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The cardiorenal hemodynamic effects of antihypertensive therapy with reserpine
The cardiorenal hemodynamic of a’ntihypertensive therapy Cli’ord S. Reusch, Captain, San Francisco, Calif.
hlC,
D
espite a considerable number of reports of data on renal clearance and cardiac hemodynamics in hypertensive individuals, few studies have been made in which these parameters were determined simultaneously. This paper will describe these functions in hypertensive patients before and during therapy with reserpine. Case material Eight patients were selected who fit the following criteria: (1) a systolic blood pressure of 180 mm. Hg or greater; (2) a diastolic blood pressure of 110 mm. Hg or greater; (3) hypertensive retinopathy not exceeding Grade II ; (4) no progressive renal disease; (5) no history of congestive heart failure; (6) no history of symptomatic coronary arterial disease; (7) willingness to discontinue all medication for 8 weeks prior to study. Selected for study were 4 men and 4 women, whose ages ranged from 32 to 65 vears. The average duration of hypertension in the individuals studied was 22 years (range, 3 months to 40 years). Preliminary evaluation of these patients included: 12lead electrocardiograms, vectorcardiograms, determination of blood urea nitrogen and seruni electrolytes, Regitine test, 24-hour urinary catecholamine determinations, and multiple-view radiograms of the chest. All patients had radiographic and/or elec-
effects with reserpine
USA*
trocardiographic evidence of left ventricular hypertrophy. The average blood urea nitrogen was 14.0 mg. per cent (range, 5 to 22 mg. per cent). Procedure Each patient was hospitalized for evaluation. On the morning of the third day the patient was prepared in the postabsorptive state; 1 liter of water was taken orally. A retention catheter was inserted into the urinary bladder. The antecubital vein was exposed, using local anesthesia but no premedication. Catheters were inserted to the level of the right atrium for injection of indocyanine green, and to the subclavian vein for the constant infusion of paraaminohippuric acid. The radial artery was cannulated percutaneously for the recording of pressure and for purposes of sampling. A constant infusion of para-aminohippuric acid was maintained with a Harvard constant-speed infusion pump. Sampling was begun after 1 hour of the constant infusion. Samples of urine were collected for two 15-minute periods in the manner suggested by Sn1ith.l Samples of blood for determination of para-aminohippuric acid were taken from the radial artery at the beginning and end of each urine-collection period. During the sampling period, serial dyedilution curves were recorded. A single cali-
Received for publication Feb. 15, 1962. This study was performed while the author was an E. W. Stewart Cardiac Fellow, George Machris Cardiac Hospital, City of Hope Medical Center, Duarte. Calif.
643
Cardiology
Section,
Elsinor
and
644
Am. Heart
Reusch
h’oaembcr,
brated syringe was used for injection of indocyanine green in all instances. Dyedilution curves were recorded continuously from the radial artery through a photoelectric cuvette. Direct arterial pressure tracings with electrically integrated tnean pressure were obtained before and after each dye-dilution curve, with an Electronics for Medicine photographic record. In 4 cases, determinations of blood volume with radioactive iodinated serutn albumin (RI!%) were performed during the sampling period, employing a 1 S-niinute dilution period. Oral reserpine therapy, augmented in 2 cases by inlravenous reserpine, was admiuistered after the initial procedure. The drug was increased daily in increments of 2.0 mg., until a hypotensive response was obtained. At the end of 1 week, hemodynamic nieasurenients were repeated in the nianner described. The average daily dose of reserpine at the end of the first week of treatment was 6.0 mg. The patients were discharged after the second procedure and followed for 6 weeks in the outpatient facility. During this interval, reserpine was the only tnedication allowed (average maintenance dose, 4.0 mg. daily). Patients were readtnitted at
the termination of the 6-week period of treatment, and the hetnodynamic studies were carried out for the third and final time. Calculation
and
The hetnodynatnic data obtained are tabulated in Table I. A definite hypotensive response was obtained in 7 of the 8 patients. The average daily dose of reserpine enzployed was 6.0 nig. in divided doses (range, 2.0 to 20.0 mg. daily). The patient who did not respond satisfactorily to the drug (Case II) had a 40-year history of hypertension, persistant albutninuria, and a blood urea nitrogen of 22 tng. per cent. The procedure outlined was deviated front in three instances. One patient (Case 1’) experienced a hypotensive reaction during the initial control period. He was allowed, therefore, to return to the control
Cardiac output (L./min.) Body surface area (M.2)
Total peripheral resistance (dynes-sec.-cm. -“)
=
Mean
time (dyetechnique)
circulation
Yulmonary
blood volume
Stroke volume Renal resistance (dynes-sec.--cm.-5)
Renal blood flow
methods
Results
=
dilution
analytical
Pat-a-amittohippuric acid was determined by the method of Sn1ith.t Cardiac output was derived front the dye-dilution curves by the method of Hatnilton,‘-” using multiple calibration points and replotting on setnilogarithmic paper. The formulas used for calculation are shown below.
