Vascular reactivity in patients with peripheral vascular disease

1. Yang SS, Bentigvoglio LG, Mamnhao V, Goldberg H. From Cardiac Catheterization Data to Hemodynamic Parameters. Philadelphia: FA Davis, 1988:42-66. 2. Flamm MD, Cohn KE, Hancock EW. Measurement of systemic cardiac output at rest and exercise in patient with atrial septal defect. AmJ Cardiol1969;23:258-265. 3. Antman EM, Marsh JD, Green LH, Grossman W. Blood oxygen measurements in the assessment of intracardiac left to right shunts: a critical appraisal of methodology. Am J Cardiol1980;46:265-271. 4. Dexter L, Haynes FW, Burwell CS, Eppinger EC, Sagerson RP, Evans JM. Stadies of congenital heart disease. II. The pressure and oxygen content of blood in the right auricle, right ventricle, and pulmonary artery in control patients with observations on the oxygen saturation and source of pulmonary “capillary” blood. .I Clin Invest 1947;26:554-560. 5. Barrat-Boyes BG, Wood EH. The oxygen saturation of blood in the vena cavae, right-heart chambers, and pulmonary vessels of healthy subjects. J Lab Clin Med 1957;50:93-106. 6. Freed MD, Miettinen 0, Nadas AS. Oximetric detection of intracardiac left-toright shunts. Br Heart J 1979;42:69&694.

7. Jain KK, Wagner HR, Lambert EC. Comparison of oxygen saturation of blood in azygous vein and superior vena cava. Circulation 1970;41:55-58. 8. Lock JE. Hemodynamic evaluation of congenital heart disease. In: Lock JE, Keane JF, Fellows KE, eds. Diagnostic and Interventional Catheterization in Congenital Heart Disease. Boston: Martinus Nijhoff, 1987:47-57. 9. Gutgesell HP, Williams RL. Caval samples as indicators of mixed venous oxygen saturation: implications in atrial septal defect Cardiovasc Dis Ta Heart Insf 1974;1:16&164. 10. Performance characteristics. In: 2500 Co-oximeter Instruction Manual. Comin; Glass Works, 1983: Rev A 7/83:41. 11. Haycock GB,Schwartz GJ, Wisotsky DH. Geometric method for measuring Holly wface area: a height-weight formula validated in infants, children and adults. J Pediatr 1978;93:62-4%. 12, Lucas RV, Krabill KA. Anomalous venous connections, pulmonary and syswnlc. In: Adams FH, Emmanouilidees GC, Riemenschneider TA, eds. Moss’ Heart Xsease in Infants, Children, and Adults. Baltimore: Williams & Wilkins, 1989: L.X!1 hi7. -. __. -

Vascular Reactivity 4n Patients With Peripheral Vascular Disease Nancy

Linda M. Harris, MD, Gian Luca Faggioli, MD, Rasesh Shah, MD, Koerner, RN, RVT, Linda Liks, RN, Paresh Dandona, PhD, Joseph L. Izzo, Brian Snyder, MD, and John J. Ricotta, MD

large body of recent data implicates impaired vasoreactivity as a marker of vessel abnormality due to A endothelial dysfunction. 1-4 Signs of altered vasoreactivity may be early indicators of abnormalities that eventually contribute to clinical atherosclerosis. Decreased reactivity in clinically uninvolved vessels may therefore represent an early stage of clinical atherosclerosis. Patients with coronary artery disease have abnormal vasodilation of clinically involved vessels.5 Abnormal vascular reactivity has also been demonstrated in patients with known risk factors for atherosclerosis: smokers, diabetics, hypertensives, and hyperlipidemics.3,“10 Data on vascular reactivity of clinically uninvolved vessels in patients with stigmata of peripheral vascular disease (PVD) have not been available. We utilized the noninvasive duplex ultrasonography examination of the brachial artery to compare patients with PVD with normal controls to determine if there are significant differences in vasoreactivity in clinically unaffected vessels between these 2 groups. . . . Fifty-one subjects, aged 20 to 90 years, were studied. Patients were divided into 2 major categories: controls including young normals (group 1) and age-matched controls (group 2), and patients with PVD, including patients with claudication, peripheral bypass surgery, or amputation (group 3). Twenty-six normal, healthy volunteers without signs or symptoms of PVD served as the control group. The study was approved by the institutional review committee before performance. All subjects abstained from alcohol, caffeine, and cigarettes for >8 hours before the study. A 7.5 MHz linear array transducer and a standard Acuson 128 system were utilized for the noninvasive From the Section of Vascular Surgery, Department of Surgery, State University of New York at Buffalo, and the Department of Medicine, State University of New York at Buffalo, 3 Gates Circle, Buffalo, New York 14209.

