THERAPY AND PREVENTIONVASODIIATORS

The effect of nitroglycerin on forearm arterialdistensibilityHAROLD SMULYAN, M.D., SAKTI MOOKHERJEE, M.D., AND ROBERT A. WARNER, M.D.

ABSTRACT Nitroglycerin acts, in part, to reduce arterial impedance, and thus left ventricular work.The reduction in arterial impedance is largely attributable to a fall in systemic vascular resistance, butmay also be due to an increased distensibility of the arterial tree. In this study, volume distensibility offorearm arteries was calculated from measurements of pulse-wave velocity before and during intrave-nous nitroglycerin infusion. Since a fall in blood pressure itself increases arterial distensibility, theinduced blood pressure change was controlled as a variable by repeating the measurements with thesubject's forearm in a plastic cylinder and repeating the measurements at a variety of altered cylinderpressures. At every studied pressure, nitroglycerin infusion increased forearm arterial distensibility,demonstrating another way in which nitroglycerin reduces left ventricular afterload. Since the pulsatileportion of cardiac work is approximately 10% of total work, the magnitude of this nitroglycerin effecton cardiac function is probably small.Circulation 73, No. 6, 1264-1269, 1986.

THE SALUTARY EFFECTS of nitroglycerin in pa-tients with angina pectoris are due to the widespreadaction of the drug as a smooth muscle vasodilator. Thisvasodilation operates in the systemic veins to inducepooling, in the arterioles to reduce coronary and sys-temic vascular resistance, and in the epicardial coro-nary arteries where both normal segments and thoseaffected by atherosclerosis are dilated. We reasonedthat nitroglycerin might also increase the distensibilityof peripheral muscular arteries. If this were true, suchan action would reduce the oscillatory component ofarterial impedance and translate into reduced left ven-tricular afterload and left ventricular work. This actionwould be yet another way in which nitroglycerin re-duces myocardial oxygen need and relieves the symp-toms of angina pectoris.

Since nitroglycerin lowers the blood pressure, and alowered blood pressure itself is known to increase arte-rial distensibility, a problem arises in demonstrating aneffect on arterial distensibility by nitroglycerin inde-pendent of its hypotensive effect. In the present study,we calculated arterial distensibility from measure-ments of pulse-wave velocity and controlled forchanges in blood pressure by repeating the pulse-wave

From the Veterans Administration and Upstate Medical Centers,State University of New York, Syracuse, NY.

Supported in part by grants from the Veterans Administration, Wash-ington, D.C.

Address for correspondence: Harold Smulyan, M.D.. Syracuse VAMedical Center, 800 Irving Ave., Syracuse, NY 13210.

Received Aug. 16, 1985: revision accepted Feb. 27, 1986.

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velocity measurements at a variety of transmural arte-rial pressures before and during administration ofnitroglycerin.

MethodsTwenty male patients, 40 to 78 years old (mean 58.5 years),

were studied. Each patient had significant coronary atheroscle-rosis, as evidenced by at least a 50% narrowing of a majorepicardial artery at coronary arteriography ( 14 patients) or elec-trocardiographically proven myocardial infarction (six pa-tients). All patients had symptomatically stable angina pectorisand were receiving individually determined doses of a variety off3-adrenergic-blocking drugs, but none was receiving calciumchannel-blocking agents. Ten patients underwent pulse-wavevelocity studies before and during intravenous infusions of ni-troglycerin, and the remaining 10 control patients were studiedbefore and during intravenous infusion of saline.

In each patient all nitrate therapy was discontinued at least 12hr before the beginning of the study. In the experimental group.nitroglycerin was administered intravenously with a calibratedHarvard infusion pump. The infusate was prepared with a nitro-glycerin concentration of 140 ug/ml and the infusion was start-ed at a rate of 50 1.g/min. Cuff blood pressures were measuredin the left arm with an Arteriosonde device every 2 min and theinfusion rate was increased every 6 min until the systolic arterialpressure had fallen at least 10 mm Hg. This rate of infusion wasthen maintained throughout the remainder of the study. Theaverage time to reach the effective infusion rate was 22.5 + 6.5min. Mean infusion rate was 89.5 jig/min, with a range of 50 to200 jug/min. The 10 control patients received a similar intrave-nous volume of normal saline for 20 min in place ofnitroglycerin.

