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Departments of 1Physiology and 2Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen; 3Department of Rehabilitation Medicine, Sint Maartenskliniek, Nijmegen; and 4Institute for Fundamental and Clinical Movement Sciences, The Netherlands
Submitted 12 January 2007 ; accepted in final form 19 June 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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venoarteriolar reflex; myogenic response; venous congestion; blood flow; vascular resistance
Local mechanisms have to play an important role in the tilt-induced increase in leg vascular tone in SCI. The myogenic response, which is triggered when transmural pressure across an arteriole is increased, seems to be partly responsible for the increase in leg vascular resistance in healthy able-bodied individuals on head-up tilt (20) but could also explain vasoconstriction in SCI individuals. Former research suggests that the local venoarteriolar reflex (VAR) (16–18, 33), which is elicited when venous transmural pressure exceeds 25 mmHg, contributes to the observed tilt-induced vasoconstriction in the leg muscle of SCI (1, 30). Originally the VAR was thought to be mediated via a sympathetic 
-adrenergic mechanism, but recent evidence suggests a nonadrenergic mechanism (5).
The mechanisms of local vasoconstriction, i.e., VAR and myogenic response, have been evaluated during venous congestion by cuff inflation, and by lowering the limb below heart level (limb dependency) (2, 25, 27, 31). During cuff inflation the reduction in blood flow may not be solely due to the VAR. A decrease in local perfusion pressure between arteries and veins may also reduce blood flow on cuff inflation. It was previously found that on lowering the hand or foot below heart level, venous as well as arterial pressure rise equally in the hand and foot, respectively (23, 28). So, assuming that limb dependency does not affect perfusion pressure, the consequent reduction in blood flow may not be solely due to the VAR via an increase in venous transmural pressure but may also be due to the myogenic response, which is elicited when arteriolar transmural pressure increases (Fig. 1). By use of limb dependency and cuff inflation of the leg, Okazaki et al. (25) calculated that in healthy men the VAR and the myogenic response contribute 55% and 45%, respectively, to local postural skin vasoconstriction.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Eleven spinal cord-injured individuals (SCI) and nine able-bodied controls (all men) volunteered to participate in this study. Individual baseline characteristics of the SCI are shown in Table 1, and baseline characteristics of both groups are presented in Table 2. The SCI continued their medication throughout the study. The study was carried out according to the principles of the Declaration of Helsinki. All subjects gave their written informed consent before participation, and the study was approved by the local ethics committee.
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Calf and forearm blood flow were measured by electrocardiography-triggered venous occlusion plethysmography using mercury-in-Silastic strain gauges (E-4 Hokanson, Hokanson, Bellevue, WA.). The electrically calibrated gauges were stretched around the thickest part of the right forearm and calf and connected to the plethysmograph (Loosco, Amsterdam, The Netherlands). The "plethysmography" cuff was wrapped around the right upper leg and arm (10 cm width) and connected to an adjustable air pressure source (E-20 Hokanson Rapid Cuff Inflator and AG-101 Cuff Inflator Pressure source, Hokanson). A double-occlusion cuff arrangement was used to measure limb blood flow during increases of local venous pressure. We therefore placed a second cuff (congesting cuff) proximal to the plethysmography cuff, which was connected to a manometer to raise local venous pressure during cuff inflation (see Fig. 1 for setup). A finger cuff was attached to the middle phalanx of the left third finger, which was kept at heart level, to measure finger arterial blood pressure using Portapres. Data were collected beat to beat during the experiment at a sampling rate of 200 Hz. A built-in expert system, Physiocal, was in operation to establish and adjust a proper volume-clamp set point. Heart rate was recorded, beat to beat, from a three-lead ECG.
Protocol
Subjects were asked to refrain from drinking coffee, tea, cola, or alcohol in the 18 h before testing and not to eat 2 h before testing. All individuals had emptied their bladder 1.5 h before testing to minimize the possibility of any reflex sympathetic activity from bladder filling on vascular tone.