MD,

evaluation of the nondominant brachial artery. The target artery was scanned in the antecubital fossa in a longitudinal fashion using the B-mode image. Depth and gain settings were set to optimize images of the lumen and arterial wall interface. The subject was tested after 10 to 30 minutes at rest, at which time a normal triphasic waveform was obtained. In all patients, 2 baseline determinations of arterial diameter and volumetric flow rates were obtained and averaged. Duplex ultrasonography was utilized to obtain baseline measurements of arterial diameter and volumetric flow rate in the brachial artery. After baseline measurements were confumed, a blood pressure cuff was insufflated to 40 mm Hg above the patient’s systolic pressure for a 5minute time period. Arterial occlusion was verified in all cases by lack of flow on color duplex and Doppler. Measurements of arterial diameter were obtained during proximal occlusion after 3 minutes of ischemia. Arterial diameter during ischemia was evaluated to obtain the intrinsic basal tone of the vessel. After 5 minutes, the cuff was released and volumetric flow and arterial diameter were measured immediately. The measurements were then repeated at 5minute intervals until arterial diameter returned to baseline. Measurements of arterial diameter during ischemia were interpreted to reflect intrinsic vasomotor tone (nondistended), whereas measurements after hyperemia were considered to reflect maximal vasodilatory capacity. The average of the 2 baseline arterial diameter measurements was utilized for statistical analysis. Arterial diameter corrected for body surface area (BSA) was utilized to compare baseline arterial diameters between patient groups, to predict disease state, and for percent change from baseline to hyperemia. BSA was calculated with the formula: BSA = 4Weight (kg) X Height (cm)/3,600. Data are expressed as percent change frolm baseline using the formula % change = (baseline - hyperemia or ischemia)/baseline X 100. Volumetric flow rate was calculated with the formula: volumetric flow rate = (arterial diameter)2 X 47.1 X time to mean velocity. BRIEF

REPORTS

207

Maximal percent change in volumetric flow rate was then calculated as previously described. Descriptive statistics are expressed as mean + SD. Differences between groups were evaluated by analysis of variance with the modified Tukey test to identify the signficant subgroups. Statistical significance was taken at the 95% confidence level (p ~0.05). All statistical analyses were performed with the statistical package for the social sciences computer program. . . . Mean age was not significantly different in groups 2 and 3. Mean age for groups 1,2, and 3 were 30.67,70.36, and 64.31 years, respectively. There were 13 women and 13 men in the control groups (group 1, 6 women and 9 men; group 2,7 women and 4 men), and 9 women and 16 men in the diseased group (group 3). No statistically significant differences in vasodilation or vasoconstriction were detected between men and women. Thirteen percent of group 1 patients were hypercholesterolemic. Hypertension was present in 27% of group 2 subjects. No other medical problems were present in control patients. Patients with PVD had hypertension (32%), hyperlipidemia (16%), and diabetes mellitus (60%). Overall, no associated diseases were present in 80.7% of control subjects (n = 21), and in 36% of patients (n = 9) with PVD.

Baseline arterial diameter, both absolute and corrected for BSA, was independent of age but increased significantly with PVD (p = 0.02) (Figure 1). Baseline values corrected for BSA area are listed in Table I. Statistical significance for baseline arterial diameter was unchanged when corrected for BSA. The average BSA was not significantly different between groups: group 1, 1.86 f 0.17; group 2, 1.91 + 0.25; and group 3, 1.92 + 0.25. Intra- and interobserver variability for baseline arterial diameter was SO.2 mm (5%). Intrinsic arterial tone was determined by measuring the change in arterial diameter from baseline to occlusion. No vessels were noted to have atherosclerotic plaques by duplex ultrasound. Also, there was no evidence of proximal occlusive disease in the arms. The degree of vasoconstriction (i.e., resting arterial tone) was significantly greater at the p
FIGURE 1. Arterial diameters (baseline): Average baseline arterial diameter of the

OLD

had arteries that were significant) larger than all o tit er subjects. *p co.02.

