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Hemodynamic and metabolic effects of angiotensin II during rest and exercise in normal healthy subjects
Hemodynamic and metabolic effects of angiotensin II during rest and exercise in normal healthy subjects Willard P. Johnson, M.D. Robert A. Bruce, M.D. Seattle. Wash.
A
ngiotensin II is a synthetic, thermostable octapeptide which causes contraction of the smooth muscle of systemic blood vessels and other tissues. When injected intravenously it causes a prompt, short-lived pressor response which is not inhibited by ganglionic blockade or subject to tachyphylaxis. It exerts no known direct cardiac inotropic or chronotropic effects, although reflex bradycardia results from the systemic pressor response. The action of renin upon renin substrate is believed to produce the decapeptide, angiotensin I. A “converting enzyme” in plasma splits off the terminal 2 amino acids, histidine and leucine, to produce the active vasoconstrictor, angiotensin II. The latter is degraded to amino acids by angiotensinase, an enzyme present in normal kidney, erythrocytes, and various tissues.‘,? Since direct techniques of identification have not yet demonstrated either renin or angiotensin in human blood, Peart3 doubts their importance in human physiology and hypertension. Nevertheless, hemodynamic effects of angiotensin II have been studied in human subjects (Table I). When blood pressure is raised to hypertensive levels, it reduces effective renal plasma flow and urinary output and produces a slight retention of sodium in normotensive patients.4 These effects persist as long as hypertension
is maintained. Hypotensive patients infused with angiotensin II have shown an increase in the output of urine, which is presumably due to more adequate perfusion of the kidneys. Finnerty and associate9 found no change in blood volume during experiments on normotensive patients, and pressor-equivalent doses of I-epinephrine blocked vasoconstrictive effects of angiotensin II. Segel and associates5 found evidence of pulmonary as well as systemicvasoconstriction, whereas others believed there was no direct effect on pulmonar!. arteries or veins. 6,7 Methods Ten normal, healthy, male volunteers were studied while they were in the fasting state without sedation. Cardiac output was measured by the direct Fick principle, utilizing cardiac catheterization for sampling of mixed venous blood from the right atrium or pulmonary artery. Pressures were recorded with a Statham P-23D pressure transducer. Arterial pressures and samples were obtained by means of a No. 18 Cournand needle inserted into a peripheral artery. Oxygen consumption and ventilation were measured with a 13-liter Collins spirometer. Indicator-dilution curves were recorded in some instances by means of an ear oximeter, using Evans blue dye.
With the technical assistance of Barbara Erickson. Wen Chiu. and Gladys P&et. From the Department of Medicine, University of Washington, Seattle, Wash. These studies have been supported in part by Grant H-908(ClO) from the United States Public Health Received for publication June 30, 1961.
212
Service.
Hemodynamic
and metabolic @ects of angioten.sin II
“Augmented central blood volume”* was calculated from mean circulation time and cardiac output derived by- the Fick principle. The peripheral resistance index (PRIj was calculated by means of the formula: Arterial Mean Pressure X 80 PI< 1 = 1. ~~ ~~~~__._ Cardiac Index which yields resistance units in dynes seconds centimeter@ times square meters of body surface area (dsc.v5 X M.“). Apparent work of the left ventricle was calculated from the formula: MAPX CO X 14.5 Work (Kg.M./min.) = 1,000 where MAP is mean arterial pressure, CO is cardiac output, and 14.5 is a constant derived from the product of the specific gravities of blood and mercury. Coronary blood flow was measured by the nitrousoxide desaturation technique9 after catheterization of the coronary sinus in 3 individuals. The temperature of the skin was recorded with a Rauh thermocouple. Lactic acid was determined by the method of Barker and Summerson,“’ pyruvic acid by the method of Segal and coworkers,” free fatty acid (FFA) by the
modified Dole procedure,r2 and glucose b> the method of Beach and TurnerI modified by Halsey. I4 “Excess lactate” (XL) for appraisal of anaerobic metabolism during experimental periods was calculated from Huckabee’s formula15: SL = (L,, - L,) - (P? - Ppj (L,/‘P,), where L, and P, represented concentrations of lactic acid and pyruvic acid in arterial blood during control periods, and L, and P, represented concentrations during experimental periods. Procedure
Control measurements were made when the subjects were in the resting steady state condition while lying supine; then angiotensin II* was infused intravenously, either into the right heart or into the pulmonary artery. The dosage was .05 micrograms per kilogram per minute (averaging 3 to 4 micrograms per subject per minute), for 30 to 60 minutes. Sufficient time was allowed for the blood pressure and heart rate to stabilize before measurements were made. Three subjects were also studied while they did leg exercises in the supine position, with and without angiotensin II. .Another subject was studied while he
*Mean circulation time which is measured by arterial sampling is shorter than that which is measured by “capillary sampling” by the earpiece oximeter. Therefore, central volume will be greater (augmented) with the latter method.
*Lyophilized crrstals of Valyls angiotensin II for this studs were supplied by Ciba Pharmaceutical Products. Inc.
Table I. Hemodynamic efects of synthetic angiotensin cardiovascular diseases”
coutro1
Mean arterial pressure(mm. Hg) Mean pulmonary arterial pressure(mm. Hg) Peripheral resistance(dsc?) Cardiac output (L./min.) Stroke
volume
Arteriovenous
dngiotensin
oxygen
$35
42
20
20
1,220 (2,122)1 6.2 (3.5)
1.780 (3.53o)t 5.5 (2.9j
80
(Kg.M./min.) difference
Per cent change%
12.1
(ml.)
work
Xzt m ber of observations
11
Heart rate Oxygen consumption (ml./min.) ventricular
reported by others in patients without
91
(1:)
Left
213
(ml./L.)
*Combined and averaged data of Lichtlen, et al.16 on 5 subjects. 17 subjects. and of &gel, et al.6 in 10 studies on 7 subjects. tParenthetica1 data have been corrected for body surface area. fFor all available data.