Cardiuc index (L./~2in./M.~)
Mean
arterial
pressure
X 1,332
X 60
Cardiac output (ml./min.) = cc ____x 4 t =
Cardiac
J. 1962
output (ml/m&.) 60
X Mean circulation time
= Cardiac output (ml./min.) Heart
rate
= Mean arterial pressure X 1,332 X 60 Renal blood flow = Renal plasma $0~ (PAH
Hematocrit - 1
clearance)
-
1 wk. 6 wk.
1 wk.
6 wk.
X 1 wk. B
1 wk. 6 wk.
1 wk. 6 wk.
under
-
Calculations.
6 wk.
Mean treated (Probability)
in text
1 wk.
Mean treated (Probability)
Mean control (Standard deviation)
Vnits are as indicated values.
_--__
_--I_
Treated
Control Treated Treated
Control
VI 42 2.40
VIII 32 1.96
65
Control Treated Control
v 47 2.20
Control Treated
Control Treated Treated
IV 47 1.90
VII 36 1.52
75
Control Treated Treated
Mean
(.2>?>.1)
(.3>;>.1)
(t77)
67 59 56
65 60
90 64 77
61 58 58
60 57 51
71 56 56
III 65 1.50
1 wk. 6 wk.
Control Treated Treated
II 49 1.88
60 55 54
Treated Treated
I 49 1.86
1 wk. 6 wk.
from
are furnished
-3) of the table, with
3.04 (.5>p>
3.32 (.2>p>.l)
2.72 (0.38)
2.65 3.00 3.20
2 39 2.61
3.16
3.12
3.10 3.77 2.52
2.31 2.21 2.57
3.93 4.60 3.43
2.18 2.51 2.63
2.69 4.56 3.22
Cardiac index
all procedures
in the lower section
105 CD.051
115 (.2>p>.l)
145 (18)
160 115 100
165 132
98
140
107 97 123
162 94 100
120 122 88
155 152 145
134 97 97
Mean arterial pressure
parameters
values
Pulse rate
and renal hemodynamic
Control
I. Cardiac
Case number, Age, Body surface area (M.2)
Table
standard
1,492 (.3>p>
1,662 (.5>p>
2,384 (759)
2,460 1,516 1,270
3,640 2.500
1,030
1,490
1,230 935 1,760
2,940 1,780 1,630
1,620 1,415 1,400
3,020 2,590 2,340
2,140 910 1,290
deviation
.2)
.3)
Total peviphevnl resistance
of control
(P
(.7>p>
.5)
measurements
634 .9)
498
661 (243)
646 824 766
517 240
1,310
1,151
442 543 900
510 447 508
450 562 448
560 312 278
550 560 492
resistance 103)
26.8 (8.7)
26.3 14.5 13.9
42.2 58.6
8.0
14.2
25.8 19.0 14.6
33.9 22.4 20.9
28.3 23.1 21.0
29.5 51.8 55.9
25.8 18.4 21.0
(x
and statistical
23.5 (.8>p>.7)
29.6 (.8>p>.7)
Renal
Drobability
of treated
115 :060
,172
,154
.I04 ,065 .065 ,162
:106 116
,078 ,081 ,086
.136 ,066 ,056
.llO ,066 .082
’ RBF/CO ratio
cn
s R.