PVD

NdRMALS

3.9

4.4

GROUPS

.. 1”

II

YOUNG

NORMALS

OLD

vascular disease ( both those with claudi: cation and patients with severe peripheral vascular disease demonstrated less vasoconstriction than controls. This m be a reflection of %Iecreased vasomotor tone in these subjeck. *p cO.OOOOO1.

NdRMALS

29.2

46.5

GROUPS 208

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FIGURE 2. Changes in arterial diameter (baseline to ischemia): Mean

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TABLE I Changes

in Arterial

Diameter

Age (yd Group 1 (n = 15) 2 (n = 11) 3 (n = 14) F ratio F prob. (p value)

With

Baseline

30.67 70.36 64.3 1

3.94 3.92 4.38

Tukey*

lschemia

AD

f 0.5 T 0.69 zt 0.65 4 0.02

Group

3

and

1

Hyperemia

Baseline AD (BSAcorrected)

2.12 2.03 2.32

% Change AD (baseline ischemia)

f 0.2 * 0.40 + 0.34 4 0.02

Group

46.54 29.16 15.31

f 18.5 f 15.4 * 5.7 24.1 0.0001

3

Group

3

% Change AD [baseline hyperemia)

% Change (VFW

18.79 19.33 10.03

f 6.02 * 11.15 f 4.54 7.91 0.000 1

Group

849.43 f 315 640.89 f 363 504.25 + 217 4.25 0.0093

3

Group

1

*Tukey test reflects the group or groups that were significantly different. Values are expressed as mecm * SD. AD = arterial diameter; BSA = body surface area; prob. = probability; VFR = volumeh-ic flow rate.

with PVD (p
FIGURE 3. Changes in arterial diameter (baseline to hyperemia): Mean percent change in arterial diameter for each group from Baseline measurement to immediately after release of the occluding cuff is depicted. patients with claudication and those with severe peripheral vascular disease (PVD) had markedly less vasodilation than controls. ‘p
YOUNG

that in both young and old controls. This is seen in both the percent change in arterial diameter with constrictialn and dilation (Figures 3 and 4; p
NORMALS

OLD

18.8

NORMALS

19.3

PVD

10.0

GROUPS r

% Change

Arterial

Diameter

120 FIGURE 4. VasoreactivBy (percent change from ischemia to hyperemic arterial diameter): Average percent change in vessel size from ischemia

100 80

. . . .._.___----_-_-________

60 2 h~i$$??s percent change in diameter is markedly diminished in patients with peripheral vascular disease (WD) than in controls. ‘p cO.OCtO1.

___..* ._.._____---

40

20 0

Young Control

Old Control

PVD

BRIEF REPORTS

209

significant difference between age-matched controls (group 2) and patients with PVD. There was a trend toward decreasing volumetric flow rate with severity of disease among age-matched subjects, but this was not statistically significant. Based on the changes identified, a profile of abnormal reactivity was developed to identify patients with PVD. Factors considered were baseline arterial diameter >2.15 when adjusted for BSA, vasoconstriction with ischemia <25%, change with hyperemia <15%, and an increase in volumetric flow rate ~600% during hyperemia. When these criteria were retrospectively applied to study patients, the sensitivity was 94% and the specificity was 74% in predicting the presence of vascular disease (group 3) versus the absence of disease (group 1 or 2). Interestingly, a few young persons displayed reactivity consistent with those of disease. .. . Experimental evidence suggests that abnormal vasoreactivity precedes the development of clinically apparent atherosclerosis.” One manifestation of endothelial dysfunction is altered vasoreactivity. Early endothelial cell dysfunction, manifested by altered vasoreactivity, may be a marker for the development of later vascular disease. Alternatively, risk factors for atherosclerosis may independently produce alterations in endothelial cell function that manifest as abnormal vasoreactivity. Morphologic changes in clinically affected arteries do not appear to be the sole cause of aberrant vasoreactivity. In vitro animal studies implicate a cellular abnormality. Dietary modifications lowering cholesterol levels in hyperlipemic monkeys were found to have a beneficial effect on ring segment vasorelaxation in studies by 6

5-

*

4$ %i E d

3-

I b 2 2-

1 -

0

1 Young

I Control

Old

I Control

I PVD

Group FIGURE 5. Brachial (PVD) experienced stimuli. ‘p <0.002. 210

artety vasoreactivity. Patients with peri heral a diminished vasomotor response to isc R emit