237 1134) ‘8.8’ (4.8) 39.6
of Sancetta.
(11, 67 240 (1361 10.3 (5.3) 45.9
et al.6 on 5 subjects,
+43
+57 Pz.1 23
(26) 23 (26‘) 31 15
-1-1
+2 --I6 +1 t I 3 .5
15
of Finnerty.
+I6
et al.4 in 22 studies
on
.I,/, ,
Table II. Hemodynamic jects at rest
and metabolic
Mean arterkl preswre (mm. Hg) Peripheral resistance index (dsc? XI.?) .%rteriovenous oxygen difference (1711./L.) Cardiac index (L./min./M.2j Stroke index (ml./M.2) Oxygen consmnption (ml./mill./Xl.“) Heart rate Left \-entricular work (Kg.~l./min./R1.*) Free fatty- acids (&q/L.) Glucose (mg. 5,; ) Lactic acid (mM./L. of blood H?O) PyrtIvic acid (mM./L. of blood HzO) “XL” (mM./L. of blood H,O)
qffPcts
10 JO in 10 10
10 10 10
qf’ angiotensin
975i95 1,866+
in
,fasting,
127.7 501
45.4 + 8.0 4 46 i 65.3 f 196 + 69+ 6 .Z +
/I
1 1.3 14 5 4.5 12 1 6
*
10.2
3.149 f 710 569i99 .z 42 f
57
$1 8_+ 9.6 188 i
.14
854 * 325 79.2 i 6 0 633 f 0 218 0 036 f 0 017
0.034
9
0.000
0 011
717 i84 9 i
276 1.3.9
0.717 * 0.213 +
0.009
,,fi,i, 1,1,/
i I’,
,“/a
supint, normcri sub-
+.31
< 00 I
$68 +25
8 .z
< <
on1 01
-23.5 -20 -4
7
< <
OL 05
1
68 + 16 6..3 j 1.2
9 9 9 9
,,I-,
-16 +7
0 1
+ 1.z .i
> I > I > 1 > I >.I > .I >
1
*Means -C standard deviations. Mean body surfaw area = 1.93 hf.?,
walked on the motor-drivell ing an infusion of angiotensin sinus catheterization wx 3 other subjects.
treadmill durII. Coronar!, performed in
Results Hemodyllamic and metabolic data obtained from 10 subjects before and during infusiotl of angiotensin J I are presented ill Table 1 I. 1. General circulatory eRects. .\ significant increase in both systolic and diastolic blood pressure occurred within 1 minute. Alean arterial Mood pressure increased h>. 31 per cent, from an average of 98 to 128 mm. Hg. The average s\-stemic resistance rose 69
per writ, iron1 1,866 to 3,149 cis~.-~hl.‘. (‘ardiw index ((‘I ) fell from 211 average of 4.46 to 3.42 L.lmin;RI.‘. Since heart rate did 11ot change, this fall was due to a corresponding decrease ilk stroke index (SJ) from ;\II average of 65 to 52 ml.,“1/J.‘. A\ngiotensin J 1 caused 110 significant change in augmented “c.entral blood volui~ie” in 3 illstances. III spite of the signific-allt increases ill arterial pressure and peripheral resistance, the average calculated apparent work of the left ventricle per minute tlitl llot c-hange, because of t-he wmpensxtor!~ fall in wrdiac output. II. J-‘ulnzonavy ciruhtiou. J’ulmonw~ arterial pressure was monitored in 4 subjwts and increased from ali average mean pressure of 11 to 17 mm. H,q. Jiight atrial from 4 to 6.5 pressure rose ill 3 subjects, mm. Hg, OII the average. Seither of these pressures rose at the same time that the systemic arterial pressure did, but rcqiiiretl several minutes to increase graduall~~, even though the ;iilgio!ensill I I reached the pulmol~ar!. ;wter!- and right atrium Mart the peripheral arteries. Thus, in this I I hxl 110 immediatt~ dosage, ari~iotcllsiri el’fect upoli the ~~ulmotlat-~~ vascul;ltur~, \vhic-h tillding c-ollfirms the tlata of Ec.1cc.rt ;ui#iotellsill II ;1trcl f
dogs and observed no rise in pressure. Rlaxwell and associate9 also found no ill rise iI1 pulmoriar~~ arterial pressure intact dogs. III. C~~taneous circztlntion. Serial measurements were made of the temperature of the skin oi’ the forehead, forearm, abdomen, and ankles, in order to assess regional differences iI1 vasoconstrictor responses to aligiotensin I I. 1:ig. I illustrates these observations iI1 a representative individual. The temperature of the skin of all areas studied dropped within 3 minutes as blood pressure rose. The greatest decline occurred iI1 the distal parts of the lower extremities. \IVithill 5 minutes after the iniusion was discoiitiiiuetl, the teniperi~tures in all areas iiicreasecl toward initial c:ontrol levels, tollcomitallt with a fall in blood pressure. In the course of these studies, angiotensill 1 I (lpg,, c.c.) was inad\w-teutly illfiltrated subcutaneously in two ilKlivitluals. In one, t tie infilttxtion wxs not detected for several millutes. So pressor rise \vas seen in either individual ;ls ;I result d this intiltratioll. There was no local reaction of tissue at that time or sul)sequentl>-. IT’. Systemic- nlefubolic clffec-ts. Os)~gell consumption did not change in response to angiotension I I, but there \\‘a5 ;I significant compensator). incre;K5e ill x-teriovenous os~yw differellce. from 45.4 to 56.0 ml. ‘L. of lk~~tl tlo\v. The level of free idtt?. acid iI1 :trterial blood W;IS not sigllifkntly altered 1~ the iniusio~~ of allgiolensin I I, although it tended to fall slightI>,, Cram 854 to 717 microecIlli\r~~lel~ts per liter. Lactic acid, p>‘ruvic- acid, ilntl glucose did Ilot change siqlitic;~lrtl>-. SL ranged iron1 _- .59 to 1.32 (aver;qe + .Ol ) niillimoles per liter of l,lootl water. Since this represellted less th:ln 1 per cent of total hod\ O-YJ~~W consumption, the increased arteriovfnous os\y:eii difference ohserved during infusioil of angiotellsiii I f full>- cotnpensated for ali). impairnieilt ot osygell transport wused by dccwasttl cardiac output.
