The pulmonary hemodynamic effects of amyl nitrite in normal man

Experimental and laboratory reports

The pulmonary hemodynamic effects of amyl nitrite in normal man Antonio C. de Leon, Jr., M.D.*

Joseph K. Perloff, M.D. Washington, D. C.

asoactive drugs have assumed roles of increasing importance in cardiac auscultation and in the phonocardiographic and hemodynamic assessment of heart disease. Amyl nitrite, a drug in this category, has proved to be a safe, simple, and reliable diagnostic adjunct. 1-8 Inferences drawn from the circulatory effects of amyl nitrite in disease states benefit from a clearer appreciation of its effects in normal subjects. Although the drug has been used for nearly a century, 7 knowledge of its action on the normal circulation remains incomplete. Accordingly, the systemic hemodynamie effects of the inhalation of amyl nitrite in normal man were recently studied in this laboratory, 8 and the present investigation was undertaken in order to extend these observations to the pulmonary circulation.

V

Materials and methods

Observations were made on 18 healthy volunteers under light pentobarbital sedation (100 mg.). All were carefully screened in order to exclude clinically evident cardiovascular disease. There were 17 males and 1 female. They ranged in age from 20 to 30 years (mean of 25 years). The nature of each procedure was ex-

plained in detail in order to minimize apprehension. Because of the possibility that the circulatorv effects of amyl nitrite might differ in older subjects, those above 40 years of age were excluded. All observations were made with the patients supine. A Cournand catheter was introduced i n t o the pulmonary artery (via a median basilic vein) using standard methods of right heart catheterization. Indwelling Cournand needles were inserted into both right and left brachial arteries. The methods of instrumentation, calibration, and data analysis were similar to those previously described. 8 Amyl nitrite was inhaled from a broken phial while the subject breathed quietly for 10 to 20 seconds until the brachial arterial systolic pressure fell 30 to 40 ram. Hg. Part I. Control observations, generally in duplicate, were made while simultaneously recording the electrocardiogram, the mean pulmonary arterial and brachial arterial pressures, and an indicator-dilution curve for cardiac output. Calibrated amounts of indocyanine green dye were injected into the pulmonary artery (transiently interrupting the mean pressure tracing), and dilution curves were inscribed by withdrawal from a brachial artery. Similar

From the Department of Medicine, Georgetown University School of Medicine, Division of Cardiology, Georgetown University Hospital, Washington, D. C. Supported in part by United States Public Health Service Grant HE-09093, and by Public Health Service Career Program Award HE-14009. A portion of this work was conducted through the Georgetown University Clinical Study Unit supported by the National Institutes of Health (FR-60). Received for publication Nov. 24, 196.5. *Address: Georgetown University Hospital, 3800 Reservoir Rd., N.W., Washington, D. C., 20007.

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A,,. Hear* J. Sepfember, 1966

7"able I. Part I Stroke volume index

(cc./m3)

Mean pulm. art. pressure (mm. He)

Mean brachial art. pressure (ram. He)

(Kg. M./M3)

3.75 (2,7-4.9)

49.5 (34-56)

12.8 (8,5-18)

91.0 (80-1113

0.66 (0.44-0.99)

6.24 (4.47-7.8)

54.3 (43-72)

15.1 (11-19)

59,0 (43-80)

1.30 (0.74-I 86)

Per cent change

+66

+10

+18

--35

+95

p Value

<0.001

<0.02

<0.001

<0.001

Cardiac index (L./min./M3)

Control Test

Parameter

Rr

minute work index

< 0 . 001

Table I I. Part I I Pulmonary arterial systolic pressure (mm. Hg)

Pulmonary arterial diastolic pressure (mm. Hg)

RV systolic pressure (mm. He)

RV diastolic pressure (mm. Hg)

(ram. Hg)

Brachial arterial diastolic pressure (mm. Hg)

Control

19 (13-26)

8.2 (4-17)

25 (15-35)

4.3 (2-9)

116 (100-148)

72 (54-90)

Test

23 (17-32)

8.7 (4-19)

27 (19-37)

2.7 (1--4)

84 (58-104)

47 (36-58)

+22

+7

+8

--38

--27.6

--34.5

< 0.001

0,5

< 0,01

< 0.05

0.001

0.001

Parameter

Per cent change p Value

Brachial arterial systolic pressure

Fig. 1. Simultaneously recorded mean brachial and pulmonary arterial pressures with a quantitative indicatordilution curve inscribed after inhalation of amyl nitrite. There is a rise in the mean pulmonary arterial tracing at lhe thne of maximal decline in systemic arterial pressure. See text for details.