Initially, the blood pressure was measured in both arms by thestandard cuff method to exclude previously undetected arterialobstruction in either arm. Pixie strain gauges, imbedded inplastic (Endevco Corporation, San Juan Capistrano, CA), wereplaced over the right brachial and right radial artery of each

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THERAPY AND PREVENTION-VASODILATORS

patient and held in place with soft elastic bands. Each gauge wasone arm of a Wheatstone Bridge, the balanced bridge outputswere amplified (model VR6, Electronics for Medicine), and theradial dilation waves of both gauges were displayed on an oscil-loscope. The gauge positions were then adjusted until undistort-ed pulse waves were observed. These pulses were then recordedon ultraviolet sensitive paper (Honeywell Visicorder, model1508) at a speed of 250 mm/sec. The moment of pulse arrivalwas arbitrarily chosen as a point on the upstroke of the brachialand radial pulse that was 10% of the maximum pulse amplitude.The time interval between these two points was measured withthe use of the inscribed time lines as a reference (figure 1). Thisinter/al was measured on 8 beats and the mean of these valueswas designated the pulse transmission time. With the use of thedistance between the strain gauges, the pulse-wave velocitybetween the two arterial loci was calculated. The pulse-wavevelocity (PWV) was then converted to volume distensibility(VD) with a modification of the Bramwell-Hill equation':

VD = (3.57/PWV)2

The frequency response of the Pixie strain gauges has beenstudied previously and an average 5% loss of signal amplitude atfrequencies up to 20 cycles/sec has been found. These gaugeshave also been found to be linear from zero force to gaugefracture .2

With the gauges in place, the supinated arm of each subject,with elbow and wrist extended, was placed in a large plasticcylinder. The cylinder was closed at the distal end and boundproximally to the upper arm with a soft rubber sleeve. Thesleeve was encircled with a blood pressure cuff and the cuff wasinflated, during pulse-wave recordings, to pressures just higherthan those within the cylinder. This arrangement produced onlyslight compression by the inflated cuff on the upper arm, butminimized air leak from within the cylinder. The cylinder pres-sures were varied in 10 mm Hg increments from 0 to + 50 mmHg. Satisfactory records could not be reliably obtained at cylin-der pressures higher than 50 mm Hg because of pulse distortionthat probably resulted from intermittent arterial collapse. Sincenitroglycerin lowered the arterial blood pressure, one set ofpulse-wave velocity measurements was made during drug infu-sion in each patient at a negative cylinder pressure of 10 mm Hg.This served to raise the transmural pressure and to match the

CONTROL GROXPATIENT F.C.

B.P.

MEAN B.P.

CYLINDERPRESSURE

TRANSMURALPRESSURE

TRANSMISSIONTIME

DISTANCE

PULSE WAVEVE LOCITY

+

transmural pressure before administration of nitroglycerin. Cyl-inder pressures, both positive and negative, were varied with anindustrial vacuum cleaner and an adjustable leak and monitoredwith a mercury U tube. In previous studies using this technique,a full range of negative cylinder pressures was also em-ployed.23 Pressures more negative than minus 10 mm Hg werenot used in this study to shorten study duration and minimize thediscomfort of the patient resulting from maintaining a constantarm position within the cylinder for long periods of time. Sincethe relationship between volume distensibility and transmuralarterial pressures is curvilinear (see below), the differences be-tween volume distensibility before and during infusion of nitro-glycerin should be small at negative cylinder (high transmural)pressures.

Altered cylinder pressures were maintained for 30 to 60 secbefore pulse waves were recorded and ambient pressures werereestablished for several minutes between runs. At the conclu-sion of each study, the gauges were removed and a strip ofadherent paper tape was placed over the forearm running be-tween the two gauge positions. The location of the skin indenta-tions from the metal gauge extension was marked on the tapeand the tape was removed. This strip was then placed on a flatsurface and the distance between the marks was measured.