systemic arteriovenous oxygen difference increased 37 per cent. This was consistent with the lack of change in apparent work of the left ventricle. I’I. Iicsponses with exevcisc. Table I\’ summarizes the hemodynamic data in 3 subjects during supine leg exercise before and tlurillg the infusion of angiotensin I I. ‘Ihblc I I I. Uyocardial obscrvatiom ctiaiduals (menage values)
10.3 930 (1.682) 1.35
in 3 ipl-
129
(7.5) 85
I x46.3 (2.6501 1.z 2 (7 .iJ 00
120.1
124.4
216
Johnson and Bruce
Mean arterial pressure rose from an average of 111 to 121 mm. Hg. The mean PRI increased from 1,355 to 1,610 dsc.-5M.z, and CI fell slightly, from 6.1 to 5.9 L./min./M.?. SI did not change, and heart rate decreased slightly, from 95 to 91. Oxygen consumption did not change significantly, but arteriovenous oxygen difference again showed a slight compensatory increase, from 83.2 to 87.3 ml/L. of blood flow. Apparent left ventricular work per minute did not change significantly because of the slight decrease in CI. Since pressure and PRI did not rise as high with angiotensin during exercise as during rest (1,610 as compared to 3,149 dsc.-6M.2), the normal vasodilatorq response to exercise in skeletal muscle still occurred. Under these circumstances vasoconstriction must be largely limited to the visceral organs and nonexercising muscles. VII. Effect on orthostatic hypotension. Orthostatic hypotension has been reported as a sequel to infusion of angiotensin II in normotensive patients.4 This occurred in one of our subjects several minutes after an infusion was stopped while he was supine. When he was standing prior to walking on the treadmill, his arterial pressure dropped to 60/44 mm. Hg. This rose to 84/72 mm. Hg when he was seated and tipped backward in a chair to enhance intrathoracic blood volume, but dropped again when he was sitting upright. Angiotensin II was reinfused, and within 3 minutes the arterial pressure rose to 170/106 mm. Hg while he was standing. He was able to walk at 1.7 miles per hour on a 10 per cent grade without difficulty-, even though the infusion was again stopped. He had no symptoms after his blood pressure was raised with angiotensin II, and hypotension did not recur subsequently after exercise was discontinued. This demonstrated the therapeutic value of angiotensin II for symptomatic hypotension (due to inappropriate neurocirculatory regulation), as well as the capacityof the subject for exertion immediately after restoration of adequate blood pressure. Discussion
In all studies on human subjects, angiotensin II causes a significant increase in arterial pressure and systemic resistance.
.-lm. firuri .I I~Flwnr~, 1962
The effects C)II heart rate. c;rr-tliac illtIes. and stroke index are variable. In previous studiesa-6,16 (Table I), heart rate has been noted to fall consistently during infusions of angiotensin II, and this has been attributed to increased vagal tone mediated by the baroceptor reflexes incident to a rise in arterial pressure.“s5 Although heart rate fell in 5 individuals in this study, there was an insignificant change in average heart rate. This is attributed to the faster heart rate in unsedated and somewhat apprehensive human subjects during cardiac catheterization. Stroke index and cardiac index fell significantly in this study (p = <.05 and <.02, respectively), in accord with the findings of Finnerty and associates,A who studied “normotensive patients,” and also with Segel and assooxygen difference ciates5 .&-teriovenous increased significantly in our subjects (p = <.Ol), whereas the cumulative average increase in previous studies was only about 0.6 volumes per cent (Table I). This discrepancv may reflect the heterogeneit) of patients included in other studies. In accord with previous reports, mean pulmonary arterial pressure rises 5 to 6 mm. Hg during continuous infusion of angiotensin II. Since this occurs after the rise in systemic arterial pressure, it may be the result of increased pressure in the pulmonary veins rather than the result of constriction of the arterioles proximal to the pulmonary capillaries. Nelson and associates” noted no change in the pulmonary arterial-pulmonary capillary pressure gradient in normotensive patients infused with natural angiotensin. Segel and associates5 reported simultaneous increases in pulmonary arterial and systemic arterial pressures, but their published data show that pulmonar>- arterial pressure continues to rise slowly long after systemic pressure has reached a plateau. If angiotensin II indeed has no primary effect on the pulmonarv vasculature, the observed increase -in pulmonary arterial pressure ma>. represent either a redistribution in blood volume to distend the blood vessels of the lung or altered distensibility of the left heart which elevates left ventricular and diastolic pressures. Indicator-dilution curves showed no increase in augmented
~‘olrmxe 63 Number 2
Hemodynamic
“central blood volume,” but no measurements were made of left ventricular pressure or pulmonary blood volume. .%though it is generally agreed that venous pressure rises slowly during infusion of angiotensin II, the existence of a primary constrictor effect on veins is controversial. Wood’8 found increased “venous tone” in normotensive subjects infused with angiotensin II, but not in hypertensive subjects. If venous constriction is primary, angiotension II is only half as potent as norepinephrine in this regard, yet is several times as potent in constricting arte-
and metabolic ejects of angiotensin II
coronary blood flow (3 subjects) or metabolic substrate levels. Pressures in the right atrium and pulmonary artery rose gradually severa minutes after the rise in systemic arterial pressure. During supine leg exercise with angiotensin II (3 subjects) the peripheral resistance index did not rise as high as it had during rest, which indicates that normal vasodilation of skeletal muscle still occurred in response to exercise. Reinfusion of angiotensin II was effective in one individual in the restoration of normal blood pressure after postinfusion hypotension.