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Pulmonary hemodynamic effects of amyl nitrite in normal man

RV ,Systemic mLnVte stLrcVe PulmonarYvascular stroke vo ~cutar work index work index work index resistance resistance (Gin. M./M. 2) ( Kg. M./ M. 2) (Gin. M./ M 3 ) (dynes sec. cm. -~ ) (dynes sec. cm. -5)

Heart rate (per rain. )

339

Recirculation time

(see.)

88 (5.6-13.7)

4.40 (2.8-6.0)

56.2 (25.6-82)

146 (85-309)

944 (654-1478)

77 (60-90)

11.7 (14-18)

11.2 (8.0.16.4)

4.68 (2.76-6.65)

40.8 (31-58.5)

98 (60-176)

414 (270-822)

115 (96-138)

8.4 (7-10)

+27

+7

-27

--33

-56

+50

--28

<0.0!

0.5

<0.01

<0.01

<0.001

<0. 001

<0. 001

Fig. 2. At the onset of the decline in brachial arterial pressure there is a rise in mean pulmonary arterial pressure which is maintained for the duration of the decline in systemic pressure. See text for details.

observations were then made after the inhalation of amyl nitrite (Figs. 1 and 2). The following data were derived (Table I) : cardiac index, stroke index, mean pulmonary arterial and brachial arterial pressures, right ventricular and left ventricular minute and stroke work indices, total pulmonary a n d systemic vascular resistances, heart rate, and mean recirculation time of injected indicator. Part II. Thirty minutes after the initial inhalation of amyl nitrite, sequential control tracings were taken of the undamped pulmonary arterial and right ventricular pressures while simultaneously recording the undamped brachial arterial pressure and the electrocardiogram. The catheter was readvanced into the pulmonary artery, and similar observations were made at the

height of the amyl-nitrite effect. The systolic and diastolic pressures in the pulmonary artery, right ventricle, and brachial artery were then measured (Table II). Part I I I . Twenty to 30 minutes after completion of Part II, the following observations were made on 3 subjects. Calibrated amounts of indocyanine green dye were injected into a large median basilic vein via a No. PE 50 polyethylene catheter, and dilution curves were inscribed by withdrawal from the pulmonary artery via the intracardiac catheter. Similar tracings were recorded at the height of the amyl-nitrite effect (Fig. 3). It is recognized that the use of a cardiac catheter as the afferent limb of the withdrawal system may introduce inaccuracies in the absolute values of flow determina-

3 40

de Leon and Perlofl" -

.~I,,,.~e,~t J. 1966

September,

1:ig. 3. Upper: Mean brachial arterial pressure and a control dilution curve obtained by withdrawal from the pulmonary artery via the catheler after injection of Cardiogreen into a mediar~ basilic vein. Lower: The same tracings after the inhalation of amyl nitrite. The area under the dilution curve has diminished, reflecting an increase in flow.

tions." H o w e v e r , t h e m e t h o d w a s n o t enlp l o y e d for the c a l c u l a t i o n of a b s o l u t e values. T h e d i l u t i o n c u r v e s were used o n l y for comparative q u a n t i f i c a t i o n in o r d e r to e s t i m a t e directional c h a n g e s in p u l m o n a r y blood flow, w i t h each p a t i e n t s e r v i n g as his own c o n t r o l .

Results Part I (Table I). CARDIAC OUTPUT. T h e a v e r a g e c o n t r o l c a r d i a c i n d e x w a s 3.75 L . / m i n . / M . " , w i t h a r a n g e of 2.7 to 4.9. A t t h e h e i g h t of t h e a m y l - n i t r i t e effect t h e a v e r a g e w a s 6.24 L . / m i n . / M Y , w i t h a r a n g e of 4.47 to 7.8, r e p r e s e n t i n g a s i g n i f i c a n t i n c r e a s e of 66 p e r c e n t (p < 0.001). STROKE VOLUME. T h e a v e r a g e c o n t r o l s t r o k e v o l u m e i n d e x w a s 49.5 m l . / M 2 , w i t h a r a n g e of 34 to 56. A t the h e i g h t of t h e a m y l - n i t r i t e effect the a v e r a g e was 54.3 m l . / ~ l . 2, w i t h a r a n g e of 43 to 72,

r e p r e s e n t i n g a s l i g h t i n c r e a s e of 10 p e r c e n t (p < 0.02). MEAN

PULMONARY

ARTlZ,'RIA[, P R E S S U R E .