Blood pressure was measured with the Arteriosonde device inthe opposite arm during the recording of arterial pulses at eachcylinder pressure. The transmural arterial pressure was calculat-ed for each run by adding or subtracting the cylinder pressurefrom the mean arterial pressure (mean arterial pressure = dia-stolic pressure + pulse pressure/3). Plots were then constructedfor pulse-wave velocity and calculated volume distensibility vstransmural pressure for each patient before and during infusion.The relationship between transmural pressure and volume dis-tensibility was curvilinear (figure 2), but that between trans-

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FIGURE 1. Technique for pulse-wave velocity measurement. The bra-chial and radial artery pulses are exact tracings from the original record.Pulse arrival time is a point on the upstroke that is 10% of the pulseamplitude. The pulse transmission time is the interval between brachialand radial arrival times. Paper speed is calibrated, but time lines are

omitted from the reproduction. See text for details.

Vol. 73, No. 6, June 1986

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-0.1 - Fourteen coronary arteriograms, seven in each group,were reviewed and the average number of coronary

-0.2 arteries significantly affected by atherosclerosis werePt. D.C. also similar in both groups. No significant differences

-0.3 L *CONTROL were found between the two groups in any of the base-\ y = -00145 x + 0.54 line volume distensibility measurements or calculated

values.-0.4 r\ The relationship of transmural pressure to volume

distensibility over the range of transmural pressures-0.5 - used in this study was curvilinear. This is illustrated by

the results from a single patient in figure 2. When log

-0.6 - volume distensibility was plotted against transmuralpressure, however, the relationship became linear (fig-

\0.7 ure 3), and could be represented by a regression line bythe method of least squares. The equation for such alinear relationship could then be applied to calculate

-0,8 - the volume distensibility for any selected transmuralpressure within the experimental range.

-0.9 - Figure 4 illustrates the similarity and reproducibilityof the log volume distensibility vs transmural pressure

-I., relationships for the same patient before and during40 50 60 70 80 90 100 control infusion of saline. For the entire control group,

there was no significant change in volume distensi-bility at any transmural pressure from 40 through 100

URE 3. Plot of calculated log volume distensibility vs transmural mm Hg during the infusion of saline. The slopes of thearteriai pressure in a single patient octore salineintusion.

mural pressure vs log volume distensibility over the range oftransmural pressures in this study was linear (figures 3 and 4).Linear regression was calculated for each plot with the methodof least squares, thus permitting the calculation of pulse-wavevelocity, log volume distensibility, and volume distensibility atany given pressure for each patient. The entire technic for mea-suring pulse-wave velocity has been described in greater detailpreviously.2 3

The pulse-wave velocity has been shown to predict satisfacto-rily the arterial distensibility measured by independent directmethods.4-7 However, calculated volume distensibility cannotdistinguish between the active or static properties of arterial wallbehavior. Use of the cylinder to provide variations in transmuralarterial pressure requires the assumption that cylinder pressuresare transmitted faithfully to the arterial wall. Previous studiestesting this assumption have shown that the transmission ofincreased or decreased air pressure is satisfactory.8 9 Since eachpatient served as his own control, individual differences inblood viscosity from patient to patient should have had littleeffect on the results. Velocity of blood flow adds to the pulse-wave velocity, but flow velocity is small when compared withthe velocity of pressure pulse travel.

Data were analyzed by use of the paired t test, and Student's ttest for group data.The study was approved by the human experimentation com-

mittee of the medical center, and each patient gave informedconsent.

Results

The control and experimental groups were similarwith regard to age, blood pressure, heart rate, and theprevalence of diabetes and myocardial infarction.

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CIRCULATION

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THERAPY AND PREVENTION-VASODILATORS

EFFECTS OF I.V NITROGLYCERINE

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TABLE 1BEffect of nitroglycerin vs saline on arterial volume distensibility

TMP VD (%A volume/mm Hg) p value(mm Hg) Control Saline (paired t test)

40 0.80±0.10 0.73+0.069 NS60 0.38+0.047 0.37+0.031 NS90 0.13+0.021 0.14+0.013 NS

Control Nitroglycerin

40 0.76 + 0.11 1.54-+ 0.22 <.00560 0.38 + 0.05 0.68 0.10 < .00190 0.14±0.014 0.20 0.030 <.01