rioles.4.19>“0
Free fatty acid has an extremely rapid rate of turnover and is believed to be the most active metabolically of all blood lipids. In the fasting state, free fatty acid is the major energy-producing substrate of striated muscle, under conditions of aerobic contraction.‘r Whereas infusions of catecholamines increase arterial levels of free fatty acid by mobilization from fat depotqZ2 no increase in arterial levels of free fatty acid occurred during infusion of angiotensin II. Since oxygen consumption and excess lactate (total body metabolism) did not increase, utilization of free fatty acid must have remained relatively constant. It is concluded that angiotensin I I, in the dosage and duration used, does not influence mobilization or utilization of free fatty acid to a significant degree.
REFERENCES 1. 2.
\3
4.
5.
6.
7.
Summary
Ten normal male subjects were studied hemodynamically by cardiac catheterization during infusions of angiotensin II. Arterial levels of free fatty acid, lactate, pyruvate, and glucose were measured. Arterial pressure and the peripheral resistance index rose 31 and 68.8 per cent, respectively (p = <.OOl for both). Cardiac index fell 23.5 per cent (p = < .02), and arteriovenous oxygen difference widened 25.3 per cent (p = <.Ol) in compensatory fashion, since oxygen consumption did not change. Stroke index fell 20.7 per cent (p = < .OS), and augmented “central blood volume” (3 subjects) fell slightly. The temperature of the skin fell as pressure rose and returned to normal concurrent with a fall in pressure after angiotensin was discontinued. No change occurred in
217
8.
9.
10.
11.
12.
13.
Page, I. H., and Bumpus, hr.: r1ngiotensit1, Physiol. Rev. 41:331, 1961. Page, I. H., McCubbin, J. \V., Schwarz, H., and Bumpus, M.: Pharmacologic aspects of synthetic angiotensin, Circulation Res. 5:%2, 1957. Peart, W. S.: Hypertension and the kidney. II. Experimental basis of renal hypertension, Brit. M. J. 2:1421, 1959. Finnerty, F. A., Jr., Massaro, G. Dec., Chupkovich, V., and Tuckman, J.: Evaluation of the pressor, cardiac, and renal hemodynamic properties of angiotensin II in man, Circulation Res. 9:256, 1961. Segel, N., Harris, P., and Bishop, J. M.: The effects of synthetic hypertensin on the systemic and pulmonary circulations in man, Clin. SC. 20:49, 1961. Sancetta, S. M.: General and pulmonary hemodynamic effects of pure decapeptide angiotensin in normotensive man, Circulation Res. 8:616, 1960. Eckcrt, G. E., and Rose, J. C.: ~1 study of angiotensin in the pulmonary circulation, Georgetown M. Bull. 13:72, 1959. Maxwell. G. hl.. Castillo. C. A.. Crumoton. C. W., Clifford, J. E., and Rowe,’ G. G.:’ The effect of synthetic angiotonin upon the heart of the intact dog, J. Lab. & Clin. Med. 54:876, 1959. Goodale, W. T., and Hackel, D. B.: Measurement of coronary blood flow in dogs and man from rate of myocardial nitrous oxide desaturation, Circulation Res. 1:502, 1953. Barker, S. B., and Summerson, IV. H.: Colorimetric determination of lactic acid in biological material, J. Biol. Chem. 535:138, 1911. Segal, S., Blair, A. E., and Wyngaarden, J. B.: Xn enzymatic spectrophotometric method for the determination of pyruvic acid in blood, J. Lab. & Clin. Med. 48:137, 1956. Trout. D. L.. Estes. E. H.. Friedberg. S. 1.: Titration of free fatty acids of plasma:-a study of current methods and a new modification, J. Lipid Res. 1:199, 1960. Beach, E. F., and Turner, J. J.: An enzymatic method for glucose determination in body fluids, Clin. Chem. 4:462, 1958.
1-l. 15.
16.
17.
18.
Halsey, Y.: Personal communication, 1960. Huckabee, W. E.: Relationships of pyruvate and lactate during anaerobic metabolism. II. Exercise and formation of oxygen debt, J. Clin. In\.est. 37:255, 1958. Lichtlen, \‘on I’., Buhlman, .\., and Schaub, F.: l’ntersuchungen iiber die blutdrucksteigernde LVirkung \-on synthetischem Hypertensin II am normotonen Menschen, Cardiologia 35:139, 1959. Nelson, R. :I., May, I,. G., Bellnett, .\., lioba),shi, &I,, and Gregory. K.: Comp;lrison oi the effects of pressor and depressor ,qents and influences on pulnionaq and systemic pressures of normotensive and h> pertensive ~1). jects, .\M. HURT J. 50:172. 1955. \%‘ootl, J. E.: :Ibseuce of the normal peripheral \~enoc.onstrictor response to infuhiow of s\‘j~-
19.
20.
21.
22.
thetic angiotensin II in patients with essential hypertension, J. Clin. Invest. 39:1040, 1960. McQueen, E. G., and Morrison, K. B. I.: The effects of synthetic angiotensin and noradrenaline on blood pressure and renal function, Brit. Heart J. 23:1, 1961. liot. P. :I., Cohn, J, N., Rose, J. C., and Frcis, I?. I).: Responses of veins and arteries to norepinephrine and angiotensin in the dog, Clin. lies. 9:141, 1961 (Abstr.). Issekutz, B., Jr., and Spiker, J. J.: Irptake of free fatty. acids by skeletal muscle during stimw lntion, f’roc. SW. Exper. Biol. & Med. l&5:21, 1960. Bruce, Ii. .A., Cobb, L. :I., and LVilliams, Ii. H.: Effects of exercise and isoproterenol on free fatty acids and carbohydrates in cardiac p;ltients, AIII. J. M. SC. 241:11)l, 1961.