i? 3 EL 5
s & z. 2 2
646
Reusch
state (Control B) 2 weeks before the final determination of simultaneous cardiac output and renal blood flow. Figures given under the heading of Conlrol A in Table I were obtained during the initial hypotensive reaction. Figures listed under Control B are those used as control values for analysis. Data from Case VI on the second procedure were technically unsatisfactory. A third patient (Case VII) withdrew from the study before the final procedure could be performed. The data presented in Table I as absolute measurements are summarized in Fig. 1 in terms of the averaged per cents of control values after 1 and 6 weeks of therapy. There was an initial increase in cardiac index, except in Case IV. This increase averaged 25 per cent for all patients. After 6 weeks of treatment the cardiac output had returned toward control levels, with an average increase of 10.0 per cent. At 1 week, mean arterial pressure was reduced in all except Case III; the average reduction was 19.9 per cent of control. :-\fter 6 weeks of treatment a reduction in mean arterial pressure was observed in all cases and averaged 27.7 per cent of control. In all cases the calculated total peripheral resistance decreased both initially and at 6 weeks. This decrease averaged 32.2 per cent of control at 1 week, and 31.0 per cent after 6 weeks of therapy. Renal blood flow decreased in 4 and increased in 3 patients at 1 week. The overall average decrease was 12.5 per cent. After 6 weeks of therapy, renal blood flow was increased in only 2 of the 6 patients in whom it was determined. When all cases are considered, renal blood flow was reduced an average of 5.0 per cent of control level after 6 weeks. The calculated renal resistance increased initially in 3 of 7 patients. The average for all patients was an increase of 9 per cent. After 6 weeks of treatment the average calculated renal resistance returned to the control level. The calculated mean circulation time was slightly reduced (average, 7.2 per cent) in 6 and unchanged in 2 patients. Pulmonaq blood volume increased in 6 patients by an average of 21.5 per cent after 1 week of therapy. After 6 weeks of therapy, 3 patients showed an average increase in pulmo-
nary blood volume of 17 per cent. Two patients (Cases III, IV) had a reduction in pulmonary blood volume of 10 per cent, and in another patient (Case VI) it was unchanged. Studies of blood volume in 4 of the 8 patients showed no change in the plasma volumes before and after treatment with reserpine. A slight increase in control plasma volume, which remained unchanged during therapy, was observed in all cases. Side reactions to reserpine were iloted in all 8 patients studied. In the order of their frequency of occurrence, these reactions were: sleepiness and lethargy (8 patients), undesirable personality changes (6 patients), hypersalivation (5 patients), sexual impotence (all 4 male patients), nasal stuffiness (2 patients), weakness of the legs (2 patients), agitation (2 patients), nightmares (2 patients), excessive appetite (2 patients), blurred vision (1 patient). Discussion Simultaneous cardiac and renal hemodynamic studies have been reported in the evaluation of a few commonly used untihypertensive agents, such as the ganglionicblocking drugs, 1 - hydrazinophthalazine, and reserpine. Reserpine has been the least studied in this manner. In part, this paucity of data on reserpine is based on the consistently rapid and good response elicited by the ganglionic-blocking agents which facilitates study. The widespread use of rauwolfia alkaloids in the treatment of essential hypertension makes adequate and reproducible physiologic data on these drugs of interest. Smith and Hoobler4 have demonstrated that the antihypertensive effect of the ganglionic-blocking drugs results in part from a reduction in cardiac output, with little or no change in the peripheral resistance. The renal blood flow and glomerular filtration rate are dramatically reduced with these agents, as shown by Moyer and associates,“,” and Ford and associates.7 A slight increase in renal resistance was effected by the bloc-king agent in the study of Moyer.6 In contrast, Rose and co-workers8 and Vander Kolk and associates9 showed that l-hydrnzinophthalazine reduces both the total peripheral vascular resistance and the renal resistance, resulting in an increase ii1
Cardiorenal hemodynamic
[=I
MEAN
ARTERIAL
CARDIAC RENAL TOTAL RENAL
efects of reserpine therupy
647
PRESSURE
1NDFX BLOOD
FLOW
PERIPHERAL
RESISTANCE
RESISTANCE
60 TREATMENT IN WEEKS
50 t
Fig. 1. Composite parameters entire study group after 1 and are expressed as the averaged represent 100 per cent.
of cardiac and renal 6 weeks of reserpine per cents of control
the renal blood flow. Cardiac output is noticeably increased as a result of the tachycnrdia induced. The long-term studies of Vander Kolkg have demonstrated that the increase in the renal blood flow is not so great after the initial period of treatment; a 6 per cent over-all increase was observed. Observations on the cardiorenal effects of reserpine in dogs are reported by Moyer,lu-n who noted that both cardiac output and renal blood flow were relatively unchanged by reserpine therapy. Redisch and coworkersr2 report simultaneously determined cardiac output and renal clearance of paraaminohippuric acid in human beings after acute intravenous administration of reserpine. They found that the delayed hypotension induced is associated with little or
hemodynamics for the therapy. Measurements values. Control values