The average control mean puhnonary a r t e r i a l p r e s s u r e w a s 12.8 ram. H g , w i t h a r a n g e of 8.5 to 18. A t the h e i g h t of t h e a m y l - n i t r i t e effect, t h e a v e r a g e w a s 15.1 ram. H g , w i t h a r a n g e of 11 to 19, r e p r e s e n t i n g a small b u t s i g n i f i c a n t i n c r e a s e of 18 p e r c e n t (p < 0.001). I n 4 i n s t a n c e s t h e r e w a s a rise of 2 to 4 m m . H g in m e a n p u l m o n a r y a r t e r i a l p r e s s u r e a t the o n s e t of t h e fall in b r a c h i a l a r t e r i a l pressure. MEAN BRACHIAL A R T E R I A L PRESSURE. T h e average control brachial arterial mean p r e s s u r e w a s 91 ram. H g , w i t h a r a n g e of 80 to 111. A t t h e h e i g h t of t h e a m y l - n i t r i t e effect t h e a v e r a g e w a s 59 ram. H g , w i t h a r a n g e of 43 to 80, r e p r e s e n t i n g a s i g n i f i c a n t d e c l i n e of 35 p e r c e n t (p < 0.001). R I G H T V E N T R I C U L A R M I N U T E VqORK. T h e

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Pulmonary hemodynamic effects of amyl nitrite in normal man

average control effective right ventricular minute work index was 0.66 K g . M . / M ? , with a range of 0.44 to 0.99. A t the height of the amyl-nitrite effect the average was 1.30 K g . M . / M 3 , with a range of 0.74 to 1.86, representing a significant increase of 95 per cent (p < 0.001). LEFT VENTRICULAR MINUTE WORK. The average control effective left ventricular minute work index was 4.40 K g . M . / M ? , with a range of 2.8 to 6.0. At the height of the amyl-nitrite effect the average was 4.68 K g . M . / M ? , with a range of 2.76 to 6.65, representing an insignificant change of 7 per cent (p < 0.5). RIGHT VENTRICULAR STROKE WORK. The average control effective right ventricular stroke index was 8.8 G m . M . / M ? , with a range of 5.6 to 13.7. At the height of the amyl-nitrite effect the average was 11.2 G m . M . / M 3 , with a range of 8.0 to 16.4, representing a significant increase of 27 per cent (p < 0.01). LEFT VENTRICULAR STROKE WORK. The average control effective left ventricular stroke work index was 56.2 G m . M . / M ? , with a range of 25.6 to 82. A t the height of the amyl-nitrite effect the average was 40.8 G m . M . / M ? , with a range of 31 to 58.5, representing a significant decline of 27 per cent (p < 0.01). PULMONARY VASCULAR RESISTANCE. The average control total p u l m o n a r y vascular resistance was 146 dynes sec. cm. -5, with a range of 85 to 309. A t the height of the amyl-nitrite effect the average was 98 dynes sec. cm. -~, with a range of 60 to 176, representing a significant decline of 33 per cent (p < 0.01). SYSTEMIC VASCULAR RESISTANCE, The average control systemic vascular resistance was 944 dynes sec. cm. -a, with a range of 654 to 1,478. At the height of the amyl-nitrite effect the average was 414 dynes sec. cm. -5, with a range of 270 to 822, representing a significant decline of 56 per cent (p < 0.001). HEART RATE. T h e average control heart rate was 77 beats per minute, with a range of 60 to 90. A t the height of the amyInitrite effect the average was 115 per minute, with a range of 96 to 138, representing a significant increase of 50 per cent (p < 0.001). CIRCULATION TIME. T h e average control

3 41

recirculation time was 11.7 seconds, with a range of 14 to 18. At the height of the amyl-nitrite effect the average was 8.4 seconds, with a range of 7 to 10, representing a significant decline of 28 per cent (p < 0.001).

Part I I (Table II). PULMONARY

ARTERIAL

SYSTOLIC

PRES-

T h e average control p u l m o n a r y arterial systolic pressure was 19 ram. Hg, with a range of 13 to 26. At the height of the amyl-nitrite effect the average was 23 ram. Hg, with a range of 17 to 32, representing a significant increase of 22 per cent (p < 0.001). SURE.