A
ngiotensin II is a synthetic, thermostable octapeptide which causes contraction of the smooth muscle of systemic blood vessels and other tissues. When injected intravenously it causes a prompt, short-lived pressor response which is not inhibited by ganglionic blockade or subject to tachyphylaxis. It exerts no known direct cardiac inotropic or chronotropic effects, although reflex bradycardia results from the systemic pressor response. The action of renin upon renin substrate is believed to produce the decapeptide, angiotensin I. A “converting enzyme” in plasma splits off the terminal 2 amino acids, histidine and leucine, to produce the active vasoconstrictor, angiotensin II. The latter is degraded to amino acids by angiotensinase, an enzyme present in normal kidney, erythrocytes, and various tissues.‘,? Since direct techniques of identification have not yet demonstrated either renin or angiotensin in human blood, Peart3 doubts their importance in human physiology and hypertension. Nevertheless, hemodynamic effects of angiotensin II have been studied in human subjects (Table I). When blood pressure is raised to hypertensive levels, it reduces effective renal plasma flow and urinary output and produces a slight retention of sodium in normotensive patients.4 These effects persist as long as hypertension
is maintained. Hypotensive patients infused with angiotensin II have shown an increase in the output of urine, which is presumably due to more adequate perfusion of the kidneys. Finnerty and associate9 found no change in blood volume during experiments on normotensive patients, and pressor-equivalent doses of I-epinephrine blocked vasoconstrictive effects of angiotensin II. Segel and associates5 found evidence of pulmonary as well as systemicvasoconstriction, whereas others believed there was no direct effect on pulmonar!. arteries or veins. 6,7 Methods Ten normal, healthy, male volunteers were studied while they were in the fasting state without sedation. Cardiac output was measured by the direct Fick principle, utilizing cardiac catheterization for sampling of mixed venous blood from the right atrium or pulmonary artery. Pressures were recorded with a Statham P-23D pressure transducer. Arterial pressures and samples were obtained by means of a No. 18 Cournand needle inserted into a peripheral artery. Oxygen consumption and ventilation were measured with a 13-liter Collins spirometer. Indicator-dilution curves were recorded in some instances by means of an ear oximeter, using Evans blue dye.
With the technical assistance of Barbara Erickson. Wen Chiu. and Gladys P&et. From the Department of Medicine, University of Washington, Seattle, Wash. These studies have been supported in part by Grant H-908(ClO) from the United States Public Health Received for publication June 30, 1961.
212
Service.
Hemodynamic
and metabolic @ects of angioten.sin II
“Augmented central blood volume”* was calculated from mean circulation time and cardiac output derived by- the Fick principle. The peripheral resistance index (PRIj was calculated by means of the formula: Arterial Mean Pressure X 80 PI< 1 = 1. ~~ ~~~~__._ Cardiac Index which yields resistance units in dynes seconds centimeter@ times square meters of body surface area (dsc.v5 X M.“). Apparent work of the left ventricle was calculated from the formula: MAPX CO X 14.5 Work (Kg.M./min.) = 1,000 where MAP is mean arterial pressure, CO is cardiac output, and 14.5 is a constant derived from the product of the specific gravities of blood and mercury. Coronary blood flow was measured by the nitrousoxide desaturation technique9 after catheterization of the coronary sinus in 3 individuals. The temperature of the skin was recorded with a Rauh thermocouple. Lactic acid was determined by the method of Barker and Summerson,“’ pyruvic acid by the method of Segal and coworkers,” free fatty acid (FFA) by the
modified Dole procedure,r2 and glucose b> the method of Beach and TurnerI modified by Halsey. I4 “Excess lactate” (XL) for appraisal of anaerobic metabolism during experimental periods was calculated from Huckabee’s formula15: SL = (L,, - L,) - (P? - Ppj (L,/‘P,), where L, and P, represented concentrations of lactic acid and pyruvic acid in arterial blood during control periods, and L, and P, represented concentrations during experimental periods. Procedure
Control measurements were made when the subjects were in the resting steady state condition while lying supine; then angiotensin II* was infused intravenously, either into the right heart or into the pulmonary artery. The dosage was .05 micrograms per kilogram per minute (averaging 3 to 4 micrograms per subject per minute), for 30 to 60 minutes. Sufficient time was allowed for the blood pressure and heart rate to stabilize before measurements were made. Three subjects were also studied while they did leg exercises in the supine position, with and without angiotensin II. .Another subject was studied while he
*Mean circulation time which is measured by arterial sampling is shorter than that which is measured by “capillary sampling” by the earpiece oximeter. Therefore, central volume will be greater (augmented) with the latter method.
*Lyophilized crrstals of Valyls angiotensin II for this studs were supplied by Ciba Pharmaceutical Products. Inc.
Table I. Hemodynamic efects of synthetic angiotensin cardiovascular diseases”
coutro1
Mean arterial pressure(mm. Hg) Mean pulmonary arterial pressure(mm. Hg) Peripheral resistance(dsc?) Cardiac output (L./min.) Stroke
volume
Arteriovenous
dngiotensin
oxygen
$35
42
20
20
1,220 (2,122)1 6.2 (3.5)
1.780 (3.53o)t 5.5 (2.9j
80
(Kg.M./min.) difference
Per cent change%
12.1
(ml.)
work
Xzt m ber of observations
11
Heart rate Oxygen consumption (ml./min.) ventricular
reported by others in patients without
91
(1:)
Left
213
(ml./L.)
*Combined and averaged data of Lichtlen, et al.16 on 5 subjects. 17 subjects. and of &gel, et al.6 in 10 studies on 7 subjects. tParenthetica1 data have been corrected for body surface area. fFor all available data.