no change in cardiac output, a late and transient rise in renal blood flow, and a slight increase in pulse rate. Although this series contains a limited number of observations, which have questionable statistical significance in magnitude, certain consistencies in the measurements are apparent. All patients at 1 and 6 weeks of treatment showed a reduction in pulse rate which averaged 1.5 per cent of the control rates. A reduction in peripheral resistance was found in all patients, including one in whom the hypotensive response was unsatisfactory. A reduction in mean arterial pressure was effected initially in 7 of the 8 patients, with a concomitant increase in the cardiac output and cardiac index. After 6 weeks of therapy the mean
648
RCUSCIZ
arterial pressure showed a continued reduction, whereas the cardiac index returned toward control levels. Associated with the increase in cardiac output was a slight reduction in mean circulation time and an increase in the puhnonary blood volume. There was no increase in venous pressure. The RISA-determined blood volume remained stationary. These data indicate that the hypotensive action of reserpine was due to a reduction in vascular tone without a reduction in cardiac output, peripheral pooling of blood, or decreased circulating blood volume. The renal hemodynamic and functional changes were less consistent and bear no statistical significance. There was only a slight over-all decrease in the renal blood flow, which varied throughout the study group. At the end of 6 weeks of therapy an over-all mild reduction in renal blood flow had occurred, despite the return of renal resistance to control levels. When viewed together, the data indicate that hypotension induced with reserpine results in satisfactory control of the peripheral resistance and the mean blood pressure, without compromising the cardiac output or peripheral circulation. The renal circulation in acute therapy is relatively diminished; however, it returns toward control levels on prolonged therapy. The distressing nature of the side effects has been mentioned by Quetsch13 as sufficient to warrant caution in administering this drug. It became necessary to discontinue reserpine therapy iu 3 patients at the end of the study period because of agitation and depression. In these 3 patients there seemed to be no level consistent with a satisfactory hypotensive response which was not associated with side effects. The remainder of the patients continued on established dosages (average, 3.2 mg. daily) after the study period. Because of the control nature of the study, no attempt was made to interfere with the development of side effects to reserpine. Summary Cardiac and renal hemodynamic data are presented on 8 patients treated with reserpine. These data are equated to control parameters determined at a time before the treatment was employed. Reserpine ther-
apy in these patients produced a sustained reduction in peripheral resistance, mean arterial pressure, and pulse rate, with au increase in cardiac output. Renal blood flow was decreased early in therapy but returned to control levels within 6 weeks. Renal resistance was usually reduced by reserpine therapy. A brief discussion of similar measurements with other antihypertensive drugs was presented. Appreciation is hereby expressed to maceutical Products, Inc., for supplying pine (Serpasil) used in this study.
Ciba the
Pharreser-
REFERENCES 1.
Smith, N. W., Firkelstein, N., Aliminosa, L.. Crawford, B., and Graber, M.: The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man, J. Clin. Invest. 24:388, 1945. J. W., Kinsman, J. M., Hamilton, W. F., 2. Moore, and Sourling, R. G.: Studies on the circulation. II. Cardiacoutput determinations; comparison of the injection method with the direct Fick procedure, Am. J. Physiol. 89:331, 1929. 3. Hamilton, W. F., Moore, J. W., Kinsman, J. M., and Spurling, 1~. C.: Studies on circulation; further analysis of injection method, and of changes in hemodynamics under physiological and pathological conditions, Am. J. Physiol. 99:534, 1932. J. R., and Hoobler, S. W.: Acute and 4. Smith, chronic cardiovascular effects of pentolinium in hypertensive patients, Circulation 14:1061, 1956. J. H., Livesay, W. R., and Seibert, 5. Moyer, R. A.: Effect of blood pressure reduction with Arfonad on renal hemodynamics and excretion of water and electrolytes, AM. HEART J. 48:817, 1954. 6. Mills, L. C., and Moyer, J. H.: Acute effects of hexamethonium on renal hemodynamics in normotensive and hypertensive human subjects, Am. J. M. SC. 226:1, 1953. R. V., Moyer, J. H., and Spurr, C. L.: 7. Ford, The effect of posture and adrenergic blockade with Dibenzyline on renal hemodynamics and excretion of water and electrolytes in patients with hypertension with and without renal damage, AM. HEART J. 46:268, 1953. E. I)., Rose, J. C., Higgins, T. F., Fin8. Freis, nerty, F. A., Kelley, R. T.i-and Partenope, E. ii.: The hemodvnamic effects of hvootensive drugs in man; l-h$dr&nophthalaz&~ Circulation 8:199. 1953. 9. Vander Kolk, K., Dontas, A. S., and Hoobler, S. W.: Renal and hypotensive effects of acute and chronic oral treatment with l-hydrazinophthalazine (Aoresoline) in hvDertension. AM. HEART J. 48:$5, 1954.. -_ 10. Moyer, J. H., Hughes, W., and Huggins, R. .4.: Cardiovascular and renal hemodynamic response to administration of reserpine (Serpasill, Am. J. M. SC. 227:640, 1954.
Cardiorenal hemodynamic efects of reserpine therapy
11.
12.
Moyer, J. H., Handley, C. A., and Huggins, R. A.: Some pharmacodynamic effects of l-hydrazinophthalazine (C-5968), with particular reference to renal function and cardiovascular response, J. Pharmacol. & Exper. Therap. 103:368, 1951. Redisch, W., Tangco, F. F., Lewis, A. J., Antonio, M. .4., Decrinis, I(., and Steele, J. M.:
13.