PULMONARY

ARTERIAL

DIASTOLIC

PRES-

T h e average control p u l m o n a r y arterial diastolic pressure was 8.2 ram. Hg, with a range of 4 to 17. A t the height of the amyl-nitrite effect the average was 8.7 ram. Hg, with a range of 4 to 19, representing an insignificant increase of 7 per cent (p < 0.5). SURE.

RIGHT

VENTRICULAR

SYSTOI.IC PRESSURE.

T h e average control right ventricular systolic pressure was 25 m m . Hg, with a range of 15 to 35. At the height of the amyl-nitrite effect the average was 27 ram. Hg, with a range of 19 to 37, representing a small b u t significant increase of 8 per cent (p < 0.01). RIGHT VENTRICULAR

DIASTOLIC PRESSURE.

T h e average control right ventricular diastolic pressure was 4.3 ram. Hg, with a range of 2 to 9. At the height of the amyl-nitrite effect the average was 2.7 ram. Hg, with a range of 1 to 4, representing a decline of 38 per cent (p <

0.05). BRACHIAL

ARTERIAL

SYSTOLIC

PRESSURE.

T h e average control brachial arterial systolic pressure was 116 m m . Hg, with a range of 100 to 148. A t the height of the amyl-nitrite effect the average was 84 ram. Hg, with a range of 58 to 104, representing a significant decline of 27.6 per cent (p < 0.001). BRACHIAL ARTERIAL DIASTOLIC PRESSURE.

T h e average control brachial arterial diastolic pressure was 72 ram. Hg, with a range of 54 to 90. At the height of the amylnitrite effect the average was 47 turn. Hg, with a range of 36 to 58, representing a significant decline of 34.5 per cent (p < 0.001).

342

de Leon and Perloff

-Part I l L QUANTIFICATION OF INDICATOR-DILUTION CURVES OBTAINED BY PERIPHERAL VENOUS INJECTION WITH PULMONARY ARTERIAL WITHDRAWAL (Fig. 3). The average control quantification was 2.97 L./min./M2. At the height of the amyl-nitrite effect the average was 5.38 L./min./M.L

Discussion Amyl nitrite, by interfering with the enzymatic decomposition of adenosine triphosphate, deprives arterial smooth muscle of the energy required for the maintenance of tone, thus initiating vasodilation? ~ The systemic hemodynamic effects of this pharmacologic intervention includeS: (1) a decrease in arterial pressure, vascular resistance, stroke work, circulation time, level of the dicrotic notch, amplitude of the dicrotic wave, and duration of the diastolic filling period, (2) an increase in heart rate, cardiac index, and ejection velocity, and (3) no change in stroke volume or minute work. During the course of the present study, many of these systemic circulatory parameters were of necessity reinvestigated and the findings were in close agreement with prior observations. 8 Effects on pressure and flow in the pulmonary circulation. Amyl nitrite causes a

marked, consistent increase in systemic flow per minute? ,8 Whether the drug exerts a similar effect on pulmonary blood flow has been unsettled. In the dog, nitroglycerin increases left ventricular output more than it increases venous return to the right heart, the difference being derived from the thoracic reservoir, n However, this reservoir appears to be insufficient to permit increases in systemic output of the degree induced by amyl nitrite, unless a commensurate increase in venous return occurs? This thesis is supported by the uniform rise in right ventricular systolic pressure after the inhalation of amyl nitrite by patients with pulmonary stenosis, ~ and is in accord with the small but significant increases in both systolic and mean pulmonary arterial pressures after the administration of amyl nitrite in this study (Fig. 2, Tables I and II). Estimates of nitrite-induced directional changes in pulmonary blood flow in 3 subjects so studied (Fig. 3) suggested that venous