237 1134) ‘8.8’ (4.8) 39.6
of Sancetta.
(11, 67 240 (1361 10.3 (5.3) 45.9
et al.6 on 5 subjects,
+43
+57 Pz.1 23
(26) 23 (26‘) 31 15
-1-1
+2 --I6 +1 t I 3 .5
15
of Finnerty.
+I6
et al.4 in 22 studies
on
.I,/, ,
Table II. Hemodynamic jects at rest
and metabolic
Mean arterkl preswre (mm. Hg) Peripheral resistance index (dsc? XI.?) .%rteriovenous oxygen difference (1711./L.) Cardiac index (L./min./M.2j Stroke index (ml./M.2) Oxygen consmnption (ml./mill./Xl.“) Heart rate Left \-entricular work (Kg.~l./min./R1.*) Free fatty- acids (&q/L.) Glucose (mg. 5,; ) Lactic acid (mM./L. of blood H?O) PyrtIvic acid (mM./L. of blood HzO) “XL” (mM./L. of blood H,O)
qffPcts
10 JO in 10 10
10 10 10
qf’ angiotensin
975i95 1,866+
in
,fasting,
127.7 501
45.4 + 8.0 4 46 i 65.3 f 196 + 69+ 6 .Z +
/I
1 1.3 14 5 4.5 12 1 6
*
10.2
3.149 f 710 569i99 .z 42 f
57
$1 8_+ 9.6 188 i
.14
854 * 325 79.2 i 6 0 633 f 0 218 0 036 f 0 017
0.034
9
0.000
0 011
717 i84 9 i
276 1.3.9
0.717 * 0.213 +
0.009
,,fi,i, 1,1,/
i I’,
,“/a
supint, normcri sub-
+.31
< 00 I
$68 +25
8 .z
< <
on1 01
-23.5 -20 -4
7
< <
OL 05
1
68 + 16 6..3 j 1.2
9 9 9 9
,,I-,
-16 +7
0 1
+ 1.z .i
> I > I > 1 > I >.I > .I >
1
*Means -C standard deviations. Mean body surfaw area = 1.93 hf.?,
walked on the motor-drivell ing an infusion of angiotensin sinus catheterization wx 3 other subjects.
treadmill durII. Coronar!, performed in
Results Hemodyllamic and metabolic data obtained from 10 subjects before and during infusiotl of angiotensin J I are presented ill Table 1 I. 1. General circulatory eRects. .\ significant increase in both systolic and diastolic blood pressure occurred within 1 minute. Alean arterial Mood pressure increased h>. 31 per cent, from an average of 98 to 128 mm. Hg. The average s\-stemic resistance rose 69
per writ, iron1 1,866 to 3,149 cis~.-~hl.‘. (‘ardiw index ((‘I ) fell from 211 average of 4.46 to 3.42 L.lmin;RI.‘. Since heart rate did 11ot change, this fall was due to a corresponding decrease ilk stroke index (SJ) from ;\II average of 65 to 52 ml.,“1/J.‘. A\ngiotensin J 1 caused 110 significant change in augmented “c.entral blood volui~ie” in 3 illstances. III spite of the signific-allt increases ill arterial pressure and peripheral resistance, the average calculated apparent work of the left ventricle per minute tlitl llot c-hange, because of t-he wmpensxtor!~ fall in wrdiac output. II. J-‘ulnzonavy ciruhtiou. J’ulmonw~ arterial pressure was monitored in 4 subjwts and increased from ali average mean pressure of 11 to 17 mm. H,q. Jiight atrial from 4 to 6.5 pressure rose ill 3 subjects, mm. Hg, OII the average. Seither of these pressures rose at the same time that the systemic arterial pressure did, but rcqiiiretl several minutes to increase graduall~~, even though the ;iilgio!ensill I I reached the pulmol~ar!. ;wter!- and right atrium Mart the peripheral arteries. Thus, in this I I hxl 110 immediatt~ dosage, ari~iotcllsiri el’fect upoli the ~~ulmotlat-~~ vascul;ltur~, \vhic-h tillding c-ollfirms the tlata of Ec.1cc.rt ;ui#iotellsill II ;1trcl f
dogs and observed no rise in pressure. Rlaxwell and associate9 also found no ill rise iI1 pulmoriar~~ arterial pressure intact dogs. III. C~~taneous circztlntion. Serial measurements were made of the temperature of the skin oi’ the forehead, forearm, abdomen, and ankles, in order to assess regional differences iI1 vasoconstrictor responses to aligiotensin I I. 1:ig. I illustrates these observations iI1 a representative individual. The temperature of the skin of all areas studied dropped within 3 minutes as blood pressure rose. The greatest decline occurred iI1 the distal parts of the lower extremities. \IVithill 5 minutes after the iniusion was discoiitiiiuetl, the teniperi~tures in all areas iiicreasecl toward initial c:ontrol levels, tollcomitallt with a fall in blood pressure. In the course of these studies, angiotensill 1 I (lpg,, c.c.) was inad\w-teutly illfiltrated subcutaneously in two ilKlivitluals. In one, t tie infilttxtion wxs not detected for several millutes. So pressor rise \vas seen in either individual ;ls ;I result d this intiltratioll. There was no local reaction of tissue at that time or sul)sequentl>-. IT’. Systemic- nlefubolic clffec-ts. Os)~gell consumption did not change in response to angiotension I I, but there \\‘a5 ;I significant compensator). incre;K5e ill x-teriovenous os~yw differellce. from 45.4 to 56.0 ml. ‘L. of lk~~tl tlo\v. The level of free idtt?. acid iI1 :trterial blood W;IS not sigllifkntly altered 1~ the iniusio~~ of allgiolensin I I, although it tended to fall slightI>,, Cram 854 to 717 microecIlli\r~~lel~ts per liter. Lactic acid, p>‘ruvic- acid, ilntl glucose did Ilot change siqlitic;~lrtl>-. SL ranged iron1 _- .59 to 1.32 (aver;qe + .Ol ) niillimoles per liter of l,lootl water. Since this represellted less th:ln 1 per cent of total hod\ O-YJ~~W consumption, the increased arteriovfnous os\y:eii difference ohserved during infusioil of angiotellsiii I f full>- cotnpensated for ali). impairnieilt ot osygell transport wused by dccwasttl cardiac output.