649
Interrelationships of drugs influencing arterial pressure in man, Circulation 17:208, 1958. Quetsch, R. M., Achor, R. W., Litin, E. M., and Faucett, R. L.: Depressive reactions in hypertensive patients; a comparison of those treated with rauwolfia and those receiving no specific antihypertensive treatment, Circulation 19:366, 19.59.
hlC,
D
espite a considerable number of reports of data on renal clearance and cardiac hemodynamics in hypertensive individuals, few studies have been made in which these parameters were determined simultaneously. This paper will describe these functions in hypertensive patients before and during therapy with reserpine. Case material Eight patients were selected who fit the following criteria: (1) a systolic blood pressure of 180 mm. Hg or greater; (2) a diastolic blood pressure of 110 mm. Hg or greater; (3) hypertensive retinopathy not exceeding Grade II ; (4) no progressive renal disease; (5) no history of congestive heart failure; (6) no history of symptomatic coronary arterial disease; (7) willingness to discontinue all medication for 8 weeks prior to study. Selected for study were 4 men and 4 women, whose ages ranged from 32 to 65 vears. The average duration of hypertension in the individuals studied was 22 years (range, 3 months to 40 years). Preliminary evaluation of these patients included: 12lead electrocardiograms, vectorcardiograms, determination of blood urea nitrogen and seruni electrolytes, Regitine test, 24-hour urinary catecholamine determinations, and multiple-view radiograms of the chest. All patients had radiographic and/or elec-
effects with reserpine
USA*
trocardiographic evidence of left ventricular hypertrophy. The average blood urea nitrogen was 14.0 mg. per cent (range, 5 to 22 mg. per cent). Procedure Each patient was hospitalized for evaluation. On the morning of the third day the patient was prepared in the postabsorptive state; 1 liter of water was taken orally. A retention catheter was inserted into the urinary bladder. The antecubital vein was exposed, using local anesthesia but no premedication. Catheters were inserted to the level of the right atrium for injection of indocyanine green, and to the subclavian vein for the constant infusion of paraaminohippuric acid. The radial artery was cannulated percutaneously for the recording of pressure and for purposes of sampling. A constant infusion of para-aminohippuric acid was maintained with a Harvard constant-speed infusion pump. Sampling was begun after 1 hour of the constant infusion. Samples of urine were collected for two 15-minute periods in the manner suggested by Sn1ith.l Samples of blood for determination of para-aminohippuric acid were taken from the radial artery at the beginning and end of each urine-collection period. During the sampling period, serial dyedilution curves were recorded. A single cali-
Received for publication Feb. 15, 1962. This study was performed while the author was an E. W. Stewart Cardiac Fellow, George Machris Cardiac Hospital, City of Hope Medical Center, Duarte. Calif.
643
Cardiology
Section,
Elsinor
and
644
Am. Heart
Reusch
h’oaembcr,
brated syringe was used for injection of indocyanine green in all instances. Dyedilution curves were recorded continuously from the radial artery through a photoelectric cuvette. Direct arterial pressure tracings with electrically integrated tnean pressure were obtained before and after each dye-dilution curve, with an Electronics for Medicine photographic record. In 4 cases, determinations of blood volume with radioactive iodinated serutn albumin (RI!%) were performed during the sampling period, employing a 1 S-niinute dilution period. Oral reserpine therapy, augmented in 2 cases by inlravenous reserpine, was admiuistered after the initial procedure. The drug was increased daily in increments of 2.0 mg., until a hypotensive response was obtained. At the end of 1 week, hemodynamic nieasurenients were repeated in the nianner described. The average daily dose of reserpine at the end of the first week of treatment was 6.0 mg. The patients were discharged after the second procedure and followed for 6 weeks in the outpatient facility. During this interval, reserpine was the only tnedication allowed (average maintenance dose, 4.0 mg. daily). Patients were readtnitted at
the termination of the 6-week period of treatment, and the hetnodynamic studies were carried out for the third and final time. Calculation
and
The hetnodynatnic data obtained are tabulated in Table I. A definite hypotensive response was obtained in 7 of the 8 patients. The average daily dose of reserpine enzployed was 6.0 nig. in divided doses (range, 2.0 to 20.0 mg. daily). The patient who did not respond satisfactorily to the drug (Case II) had a 40-year history of hypertension, persistant albutninuria, and a blood urea nitrogen of 22 tng. per cent. The procedure outlined was deviated front in three instances. One patient (Case 1’) experienced a hypotensive reaction during the initial control period. He was allowed, therefore, to return to the control
Cardiac output (L./min.) Body surface area (M.2)
Total peripheral resistance (dynes-sec.-cm. -“)
=
Mean
time (dyetechnique)
circulation
Yulmonary
blood volume
Stroke volume Renal resistance (dynes-sec.--cm.-5)
Renal blood flow
methods
Results
=
dilution
analytical
Pat-a-amittohippuric acid was determined by the method of Sn1ith.t Cardiac output was derived front the dye-dilution curves by the method of Hatnilton,‘-” using multiple calibration points and replotting on setnilogarithmic paper. The formulas used for calculation are shown below.