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Harrison et a1,12and in hyperlipemic pigs by Shimokawa and Vanhoutte.13 In vivo and in vitro animal studies showed impaired relaxation to acetylcholine and other endothelial-dependent substances in atherosclerotic animals that was reversible with dietary modification.12 The effects of impaired vasodilation were normalized by lovastatin administration. Hypercholesterolemia has also been implicated in impaired vasodilation in resistance vessels without clinical evidence of atherosclerotic lesions in studies by Osborne et al9 on New Zealand rabbits. Contrary to most current hypotheses, Minor et all4 found that the vessels from hypercholesterolemic or atherosclerotic animals actually produced markedly increased levels of nitric oxide, a vasodilatory substance. However, the effluent from these vessels produced a paradoxic vasoconstriction. Further, the vessels from diseased animals responded with a greater increase in nitric oxide levels than normal vessels to nitric oxide agonists. This suggests an actual up-regulation of nitric oxide synthesis in diseased states. The impairment in vasodilation seen in these studies14 has been suggested to be secondary to accelerated degradation. In human studies, Celermajer et al4 found a marked decrease in flow-mediated vasodilation in response to an ischemic stimulus in smokers, children with familial hypercholesterolemia, and patients with coronary artery disease. He proposed an endothelial-dependent defect based on a normal observed vasodilatory response to glyceryl trinitrate, a direct-acting smooth muscle vasodilator. Hypertensive patients have also been shown to have decreased vasoreactivity in studies by Panza et al.1° Studies of diabetics with peripheral neuropathy also show diminished hyperemic response that appears to be related to the duration of disease.15 Decreased vasorelaxation has also been identified in diabetics without clinical sequelae of PVD, in the lower extremity vessels; this was directly correlated to the duration of the disease.15 Decreased vasodilitation with hypercholesterolemia has also been identified and related to both smooth muscle and endothelial cell dysfunctions with in vitro studies of atherosclerotic vessels.16 Current hypotheses suggest that endothelial dysfunction may impair vasodilation by affecting the release of endothelium-derived relaxing factor. l7 Clinically normal vessels may indeed be morphologically diseased to a degree not detectable clinically. Prior to clinically evident disease, microscopic changes preceding atherosclerosis are present in children. Fatty streaks and preatheromatous lesions have been identified on postmortem examination in 65% of teenagers.12 In addition to endothelial cell dysfunction, data by Sjolund et alI* suggest that smooth muscle cell abnormalities vascular disease may play a role in impaired response and hyperemic to vasoactive stimulation. The smooth JULY 15,