systemic arteriovenous oxygen difference increased 37 per cent. This was consistent with the lack of change in apparent work of the left ventricle. I’I. Iicsponses with exevcisc. Table I\’ summarizes the hemodynamic data in 3 subjects during supine leg exercise before and tlurillg the infusion of angiotensin I I. ‘Ihblc I I I. Uyocardial obscrvatiom ctiaiduals (menage values)
10.3 930 (1.682) 1.35
in 3 ipl-
129
(7.5) 85
I x46.3 (2.6501 1.z 2 (7 .iJ 00
120.1
124.4
216
Johnson and Bruce
Mean arterial pressure rose from an average of 111 to 121 mm. Hg. The mean PRI increased from 1,355 to 1,610 dsc.-5M.z, and CI fell slightly, from 6.1 to 5.9 L./min./M.?. SI did not change, and heart rate decreased slightly, from 95 to 91. Oxygen consumption did not change significantly, but arteriovenous oxygen difference again showed a slight compensatory increase, from 83.2 to 87.3 ml/L. of blood flow. Apparent left ventricular work per minute did not change significantly because of the slight decrease in CI. Since pressure and PRI did not rise as high with angiotensin during exercise as during rest (1,610 as compared to 3,149 dsc.-6M.2), the normal vasodilatorq response to exercise in skeletal muscle still occurred. Under these circumstances vasoconstriction must be largely limited to the visceral organs and nonexercising muscles. VII. Effect on orthostatic hypotension. Orthostatic hypotension has been reported as a sequel to infusion of angiotensin II in normotensive patients.4 This occurred in one of our subjects several minutes after an infusion was stopped while he was supine. When he was standing prior to walking on the treadmill, his arterial pressure dropped to 60/44 mm. Hg. This rose to 84/72 mm. Hg when he was seated and tipped backward in a chair to enhance intrathoracic blood volume, but dropped again when he was sitting upright. Angiotensin II was reinfused, and within 3 minutes the arterial pressure rose to 170/106 mm. Hg while he was standing. He was able to walk at 1.7 miles per hour on a 10 per cent grade without difficulty-, even though the infusion was again stopped. He had no symptoms after his blood pressure was raised with angiotensin II, and hypotension did not recur subsequently after exercise was discontinued. This demonstrated the therapeutic value of angiotensin II for symptomatic hypotension (due to inappropriate neurocirculatory regulation), as well as the capacityof the subject for exertion immediately after restoration of adequate blood pressure. Discussion
In all studies on human subjects, angiotensin II causes a significant increase in arterial pressure and systemic resistance.
.-lm. firuri .I I~Flwnr~, 1962
The effects C)II heart rate. c;rr-tliac illtIes. and stroke index are variable. In previous studiesa-6,16 (Table I), heart rate has been noted to fall consistently during infusions of angiotensin II, and this has been attributed to increased vagal tone mediated by the baroceptor reflexes incident to a rise in arterial pressure.“s5 Although heart rate fell in 5 individuals in this study, there was an insignificant change in average heart rate. This is attributed to the faster heart rate in unsedated and somewhat apprehensive human subjects during cardiac catheterization. Stroke index and cardiac index fell significantly in this study (p = <.05 and <.02, respectively), in accord with the findings of Finnerty and associates,A who studied “normotensive patients,” and also with Segel and assooxygen difference ciates5 .&-teriovenous increased significantly in our subjects (p = <.Ol), whereas the cumulative average increase in previous studies was only about 0.6 volumes per cent (Table I). This discrepancv may reflect the heterogeneit) of patients included in other studies. In accord with previous reports, mean pulmonary arterial pressure rises 5 to 6 mm. Hg during continuous infusion of angiotensin II. Since this occurs after the rise in systemic arterial pressure, it may be the result of increased pressure in the pulmonary veins rather than the result of constriction of the arterioles proximal to the pulmonary capillaries. Nelson and associates” noted no change in the pulmonary arterial-pulmonary capillary pressure gradient in normotensive patients infused with natural angiotensin. Segel and associates5 reported simultaneous increases in pulmonary arterial and systemic arterial pressures, but their published data show that pulmonar>- arterial pressure continues to rise slowly long after systemic pressure has reached a plateau. If angiotensin II indeed has no primary effect on the pulmonarv vasculature, the observed increase -in pulmonary arterial pressure ma>. represent either a redistribution in blood volume to distend the blood vessels of the lung or altered distensibility of the left heart which elevates left ventricular and diastolic pressures. Indicator-dilution curves showed no increase in augmented
~‘olrmxe 63 Number 2
Hemodynamic
“central blood volume,” but no measurements were made of left ventricular pressure or pulmonary blood volume. .%though it is generally agreed that venous pressure rises slowly during infusion of angiotensin II, the existence of a primary constrictor effect on veins is controversial. Wood’8 found increased “venous tone” in normotensive subjects infused with angiotensin II, but not in hypertensive subjects. If venous constriction is primary, angiotension II is only half as potent as norepinephrine in this regard, yet is several times as potent in constricting arte-
and metabolic ejects of angiotensin II
coronary blood flow (3 subjects) or metabolic substrate levels. Pressures in the right atrium and pulmonary artery rose gradually severa minutes after the rise in systemic arterial pressure. During supine leg exercise with angiotensin II (3 subjects) the peripheral resistance index did not rise as high as it had during rest, which indicates that normal vasodilation of skeletal muscle still occurred in response to exercise. Reinfusion of angiotensin II was effective in one individual in the restoration of normal blood pressure after postinfusion hypotension.
rioles.4.19>“0
Free fatty acid has an extremely rapid rate of turnover and is believed to be the most active metabolically of all blood lipids. In the fasting state, free fatty acid is the major energy-producing substrate of striated muscle, under conditions of aerobic contraction.‘r Whereas infusions of catecholamines increase arterial levels of free fatty acid by mobilization from fat depotqZ2 no increase in arterial levels of free fatty acid occurred during infusion of angiotensin II. Since oxygen consumption and excess lactate (total body metabolism) did not increase, utilization of free fatty acid must have remained relatively constant. It is concluded that angiotensin I I, in the dosage and duration used, does not influence mobilization or utilization of free fatty acid to a significant degree.