Cardiuc index (L./~2in./M.~)
Mean
arterial
pressure
X 1,332
X 60
Cardiac output (ml./min.) = cc ____x 4 t =
Cardiac
J. 1962
output (ml/m&.) 60
X Mean circulation time
= Cardiac output (ml./min.) Heart
rate
= Mean arterial pressure X 1,332 X 60 Renal blood flow = Renal plasma $0~ (PAH
Hematocrit - 1
clearance)
-
1 wk. 6 wk.
1 wk.
6 wk.
X 1 wk. B
1 wk. 6 wk.
1 wk. 6 wk.
under
-
Calculations.
6 wk.
Mean treated (Probability)
in text
1 wk.
Mean treated (Probability)
Mean control (Standard deviation)
Vnits are as indicated values.
_--__
_--I_
Treated
Control Treated Treated
Control
VI 42 2.40
VIII 32 1.96
65
Control Treated Control
v 47 2.20
Control Treated
Control Treated Treated
IV 47 1.90
VII 36 1.52
75
Control Treated Treated
Mean
(.2>?>.1)
(.3>;>.1)
(t77)
67 59 56
65 60
90 64 77
61 58 58
60 57 51
71 56 56
III 65 1.50
1 wk. 6 wk.
Control Treated Treated
II 49 1.88
60 55 54
Treated Treated
I 49 1.86
1 wk. 6 wk.
from
are furnished
-3) of the table, with
3.04 (.5>p>
3.32 (.2>p>.l)
2.72 (0.38)
2.65 3.00 3.20
2 39 2.61
3.16
3.12
3.10 3.77 2.52
2.31 2.21 2.57
3.93 4.60 3.43
2.18 2.51 2.63
2.69 4.56 3.22
Cardiac index
all procedures
in the lower section
105 CD.051
115 (.2>p>.l)
145 (18)
160 115 100
165 132
98
140
107 97 123
162 94 100
120 122 88
155 152 145
134 97 97
Mean arterial pressure
parameters
values
Pulse rate
and renal hemodynamic
Control
I. Cardiac
Case number, Age, Body surface area (M.2)
Table
standard
1,492 (.3>p>
1,662 (.5>p>
2,384 (759)
2,460 1,516 1,270
3,640 2.500
1,030
1,490
1,230 935 1,760
2,940 1,780 1,630
1,620 1,415 1,400
3,020 2,590 2,340
2,140 910 1,290
deviation
.2)
.3)
Total peviphevnl resistance
of control
(P
(.7>p>
.5)
measurements
634 .9)
498
661 (243)
646 824 766
517 240
1,310
1,151
442 543 900
510 447 508
450 562 448
560 312 278
550 560 492
resistance 103)
26.8 (8.7)
26.3 14.5 13.9
42.2 58.6
8.0
14.2
25.8 19.0 14.6
33.9 22.4 20.9
28.3 23.1 21.0
29.5 51.8 55.9
25.8 18.4 21.0
(x
and statistical
23.5 (.8>p>.7)
29.6 (.8>p>.7)
Renal
Drobability
of treated
115 :060
,172
,154
.I04 ,065 .065 ,162
:106 116
,078 ,081 ,086
.136 ,066 ,056
.llO ,066 .082
’ RBF/CO ratio
cn
s R.