A,,. H ~ t J

~cptember, 1966

return increased roughly in parallel with the augmentation of systemic output. Should an increase in venous return be of the same order as the increment in cardiac output, then the pulmonary vascular resistance would of necessity decline (Table I). However, the magnitude of this decline is far less than the fall in systemic resistance (Table I)? ,8 These data do not indicate whether the lesser circulation dilates passively to accommodate the increase in flow or whether amyl nitrite exerts a direct vasodilatory effect. The drug does appear to act as an active dilator in the vasoconstrictive puhnonary hypertension of large ventricular septal defect, in which the left-to-right shunt provides a pathway for the entry of relatively undiluted nitrite into the pulmonary circulation, n~ Response to the drug in this context may, therefore, relate to the increased concentration of active principle acting upon highly vasoreactive arterioles. n" In the presence of a normal circulation, relatively dilute nitrite enters a less reactive pulmonary bed. Although the drug may still exert a direct effect in normal man, additional passive dilatation remains a plausible consideration with regard to the primary pharmacologic influence on the pulmonary vascular resistance. 4 The small but significant nitrite-induced rise in pulmonary systolic pressure with little or no change in diastolic pressure resulted in a modest increase in pulse pressure (Table 1I). The contour of the pulmonary arterial pulse, including the level of the dicrotic notch, remained unchanged after the inhalation of amyl nitrite in contrast to the nlarked alterations in systemic arterial contour. 8 There was a slight but significant increase in right ventricular systolic pressure, with a 38 per cent decline in diastolic filling pressure (borderline significance) (Table II). Opinion differs with regard to the effect of amyl nitrite upon the systemic venous bed; some authors hold that the drug induces venoconstrietion,~2 whereas others believe that venodilatation occursY In dogs on right heart bypass with fixed systemic outputs, ~4 amyl nitrite induces an initial transient increase in venous return as the systemic arterial pressure begins

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Pulmonary hemodynamic effects of amyl nitrite in normal man

to fall, but subsequently induces a decrease in venous return as the systemic pressure falls maximally. These observations suggest that the initial effect is reflex venoconstriction in response to the fall in systemic arterial pressure, and that the subsequent effect is venodilatation in response to the direct effect of the drug upon the venous bed. In the light of this information it was pertinent that 4 of our subiects showed a small distinct rise in mean pulmonary arterial pressure at the onset of the fall in brachial arterial pressure (Fig. 2). This suggests that in man the inhalation of amyl nitrite may induce an initial increase in venous return due to transient venoconstriction, followed by an additional increase in venous return associated with augmented cardiac output. Effect on ventricular work (Table I). Since amyl nitrite caused only a moderate decline in pulmonary resistance, the mean pulmonary arterial pressure rose slightly in the face of the large increment in flow. Accordingly, right ventricular minute work increased appreciably. Furthermore, the rise in pulmonary mean pressure occurred with a relatively constant stroke volume, so that right ventricular stroke work rose, although to a lesser degree than work per minute. These results were in marked contrast to the effect of amyl nitrite on left ventricular work? The increase in cardiac output was uniformly associated with a fall in systemic arterial pressure that was sufficient to leave left ventricular minute work relatively constant. Since stroke volume changed little, if at all, as systemic pressure fell, left ventricular stroke work regularly and strikingly decreased. Thus, amyl nitrite had opposite effects upon the two ventricles and appeared to be a pharmacologic means of selectively stressing the right heart. Diagnostic implications of the foregoing effects of amyl nitrite. Under the influence of amyl nitrite the gradient and murmur of tricuspid stenosis increase because of augmented flow into the right atrium, together with a shortened diastolic filling period. I~ As the right ventricle is stressed, tricuspid regurgitant flow should increase, and the murmur of tricuspid incompetence should get louder. ~ In pul-

3 43

monary stenosis with intact ventricular septum, 2 the increase in circulatory flow rate and venous return augment both the gradient and the murmur. In patients with mild pulmonary stenosis and nondiagnostic gradients, the inhalation of amyl nitrite may induce a significant difference in right ventricular-pulmonary arterial systolic pressures in a fashion analogous to the effect of the drug in occult obstruction to left ventricular outflow. 6 In cyanosed Fallot's tetralogy,3 the ventricular septal defect permits the right ventricular pressure to fall in parallel with the decline in systemic pressure, so that the right-toleft shunt increases, the pulmonary flow diminishes, and the murmur becomes shorter and softer. Maintenance of pulmonary arterial diastolic pressure in nonvasoreactive pulmonary hypertension should prevent a decrease in the Graham Steell murmur, whereas a uniform fail in systemic diastolic pressure regularly reduces the intensity of the murmur of aortic incompetence. The disproportionate fall in systemic vascular resistance diminishes left-to-right shunts through nonpulmonary hypertensive aortopulmonary or interventricular communications. On the other hand, in the presence of patent ductus with fixed pulmonary hypertension and a balanced shunt, the inhalation of amyl nitrite may cause diagnostic differential cyanosis by selectively decreasing systemic arterial pressure.