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muscle cell was found to change from a contractile to a reactivity, which we believe reflects abnormalities in vassynthetic phenotype in areas of atherosclerosis.‘” cular function. Our data indicate that a specific pattern of vascular Our data show that postischemic vasodilation after hyperemia is significantly diminished in patients with reactivity (i.e., increased baseline arterial diameter, PVD, even in clinically normal vessels despite no sig- decreased constriction with ischemia, and reduced response to hyperemia) is characteristic of patients with nificant difference in flow between diseased populations and age-matched controls. The deficiency in Aow-mediatherosclerosis. These data also raise the possibility that this pattern may be useful in identifying patients at risk ated vasodilation cannot be accounted for by smaller increases in actual flow, since the upper extremity ves- for PVD, although this remains to be tested prospecsels of patients with PVD contained no occlusive lesions. tively. There were several young persons identified Ischemia is a potent vasodilatory stimulus for large ves- whose profiles seemed more consistent with those of subsels. In the absence of proximal flow-limiting lesions, it jects with PVD. At this time, we are unable to identify should reflect the maximal vasodilatory capacity of the whether these persons are at increased risk for developresistance vessels. Although a mild decrease in reactiv- ing atherosclerotic lesions. However, the hypothesis that ity appeared to occur with age in our patients, this was abnormal reactivity may be used to predict patients at not statistically significant. Other changes in the endothe- risk for atherosclerosis is an intriguing one. Finally, this lial functions related to secretory activity and perme- method might also prove worthwhile in prospectively ability have been shown to occur in the vasculature of evaluating patients’ responses to various medications the forearm in patients with PVD. Ongoing research in and other interventions, such as control of hypercholesour laboratory suggests that the response to sublingual terolemia or smoking cessation. nitroglycerin, a smooth muscledependent vasodilation, Patients with abnormal reactivity may be “prone” to is not impaired in patients with PVD; nor does this developing atherosclerosis. Further prospective longituresponse appear to be affected by hypercholesterolemia dinal studies of patients deemed at high risk versus those or diabetes. The etrects of age (group 1 vs 2) are much judged to be at low risk may deline whether this is truless than the effects of disease (group 2 vs 3). The arter- ly the case, and whether abnormal function actually preies of patients with PVD also appear to have decreased cedes atherosclerotic plaque development. One may resting tone compared with patients without evidence of speculate that early intervention in patients displaying vascular disease. The mechanism for impaired vaso- characteristics of PVD, manifested by aberrations in constriction in clinically normal vessels remains to be vasoreactivity, could delay or prevent the development delineated. Similar changes were observed by Gaylarde of clinically significant atherosclerosis. Our noninvasive et al*O in diabetics whose cutaneous capillary blood flow, technique can be utilized to prospectively study this as reflected in transcutaneous partial pressure of oxygen, hypothesis. The technique would also serve as a mechwas increased basally, but whose capacity to increase anism to monitor patients for modifications of behavior, transcutaneous partial pressure of oxygen after a ther- diet, and medication to alter and possibly avert the athmal stimulus was significantly impaired. erosclerotic process. The relative importance of abnormal vasoreactivity Noninvasive techniques have been used to demonas a result of atherosclerosis, or as a marker of increased strate a specific pattern of impaired vasoactive rerisk of developing atherosclerosis, is yet to be deter- sponse in the normal brachial artery of patients with mined. We have demonstrated that small changes in ves- clinical atherosclerosis. This is a physiologic rellecsel diameter can be reliably detected utilizing high-fretion of the systemic nature of atherosclerosis and may quency duplex ultrasound technology. We have de- be useful as a marker for identifying patients with scribed a noninvasive method of documenting vascular preclinical atherosclerotic disease: - -

FIGURE 6. Change in w&metric flow rate (baseline to hyperemia): tin rcent change in v orumetric flow rate is significant-

other groups. FVD = peripheral cular disease. p 4t.001.

l

vasYOUNG

NORMALS

849

OLD

NORMALS

640

PVD

504

GROUPS

BRIEF REPORTS

211

1. Healy B. Endothelial cell dysfunction: an emerging endocrinopathy linked to conmay disease. J Am Coil Car&d 1990;16:357-358. 2. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376. 3. Creager MA, Cooke JP. Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of foreann resistance vessels in hypercholesterolemic humans. J Gin fnvest 1990;86: 228-234. 4. Celennajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller 01, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340: 111 l-l 115. 5. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelial-dependent mechanism that fails in patients with atherosclerosis. J Am Coil Car&l 199&16x349-356. 6. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5’.monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:170-174. 7. Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circuktion 1993;87(suppl V):V-67-V-76. 8. Laurent S, Lacolley P, Bmnel P, Laloux B, Pannier B, Safer M. Flow-dependent vasodilation of brachial artery in essential hypertension. Am J Physiol 1990; 258:Hl&HlOll. 9. Osborne JA, Lento PH, Siegfried MR, Stahl GL, Fusman B, Lefer AM Cardiovascular effects of acute hypercholesterolemia in rabbits: reversal with lovastatin treatment. J Clin Invest 1989;83:465473. 10. Panza JA, Quyymni AA, Brush JE Jr, Epstein SE. Abnormal endotheliumdependent vascular relaxation in patients with essential hypertention. NEagl J&fed 1990;323:22-27.