i? 3 EL 5
s & z. 2 2
646
Reusch
state (Control B) 2 weeks before the final determination of simultaneous cardiac output and renal blood flow. Figures given under the heading of Conlrol A in Table I were obtained during the initial hypotensive reaction. Figures listed under Control B are those used as control values for analysis. Data from Case VI on the second procedure were technically unsatisfactory. A third patient (Case VII) withdrew from the study before the final procedure could be performed. The data presented in Table I as absolute measurements are summarized in Fig. 1 in terms of the averaged per cents of control values after 1 and 6 weeks of therapy. There was an initial increase in cardiac index, except in Case IV. This increase averaged 25 per cent for all patients. After 6 weeks of treatment the cardiac output had returned toward control levels, with an average increase of 10.0 per cent. At 1 week, mean arterial pressure was reduced in all except Case III; the average reduction was 19.9 per cent of control. :-\fter 6 weeks of treatment a reduction in mean arterial pressure was observed in all cases and averaged 27.7 per cent of control. In all cases the calculated total peripheral resistance decreased both initially and at 6 weeks. This decrease averaged 32.2 per cent of control at 1 week, and 31.0 per cent after 6 weeks of therapy. Renal blood flow decreased in 4 and increased in 3 patients at 1 week. The overall average decrease was 12.5 per cent. After 6 weeks of therapy, renal blood flow was increased in only 2 of the 6 patients in whom it was determined. When all cases are considered, renal blood flow was reduced an average of 5.0 per cent of control level after 6 weeks. The calculated renal resistance increased initially in 3 of 7 patients. The average for all patients was an increase of 9 per cent. After 6 weeks of treatment the average calculated renal resistance returned to the control level. The calculated mean circulation time was slightly reduced (average, 7.2 per cent) in 6 and unchanged in 2 patients. Pulmonaq blood volume increased in 6 patients by an average of 21.5 per cent after 1 week of therapy. After 6 weeks of therapy, 3 patients showed an average increase in pulmo-
nary blood volume of 17 per cent. Two patients (Cases III, IV) had a reduction in pulmonary blood volume of 10 per cent, and in another patient (Case VI) it was unchanged. Studies of blood volume in 4 of the 8 patients showed no change in the plasma volumes before and after treatment with reserpine. A slight increase in control plasma volume, which remained unchanged during therapy, was observed in all cases. Side reactions to reserpine were iloted in all 8 patients studied. In the order of their frequency of occurrence, these reactions were: sleepiness and lethargy (8 patients), undesirable personality changes (6 patients), hypersalivation (5 patients), sexual impotence (all 4 male patients), nasal stuffiness (2 patients), weakness of the legs (2 patients), agitation (2 patients), nightmares (2 patients), excessive appetite (2 patients), blurred vision (1 patient). Discussion Simultaneous cardiac and renal hemodynamic studies have been reported in the evaluation of a few commonly used untihypertensive agents, such as the ganglionicblocking drugs, 1 - hydrazinophthalazine, and reserpine. Reserpine has been the least studied in this manner. In part, this paucity of data on reserpine is based on the consistently rapid and good response elicited by the ganglionic-blocking agents which facilitates study. The widespread use of rauwolfia alkaloids in the treatment of essential hypertension makes adequate and reproducible physiologic data on these drugs of interest. Smith and Hoobler4 have demonstrated that the antihypertensive effect of the ganglionic-blocking drugs results in part from a reduction in cardiac output, with little or no change in the peripheral resistance. The renal blood flow and glomerular filtration rate are dramatically reduced with these agents, as shown by Moyer and associates,“,” and Ford and associates.7 A slight increase in renal resistance was effected by the bloc-king agent in the study of Moyer.6 In contrast, Rose and co-workers8 and Vander Kolk and associates9 showed that l-hydrnzinophthalazine reduces both the total peripheral vascular resistance and the renal resistance, resulting in an increase ii1
Cardiorenal hemodynamic
[=I
MEAN
ARTERIAL
CARDIAC RENAL TOTAL RENAL
efects of reserpine therupy
647
PRESSURE
1NDFX BLOOD
FLOW
PERIPHERAL
RESISTANCE
RESISTANCE
60 TREATMENT IN WEEKS
50 t
Fig. 1. Composite parameters entire study group after 1 and are expressed as the averaged represent 100 per cent.
of cardiac and renal 6 weeks of reserpine per cents of control
the renal blood flow. Cardiac output is noticeably increased as a result of the tachycnrdia induced. The long-term studies of Vander Kolkg have demonstrated that the increase in the renal blood flow is not so great after the initial period of treatment; a 6 per cent over-all increase was observed. Observations on the cardiorenal effects of reserpine in dogs are reported by Moyer,lu-n who noted that both cardiac output and renal blood flow were relatively unchanged by reserpine therapy. Redisch and coworkersr2 report simultaneously determined cardiac output and renal clearance of paraaminohippuric acid in human beings after acute intravenous administration of reserpine. They found that the delayed hypotension induced is associated with little or
hemodynamics for the therapy. Measurements values. Control values