Values are mean ± SE.VD = volume distensibility; other abbreviations as in table IA.

regression lines relating these two variables were alsounchanged.The infusion of saline also produced no significant

change in heart rate or systolic, diastolic, or meanblood pressure (figure 5). Figure 5 also illustrates thatnitroglycerin infusion significantly reduced systolicand mean blood pressure but had no effect on diastolicblood pressure or heart rate. Tables lA and lB displaythe volume distensibility and pulse-wave velocity datafrom the control and nitroglycerin groups for represen-tative transmural pressures of 40, 60, and 90 mm Hg.At these illustrative transmural pressures, nitroglycer-in significantly increased volume distensibility whenpatients served as their own controls or when the re-sponse to nitroglycerin was compared with that to sa-line. The effect of nitroglycerin on volume distensi-bility over the full range of transmural pressures can beseen in figure 6, and the effects of nitroglycerin on thelog volume distensibility vs transmural pressure rela-tionship are illustrated in figure 7. The slope of theregression line before and after nitroglycerin was notsignificantly different.

TABLE 1AEffect of nitroglycerin vs saline on pulse-wave velocity

PWV (ml/sec)TMP p value

(mm Hg) Control Saline (paired t test)

40 4.19+0.41 4.14+0.33 NS

60 6.57 0.53 6.34 0.40 NS

90 10.14+0.73 9.64+0.55 NS

Control Nitroglycerin

40 4.06 + 0.53 2.74 + 0.24 <.025

60 6.35+0.42 4.97+0.33 <.001

90 9.81±0.52 8.32+0.54 <.001

Values are mean ± SE.PWV = pulse-wave velocity; TMP = transmural pressure.

Vol. 73, No. 6, June 1986

DiscussionThe difficulty in understanding the mechanism of

nitroglycerin action in patients with angina pectorisarises from the multiplicity of demonstrated pharma-cologic effects and the lack of information regardingthe precise role played by each.10 Nitroglycerin pro-duces both its peripheral vascular and secondary cardi-ac effects by relaxing smooth muscle through the acti-vation of guanylate cyclase and the resultant increasein the levels of cyclic guanosine monophosphate."1This relaxation operates in the smooth muscle of arteri-oles, venules, and systemic veins and in the epicardialcoronary arteries.'2' 13 The mid-sized systemic arteriesare muscular in nature and thus susceptible to nitro-glycerin action, but there has been little study of theeffects of nitroglycerin on arterial distensibility. Si-

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FIGURE 6. Plot of calculated volume distensibility vs transmural arte-

rial pressure before and during nitroglycerin infusion for the entiregroup.

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SMULYAN et al.

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3 ~~~~~x-- xN1TROGLYCERINE2 I STD ERROR measurements are difficult to obtain in vivo. Since

volume distensibility can be calculated from the nonin-vasive measurements of pulse-wave velocity withoutexplicit knowledge of arterial geometry, volume dis-tensibility has been frequently used to assess arterial

a % stiffness in noninvasive studies in vivo.

In the present study, the infusion of nitroglycerinreduced the mean arterial blood pressure from 90 to 85mm Hg. Without nitroglycerin, this reduction in bloodpressure alone would induce an increase in volume

7 KX distensibility of 15%. The same reduction in bloodpressure induced by nitroglycerin increased volumedistensibility by 69%. It is well understood that disten-

030 40 50 60 70 80 90 100 sible arteries present less opposition to left ventricular

TRANSMURAL PRESSURE (mmHg) ejection than do stiff ones. However, the changes involume distensibility demonstrated here are difficult to

[E 7. Plot of calculated log volume distensibility vs transmural relate quantitatively to the reduction in left ventricularpressure before and during nitroglycerin infusion for the entire work.