Summary Amyl nitrite has assumed a role of considerable importance in clinical auscultation of the heart and in the phonocardiographic and physiologic evaluation of the cardiac patient. The systemic hemodynamic effects of the inhalation of amyl nitrite were recently investigated in this laboratory. The purpose of the present study was to extend these observations to the lesser circulation. Results indicate that the inhalation of amyl nitrite in normal man causes: (1) a marked increase in blood flow which is primarily rate related, (2) a profound decline in total systemic resistance resulting in a decline in left ventricular stroke work, but no change in left ventrieular minute work, (3) a less profound decline in total

344

de Leon and Perlojf

p u l m o n a r y r e s i s t a n c e , (4) a s m a l l b u t sign i f i c a n t rise in p u l m o n a r y a r t e r i a l s y s t o l i c a n d m e a n p r e s s u r e s , a n d (5) a n i n c r e a s e in effective right ventricular ininute and stroke work. Diagnostic implications were b r i e f l y d i s c u s s e d . K n o w l e d g e of t h e c i r c u l a t o r y a c t i o n of t h e d r u g in n o r m a l 1nan s h o u l d e n h a n c e its u s e f u l n e s s in d i s e a s e states. The authors sincerely thank Dr. James A. Ronan, Dr. Peter A. Binnion, and Dr. Turkan Gurel, each of whom participated in one or more of the studies. We also wish to acknowledge the interest and assistance of Rosemary Galsheen, Chief Nurse, Cardiac Diagnostic Laboratory. REFERENCES 1, Barlow, J., and Shillingford, J.: The use of amyl nitrite in differentiating mitral and aortic murmurs, Brit. Heart. J. 20:162, 1958. 2. Vogelpoel, L., and Schrire, V.: Auscultatory and phonocardiographic assessment of pulmonary stenosis with intact ventricular septum, Circulation 11"*=55, 1960. .3. Vogelpoel, L., and Schrire, V.: Auscultatory and phonocardiographic assessment of Fallot's tetralogy, Circulation "*2:73, 1960. 4. Bousvaros, G. A., and Lessof, M. H.: Inhalation of amyl nitrite: A useful test in the assessment of heart murmurs, Guy's Hosp. Rep. 111:1, 1962. 5. Beck, W., Schrire, V., Vogelpoel, 1~., Nellen, M., and Swanepoel, A.: ttemodynamic effects of amyl nitrite and phenylephrine on the norreal hmnan circulation and their relation to changes in cardiac murmur, Am. J. Cardiol. 8:341, 1961. 6. Marcus, F. 1., Perloff, J. K., and de Leon, A. C. :

.4=. H,,.~tJ. Xepternber, 1966

The use of amyl nitrite in the hemodynamic assessnlent of aortic valvular and muscular subaortic stenosis, AM. HI~:a~T J. 68:468, 1964. 7. Brunton, T. 1..: On the use of nitrite of amyl in angina pectoris, Lancet 2:97, 1867. 8. Perloff, J. K., Calvin, J., de Leon, A. C., and Bowen, P.: Systemic hemod3namic effects of amyl nitrite in normal man, Au. HEART J. 66:460, 1963. 9. Milnor, W. P,., and Jose, A. D.: l)istortion of indicator-dilution curves by sampling systems, J. Appl. Physiol. 15=177, 1960. 10. Krantz, J. C., Carr, C. J., and Knapp, M. J.: The effect of nitrites and nitrates on arterial adenosine triphosphatase, J. Pharmacol. & Exper. Therap. 10`*:16, 1951. 11. Honig, C. P,., Tenny, S. M., and Gabel, P. V.: The mechanism of cardiovascular action of nitroglycerin, Am. J. Med. 29=910, 1960. l la. Vogelpoel, L., Schrire, V.- Beck, W., Nellen, M., and Swanepoel, A.: Variations in the response of the systolic murmur to vasoactive drugs ill ventricular septal defect, with special reference to the paradoxical response in large defects with pulmonary hypertension, AM. HEART J. 64:169, 1962. 12. Mason, D. T., and l~lraunwald, E.: Effects of amyi nitrite and nitroglycerin on forearm arterial and venous tone, (Abstract) Clin. Res. 12:433, 1964. 13. Sharpey-Schafer, E. P., and Ginsburg, J.: Humoral agents and venous tone. Effects of catecholamines, 5-hydroxytraptamine, histamine and nitrites, Lancet '1:1337, 1962. 14. Kot, P. A., Croke, R. P., and Pinkerson, A. L.: Effects of amyl nitrite on total vascular volume in the dog. In preparation. 15. Sanders, C. A., Harthorne, J. W., DeSanctis, R. W., and Austen, W. G.: Tricuspid stenosis: A difficult diagnosis in the presence of atrial fibrillatioib Circulation 33:26, 1966.