels are relevant to the problem of tolerance during prazosin therapy of congestive heart failure. ACKNOWLEDGMENT
We wish to extend special thanks to Jean Statza, R.N. and Carol Robideau for their invaluable assistance during the conduct of the research.
REFERENCES 1. Chidsey
2.
3.
4. 5. 6.
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11.
12.
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14.
15.
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16. Awan NA, Miller RR, Maxwell S, Mason DT: Development of svstemic vasodilator tolerance to urazosin with chronic useof the agent in ambulatory therapy of severe congestive heart failure (abstrl. Am 1Cardiol 1978; 41: 367. 17. Harper R. Claxton H. Mid&brook K, Anderson S. Pitt A: Acute and chronic effects of prazosin in severe congestive cardiac failure (abstr]. Circulation 1979; 59. 60 (suppl): II129. 18. Boren KR. Henry DP. Selkurt EE. Wcinbergcr MH: Renal modulation of urinary catccholamine excretion during volume expansion in the clog. Hypertension 1980; 2: 383-389. 39. Coyle JT, Henry DP: Catecholamincs in fetal and newborn rat brain. J Neurochem 1973; 21: 61-67. 20. Weinberger MH, Kern DC, Gomez-Sanchez NJ, Kramer BT. Martin BT. Nuaent CA: The effect of dexamethasone on the control’of pGsma aldostcrone concentration in normal recumbent man. J Lab Clin Med 1975; 85: 957-967. 21. Sole MJ, Drobac M, Schwartz L, Hussein MN, Vaughan-Neil El? The extraction of circulating catecholamines by the lungs in normal man and in patients with pulmonary hypertension. Circulation 1979; 60: 160-163. 22. Silverberg AB, Shah SD, Haymond MW. Cryer PE: Norepinephrine: hormone and neurotransmitter in man. Am J Phvsiol1978: 234: E252-E256. 23. Berthelsen S. Pettinger WA: A functional basis for classification of a-adrenergic receptors. Life Sci 1977: 21: 595606. 24. Pettinger WA, Keeton TK. Campbell WB. Harper DC: Evidence for a renal a-adrenerrric recentor inhibiting renin release. Circ Res 1976; 38: 338-346. ’ 25. Davey MJ, Massingham R: A review of the biological effects of prazosin including recent pharmacological findings. Curr Med Res Opin 1976; 4: 47-60. 26. Iwasawa Y, Gillis CN: Pharmacological analysis of norepinephrine and 5.hydroxytryptamine removal from the pulmonary circulation. J Pharmacol Exper Therap 1974; 188: 386-393. 27. Koshv MC: Phvsiolonic evaluation of a new antihvnertensive agent: prazosin HCL. Circulation 1977; 55: 533-537. 28. Haves lM: Experience with prazosin in the treatment of patients with-severe hypertension. Med J Aust 1976; 1: 562-564. 29. Wilson-Mulvihill J. Graham RM, Pettinger W. ct al.: Comparative effects of prazosin and phenoxybenzamine on arterial blood pressure, heart rate, and plasma catecholamines in essential hypertension. J Cardiov Pharmac 1979: 1 (suppl): Sl. 30. Colucci WS, Wynne J. Holman BL, Braunwald E: Long term therapy of heart failure with prazosin: a randomized double blind trial. Am J Cardiol 1980; 45:337-344. 31. Weil JV. Chidsey CA: Plasma volume expansion resulting from interference with adrenergic function in man. Circulation 1968: 37: 54-61. 32. Ibsen H: Changes in plasma volume and extracellular fluid volume after addition of prazosin to propranolol treatment in patients with hypertension. Stand J Clin Lab Invest 1978; 38: 425-429.
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