Total left ventricular work can be divided into twomajor parts. The first is that portion of cardiac effort

.t al.,"4 using a pulsed Doppler technique with a that drives the blood steadily through the peripherale transducer probe, have shown an increase in the resistance and is usually calculated as the product ofter of the brachial artery during the infusion of mean blood pressure and mean flow. The second is the,lycerin. These authors also used the diastolic ventricular work that drives no blood, but is spent inn of the brachial arterial pressure curve and the making the system pulsatile. Under basal conditionsnic vascular resistance, calculated from blood this pulsatile component is approximately 10% of theire and cardiac output measurements, to demon- total ventricular work'5 and is determined largely byan increase in arterial compliance. Although in the distensibility of the arterial tree. Measurement ofment with the results of the present study, some arterial impedance offers a means for assessing thatincreased arterial compliance demonstrated by portion of the total opposition to left ventricular ejec-

n et al. could have been due to the fall in blood tion that is due to the stiffness of the arterial tree. Totalire itself. In that study, nitroglycerin was admin- arterial impedance is frequency dependent. At zerod in a lower dose, which reduced the systolic but frequency, the impedance is due to "steady flow" ande mean or diastolic pressure. In the present inves- is equal to the systemic vascular resistance. Corre-n, both systolic and mean blood pressures were spondingly smaller is the input impedance from pul-ed, with no significant change in heart rate. This sations, which represents the opposition to left ven-bly was due to the concomitant use of,3-adrener- tricular ejection at higher frequencies. This inputlocking agents in our patients. Nitroglycerin, impedance is determined by several factors, includingver, increased forearm arterial distensibility at reflected waves, pulse-wave velocity, and arterial dis-studied transmural pressure. tensibility. Averaging the higher frequency impe-

;erial stiffness may be characterized by two quan- dances yields the "characteristic impedance," which is- volume distensibility and the modulus of elas- determined largely by arterial distensibility. Pulse-(Young's modulus). Volume distensibility mea- wave velocity is directly related to characteristic arteri-the percentage change in volume of an arterial al impedance'6 when the latter is expressed in terms of-nt resulting from a unit change in distending linear flow velocity (dyne-sec.cm-3) rather than inire and is therefore independent of arterial di- terms of the more familiar volume flow (dyne.sec.r. The elastic modulus, on the other hand, is a cm-5). Although our measurements of pulse-waveire of the stress-strain relationship for the blood velocity can be used to calculate characteristic im-wall and quantifies its behavior when it is de- pedance of the forearm arteries, the aortic input im-

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THERAPY AND PREVENTION-VASODILATORS

pedance and systemic vascular resistance were notmeasured.

Calculation of characteristic impedances of the bra-chial artery from our pulse-wave velocity data showedthat a reduction in mean blood pressure from 90 to 85mm Hg without nitroglycerin would reduce character-istic impedance by 5.8%, while the same reduction dueto nitroglycerin lowered characteristic impedance by21%. Larger doses of nitroglycerin might, of course,have a larger effect. Since the influence of the charac-teristic impedance of the brachial artery on the aorticinput impedance is unknown in these patients and sincethe portion of the arterial tree that behaves like theforearm arteries is also unknown, any further attemptto quantify the reduction in left ventricular work bythis mechanism would be largely speculative.The only other agent that is similar to nitroglycerin

whose effects on arterial stiffness have been studied isnitroprusside, and these results have been conflicting.Pepine et al.17 reported a reduction in characteristicaortic impedance during the infusion of nitroprussidein patients with cardiomyopathy and congestive heartfailure. This reduction was sustained in three patientseven when their blood pressures were restored to base-line levels by phenylephrine. These results could notbe confirmed in the aorta by Yin et al.,"' who did,however, find a reduction of characteristic impedancein the pulmonary artery. In patients with angina pec-toris but no heart failure, Gundel et al.'9 also reportedno significant change in aortic input impedance duringthe infusion of nitroprusside. There are obvious differ-ences between these studies and the present one. Nitro-glycerin and nitroprusside may differ in their effects onarterial smooth muscle. Measurements of aortic inputimpedance may be more sensitive to changes in theproximal aortic wall, where there is less smooth mus-cle, than to changes in the more muscular peripheralarteries. Finally, there have been no studies of effectsof nitroglycerin on aortic input impedance or of nitro-prusside on the distensibility of peripheral arteries.