no change in cardiac output, a late and transient rise in renal blood flow, and a slight increase in pulse rate. Although this series contains a limited number of observations, which have questionable statistical significance in magnitude, certain consistencies in the measurements are apparent. All patients at 1 and 6 weeks of treatment showed a reduction in pulse rate which averaged 1.5 per cent of the control rates. A reduction in peripheral resistance was found in all patients, including one in whom the hypotensive response was unsatisfactory. A reduction in mean arterial pressure was effected initially in 7 of the 8 patients, with a concomitant increase in the cardiac output and cardiac index. After 6 weeks of therapy the mean
648
RCUSCIZ
arterial pressure showed a continued reduction, whereas the cardiac index returned toward control levels. Associated with the increase in cardiac output was a slight reduction in mean circulation time and an increase in the puhnonary blood volume. There was no increase in venous pressure. The RISA-determined blood volume remained stationary. These data indicate that the hypotensive action of reserpine was due to a reduction in vascular tone without a reduction in cardiac output, peripheral pooling of blood, or decreased circulating blood volume. The renal hemodynamic and functional changes were less consistent and bear no statistical significance. There was only a slight over-all decrease in the renal blood flow, which varied throughout the study group. At the end of 6 weeks of therapy an over-all mild reduction in renal blood flow had occurred, despite the return of renal resistance to control levels. When viewed together, the data indicate that hypotension induced with reserpine results in satisfactory control of the peripheral resistance and the mean blood pressure, without compromising the cardiac output or peripheral circulation. The renal circulation in acute therapy is relatively diminished; however, it returns toward control levels on prolonged therapy. The distressing nature of the side effects has been mentioned by Quetsch13 as sufficient to warrant caution in administering this drug. It became necessary to discontinue reserpine therapy iu 3 patients at the end of the study period because of agitation and depression. In these 3 patients there seemed to be no level consistent with a satisfactory hypotensive response which was not associated with side effects. The remainder of the patients continued on established dosages (average, 3.2 mg. daily) after the study period. Because of the control nature of the study, no attempt was made to interfere with the development of side effects to reserpine. Summary Cardiac and renal hemodynamic data are presented on 8 patients treated with reserpine. These data are equated to control parameters determined at a time before the treatment was employed. Reserpine ther-
apy in these patients produced a sustained reduction in peripheral resistance, mean arterial pressure, and pulse rate, with au increase in cardiac output. Renal blood flow was decreased early in therapy but returned to control levels within 6 weeks. Renal resistance was usually reduced by reserpine therapy. A brief discussion of similar measurements with other antihypertensive drugs was presented. Appreciation is hereby expressed to maceutical Products, Inc., for supplying pine (Serpasil) used in this study.
Ciba the
Pharreser-
REFERENCES 1.
Smith, N. W., Firkelstein, N., Aliminosa, L.. Crawford, B., and Graber, M.: The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man, J. Clin. Invest. 24:388, 1945. J. W., Kinsman, J. M., Hamilton, W. F., 2. Moore, and Sourling, R. G.: Studies on the circulation. II. Cardiacoutput determinations; comparison of the injection method with the direct Fick procedure, Am. J. Physiol. 89:331, 1929. 3. Hamilton, W. F., Moore, J. W., Kinsman, J. M., and Spurling, 1~. C.: Studies on circulation; further analysis of injection method, and of changes in hemodynamics under physiological and pathological conditions, Am. J. Physiol. 99:534, 1932. J. R., and Hoobler, S. W.: Acute and 4. Smith, chronic cardiovascular effects of pentolinium in hypertensive patients, Circulation 14:1061, 1956. J. H., Livesay, W. R., and Seibert, 5. Moyer, R. A.: Effect of blood pressure reduction with Arfonad on renal hemodynamics and excretion of water and electrolytes, AM. HEART J. 48:817, 1954. 6. Mills, L. C., and Moyer, J. H.: Acute effects of hexamethonium on renal hemodynamics in normotensive and hypertensive human subjects, Am. J. M. SC. 226:1, 1953. R. V., Moyer, J. H., and Spurr, C. L.: 7. Ford, The effect of posture and adrenergic blockade with Dibenzyline on renal hemodynamics and excretion of water and electrolytes in patients with hypertension with and without renal damage, AM. HEART J. 46:268, 1953. E. I)., Rose, J. C., Higgins, T. F., Fin8. Freis, nerty, F. A., Kelley, R. T.i-and Partenope, E. ii.: The hemodvnamic effects of hvootensive drugs in man; l-h$dr&nophthalaz&~ Circulation 8:199. 1953. 9. Vander Kolk, K., Dontas, A. S., and Hoobler, S. W.: Renal and hypotensive effects of acute and chronic oral treatment with l-hydrazinophthalazine (Aoresoline) in hvDertension. AM. HEART J. 48:$5, 1954.. -_ 10. Moyer, J. H., Hughes, W., and Huggins, R. .4.: Cardiovascular and renal hemodynamic response to administration of reserpine (Serpasill, Am. J. M. SC. 227:640, 1954.
Cardiorenal hemodynamic efects of reserpine therapy
11.
12.
Moyer, J. H., Handley, C. A., and Huggins, R. A.: Some pharmacodynamic effects of l-hydrazinophthalazine (C-5968), with particular reference to renal function and cardiovascular response, J. Pharmacol. & Exper. Therap. 103:368, 1951. Redisch, W., Tangco, F. F., Lewis, A. J., Antonio, M. .4., Decrinis, I(., and Steele, J. M.:
13.
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Interrelationships of drugs influencing arterial pressure in man, Circulation 17:208, 1958. Quetsch, R. M., Achor, R. W., Litin, E. M., and Faucett, R. L.: Depressive reactions in hypertensive patients; a comparison of those treated with rauwolfia and those receiving no specific antihypertensive treatment, Circulation 19:366, 19.59.