I 1. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arterioscler Thromb 1989;9(suppl):I-19-I-32. 12. Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Znvest 1987;80:1808-1811. 13. Shimokawa H, Vanhoutte PM. Dietary cod-liver oil improves endotheliumdependent responses in hypercholesterolemic and atherosclerotic porcine coronary arteries. Circulation 1988;78:1421-1430. 14. Minor RL Jr, Myers PR, Guerra R Jr, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest 1990;86:2109-2116. 15. Janka HU, Stand1 E, Mehnert H. Peripheral vascular disease and its relation to cardiovascular risk factors: screening with Doppler ultrasonic technique. Diabetes Care 1980:3:207-213. 16. Raines E, Ross R. Smooth muscle cells and the pathogen&s of the lesions of atherosclerosis. Br Hearr J 1993;69(suppl):S3O-S37. 17. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral tieriolar tone in man. Lancet 1989;337:997-1000. 18. Sjolund M, Hedin U, Sejersen T, Heldin CH, Thyberg J. Arterial smooth muscle cells express platelet&rived growth factor (PDGfl A chain mRNA, secrete a PDGF-like mitogen, and bid exogenous PDGF in a phenotypeand growth statedependent manner. J Cell Biol 1988;106:403-413, 19. Campbell GR, Campbell JH. The phenotypes of smooth muscle expressed in human atheroma. Ann NYAcad Sci 1990;598:143-158. 20. Gaylarde PM, Fonseca VA, Llewellyn G, Sarkany I, Thomas PK, Dandona P. Transcutaneous oxygen tension in legs and feet of diabetic patients. Diabetes 1988; 37:71&716.

Effects of Forearm Venous Occlusion on Peroneal Muscle Sympathetic Nerve Activity in Healthy Subjects Xueyu

Chen,

PhD, M. Atiar

MB, PhD, and John S. Floras,

Rahman,

enriksen and other investigatorslA have provided H considerable evidence for a local venoarterial sympathoexcitatory reflex to venous distension in normal

MD, DPhil

From the Division of Cardiology, Toronto Hospital and Center for Cardiovascular Research, University of Toronto, Toronto, Canada. This study was supported in part by Operating Grant MT972 1 from the Medical Research Council of Canada, Ottawa. Dr. Chen is the recipient of a Summer Scholarship from Faculty of Medicine, University of Toronto. Dr. Rahman is a Fellow of the Medical Research Council of Canada. Dr. Floras is the recipient of a Career Scientist Award from the Ministry of Health of the Province of Ontario. Dr. Floras address is: Division of Cardiology, Room 16 1.5, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1 X5. Manuscript received February 17, 1995; revised manuscript received and accepted April 15, 1995.

responsible for the varying degrees of sympathetic activation observed in heart failure remains incomplete.5 .. . We studied 7 healthy male volunteers, aged 21 + 1.4 years (mean r SD). All subjects were normal by medical history and physical examination, and had jugular venous pressures within the normal range. This protocol constituted part of a larger series of experiments approved by our institutional Human Subjects Review Committee. All subjects gave informed written consent. Experiments were repeated on 2 occasions using the same protocol 22 weeks apart in the same laboratory at constant room temperature and humidity, and at the same time of day. Subjects were instructed to avoid alcohol, caffeine-containing beverages, and tobacco 24 hours before each study day. Subjects were studied in the supine position. Blood pressure was measured from the left arm by an automatic cuff recorder. A standard adult-sized blood pressure cuff was wrapped around the right arm, which was elevated and supported so that the proximal part of the forearm was about 10 cm above the anterior chest wall. To produce venous occlusion, the cuff was inflated sequentially from a reservoir of compressed air for 2 minutes each at 10,20,30, and 40 mm Hg. Multiunit recordings of postganglionic muscle sympathetic nerve activity (MSNA) were obtained with a unipolar tungsten electrode inserted into a muscular branch of the peroneal nerve, posterior to the fibular head.7 MSNA was quantitated both in terms of burst frequency (bursts/min) and (to adjust for the pulse synchronous nature of MSNA) burst incidence (bursts/100 cardiac cycles). After a 30-minute rest, blood pressure and heart rate were measured every minute, and MSNA was recorded

212

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humans, whereas evidence for a generalized sympathoexcitatory response is scarce. This question has not been assessed by means of direct recording of efferent sympathetic nerve traffic in humans. Our objective in these experiments was to determine the effect of incremental increases in forearm venous pressure on efferent muscle sympathetic nerve traffic, as recorded by microneurography from the peroneal nerve. If present, a systemic sympathoexcitatory response to elevated venous pressure may have important pathophysiologic implications for conditions such as congestive heart failure, in which an altered balance between inhibitory and excitatory afferent input to vasomotor centers results in a generalized increase in efferent sympathetic nerve traffic, with consequent adverse effects on the heart, kidney, peripheral vasculature, and ultimately prognosis.5,6 Although some of these disturbances in the reflex control of sympathetic nerve traflic have been characterized in experimental and human heart failure, overall, our understanding of efferent excitatory mechanisms that may be

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