REFERENCES 1. 2.
\3
4.
5.
6.
7.
Summary
Ten normal male subjects were studied hemodynamically by cardiac catheterization during infusions of angiotensin II. Arterial levels of free fatty acid, lactate, pyruvate, and glucose were measured. Arterial pressure and the peripheral resistance index rose 31 and 68.8 per cent, respectively (p = <.OOl for both). Cardiac index fell 23.5 per cent (p = < .02), and arteriovenous oxygen difference widened 25.3 per cent (p = <.Ol) in compensatory fashion, since oxygen consumption did not change. Stroke index fell 20.7 per cent (p = < .OS), and augmented “central blood volume” (3 subjects) fell slightly. The temperature of the skin fell as pressure rose and returned to normal concurrent with a fall in pressure after angiotensin was discontinued. No change occurred in
217
8.
9.
10.
11.
12.
13.
Page, I. H., and Bumpus, hr.: r1ngiotensit1, Physiol. Rev. 41:331, 1961. Page, I. H., McCubbin, J. \V., Schwarz, H., and Bumpus, M.: Pharmacologic aspects of synthetic angiotensin, Circulation Res. 5:%2, 1957. Peart, W. S.: Hypertension and the kidney. II. Experimental basis of renal hypertension, Brit. M. J. 2:1421, 1959. Finnerty, F. A., Jr., Massaro, G. Dec., Chupkovich, V., and Tuckman, J.: Evaluation of the pressor, cardiac, and renal hemodynamic properties of angiotensin II in man, Circulation Res. 9:256, 1961. Segel, N., Harris, P., and Bishop, J. M.: The effects of synthetic hypertensin on the systemic and pulmonary circulations in man, Clin. SC. 20:49, 1961. Sancetta, S. M.: General and pulmonary hemodynamic effects of pure decapeptide angiotensin in normotensive man, Circulation Res. 8:616, 1960. Eckcrt, G. E., and Rose, J. C.: ~1 study of angiotensin in the pulmonary circulation, Georgetown M. Bull. 13:72, 1959. Maxwell. G. hl.. Castillo. C. A.. Crumoton. C. W., Clifford, J. E., and Rowe,’ G. G.:’ The effect of synthetic angiotonin upon the heart of the intact dog, J. Lab. & Clin. Med. 54:876, 1959. Goodale, W. T., and Hackel, D. B.: Measurement of coronary blood flow in dogs and man from rate of myocardial nitrous oxide desaturation, Circulation Res. 1:502, 1953. Barker, S. B., and Summerson, IV. H.: Colorimetric determination of lactic acid in biological material, J. Biol. Chem. 535:138, 1911. Segal, S., Blair, A. E., and Wyngaarden, J. B.: Xn enzymatic spectrophotometric method for the determination of pyruvic acid in blood, J. Lab. & Clin. Med. 48:137, 1956. Trout. D. L.. Estes. E. H.. Friedberg. S. 1.: Titration of free fatty acids of plasma:-a study of current methods and a new modification, J. Lipid Res. 1:199, 1960. Beach, E. F., and Turner, J. J.: An enzymatic method for glucose determination in body fluids, Clin. Chem. 4:462, 1958.
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Halsey, Y.: Personal communication, 1960. Huckabee, W. E.: Relationships of pyruvate and lactate during anaerobic metabolism. II. Exercise and formation of oxygen debt, J. Clin. In\.est. 37:255, 1958. Lichtlen, \‘on I’., Buhlman, .\., and Schaub, F.: l’ntersuchungen iiber die blutdrucksteigernde LVirkung \-on synthetischem Hypertensin II am normotonen Menschen, Cardiologia 35:139, 1959. Nelson, R. :I., May, I,. G., Bellnett, .\., lioba),shi, &I,, and Gregory. K.: Comp;lrison oi the effects of pressor and depressor ,qents and influences on pulnionaq and systemic pressures of normotensive and h> pertensive ~1). jects, .\M. HURT J. 50:172. 1955. \%‘ootl, J. E.: :Ibseuce of the normal peripheral \~enoc.onstrictor response to infuhiow of s\‘j~-
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thetic angiotensin II in patients with essential hypertension, J. Clin. Invest. 39:1040, 1960. McQueen, E. G., and Morrison, K. B. I.: The effects of synthetic angiotensin and noradrenaline on blood pressure and renal function, Brit. Heart J. 23:1, 1961. liot. P. :I., Cohn, J, N., Rose, J. C., and Frcis, I?. I).: Responses of veins and arteries to norepinephrine and angiotensin in the dog, Clin. lies. 9:141, 1961 (Abstr.). Issekutz, B., Jr., and Spiker, J. J.: Irptake of free fatty. acids by skeletal muscle during stimw lntion, f’roc. SW. Exper. Biol. & Med. l&5:21, 1960. Bruce, Ii. .A., Cobb, L. :I., and LVilliams, Ii. H.: Effects of exercise and isoproterenol on free fatty acids and carbohydrates in cardiac p;ltients, AIII. J. M. SC. 241:11)l, 1961.