The reduced arterial stiffness demonstrated in thisstudy resulted from brief infusions of nitroglycerin andmay not be applicable to longer acting forms of nitratetherapy. However brief, any increase in arterial disten-sibility should reduce the pulsatile component of arte-rial impedance and thus reduce left ventricular work.Such an effect could conceivably occur with or evenwithout a concomitant reduction in systemic vascular

resistance. It remains uncertain, however, whether thechanges in arterial distensibility are of sufficient mag-nitude to play a significant role in the relief of anginapectoris or in improvement in patients with congestiveheart failure.

We thank Mr. Edwin Jordan for painstaking and meticuloustechnical work and Thomas J. Csermely, Ph.D., Associate Pro-fessor of Electrical and Computer Engineering, Syracuse Uni-versity, for manuscript review.

References1 Bramwell JC, Hill AV: The velocity of the pulse wave in man. Proc

R Soc Lond (Biol) 93: 298, 19222. Smulyan H, Csermely TJ, Mookherjee S. Warner RA: Effect of

age on arterial distensibility in asymptomatic humans. Arterioscle-rosis 3: 199, 1983

3. Smulyan H, Vardan S, Griffiths A, Gribbin B: Forearm arterialdistensibility in systolic hypertension. J Am Coll Cardiol 3: 387,1984

4. Arndt JO, Klauske J, Mersch F: The diameter of the intact carotidartery in man and its change with pulse pressure. Pflugers Arch301: 230, 1968

5. Gow BS, Taylor MG: Measurement of viscoelastic properties ofarteries in the living dog. Circ Res 23: 111, 1968

6. Patel DJ, Janicki JS, Carew TE: Static anisotropic elastic propertiesof the aorta in living dogs. Circ Res 25: 765, 1969

7. Greenwald SE, Newman DL, Bowden NLR: Comparison betweentheoretical and directly measured pulse propagation velocities inthe aorta of the anaestheti7ed dog. Cardiovasc Res 12: 407, 1978

8. Ludbrook J, Collins GM: Venous occlusion pressure plethysmog-raphy in the human upper limb. Circ Res 21: 139, 1967

9. Caro CG, Foley TH, Sudlow MF: Early effects of abrupt reductionof local pressure on the forearm and its circulation. J Physiol(London) 194: 645, 1968

10. McGregor M: Pathogenesis of angina pectoris and role of nitrates inrelief of myocardial ischemia. Am J Med 74(suppl): 21, 1983

11. Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL,Kadowitz PJ, Gruetter CA: Mechanism of vascular smooth musclerelaxation by organic nitrates, nitrites, nitroprusside and nitric ox-ide: evidence for the involvement of S-nitrosothiols as active inter-mediates. J Pharmacol Exp Ther 218: 739, 1981

12. McGregor M: Nitrates and myocardial ischemia. Circulation 66:689, 1982

13. Feldman RL, Pepine CJ, Conti CR: Magnitude of dilation of largeand small coronary arteries by nitroglycerin. Circulation 64: 324,1981

14. Simon ACH, Levenson JA, Levy BY, Bouthier JE, Peronneau PP,Safar ME: Effect of nitroglycerin on peripheral large arteries inhypertension. Br J Clin Pharmacol 14: 241, 1982

15. O'Rourke MF: Steady and pulsatile energy losses in the systemiccirculation under normal conditions and in simulated arterial dis-ease. Cardiovasc Res 1: 313, 1967

16. O'Rourke MF: Arterial function in health and disease. New York,1982, Churchill Livingstone, p 117

17. Pepine CJ, Nichols WW, Curry RC Jr, Conti CR: Aortic inputimpedance during nitroprusside infusion. J Clin Invest 64: 643,1979

18. Yin FCP, Guzman PA, Brin KP, Maughan WL, Brinker JA, TraillTA, Weiss JL, Weisfeldt ML: Effect of nitroprusside on hydraulicvascular loads on the right and left ventricle of patients with heartfailure. Circulation 67: 1330, 1983

19. Gundel W, Cherry G, Rajagopalan B, Tan L-B, Lee G, Schultz D:Aortic input impedance in man: acute response to vasodilatordrugs. Circulation 63: 1305, 1981

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H Smulyan, S Mookherjee and R A WarnerThe effect of nitroglycerin on forearm arterial distensibility.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1986 American Heart Association, Inc. All rights reserved.

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