All tests were performed in the afternoon with the subjects in supine position in a quiet temperature-controlled room.
Each experiment consisted of four measurements: forearm blood flow as well as calf blood flow were measured during both cuff inflation and limb dependency. The order of the measuring site (forearm or calf) and the order of the condition (limb dependency or cuff inflation) were randomized among the subjects.
Cuff inflation (Fig. 1). Calf and forearm blood flow were measured during an increase in supine local venous pressure by inflating a cuff (congesting cuff) proximal to the plethysmography cuff. Congesting cuff pressure was set at different levels: baseline, 15 mmHg, and 25 mmHg for the arm; and baseline, 15, and 30 mmHg for the leg. Calf or forearm blood flow was first measured in supine position without increasing local venous pressure, with the limb just above heart level, for 4 min with the plethysmography cuff pressurized intermittently to 40 mmHg (14). To increase local venous pressure, the proximal congesting cuff at the arm and thigh were inflated to 15 mmHg for 4 min, which increases local venous pressure to a similar magnitude (4, 9, 15). Blood flow was measured with the plethysmography cuff pressure adjusted to local venous pressure and was set at 55 mmHg. After 4 min, local venous pressure was raised to 25 and 30 mmHg for the forearm and calf, respectively, and blood flow was measured with the plethysmography cuff pressurized to 65 and 70 mmHg, respectively. For all individuals, diastolic blood pressure was >70 mmHg, so blood flow measured by venous occlusion plethysmography was not affected (14).
Limb dependency (Fig. 1). To match the increase in local venous pressure during limb dependency with cuff inflation, the limb was lowered such that the strain gauge was 0, 19, and 32 cm below heart level for the forearm and 0, 19, and 39 cm below heart level for the calf. The hydrostatic pressure column (in mmHg) was calculated with the formula 0.776 x hydrostatic pressure (in cm blood). Calf or forearm blood flow was first measured in supine position. Thereafter, the limb was lowered such that the strain gauge was 19 cm below heart level, and blood flow measurements continued for 4 min. Subsequently, blood flow was measured with the forearm and calf lowered to 32 and 39 cm below heart level, respectively. Cuff pressure for blood flow measurements was adjusted to the hydrostatic pressure column when the plethysmography cuff was below heart level. Because of a hip contracture or an increase in spasm in two SCI individuals, the limb was lowered to 32 and 36 cm, respectively.
With limb dependency, transmural pressure in the arterioles increases in accordance with the hydrostatic pressure gradient between the heart and the limb (28). Initially, the venous valves restrict the backward flow, preventing limb venous pressure to increase to the same hydrostatic pressure. However, as blood continues to flow from the arteries into the dependent veins, they are filled with blood, and the valves are forced open in a heartward progression until there is an uninterrupted hydrostatic column between the central circulation and the limbs (28). So, once all venous valves are open, the limb venous pressure is the sum of the dynamic pressure and the hydrostatic pressure (28). Therefore, the premise of this study is that there is no net change in perfusion pressure during limb dependency.
When local venous pressure is 30 mmHg, the venous system is still at its steep compliant part of the curve, which indicates that venous occlusion plethysmography represents arterial inflow and is not affected by venous compliance (22). This is illustrated in Fig. 2, whereupon the highest level of leg dependency, the increase in leg volume is linear during the first 5 s of cuff inflation, indicating that blood flow measurements using venous occlusion plethysmography during leg dependency are not compromised by a decrease in venous compliance.
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Data were digitalized with a sample frequency of 100 Hz (MIDAC, Instrumentation Department, Radboud University Nijmegen Medical Centre, The Netherlands) and analyzed by a customized computer program (Matlab 6.1; Mathworks, Natick, MA). Blood flow was calculated as the slope of the volume change over a 4-s interval. An initial steep rise, previously observed and attributed to a cuff inflation artifact (3), was skipped. Registrations with artifacts, due to movements, were excluded. The blood flow values over the last 2 min in each stage of cuff inflation or limb dependency (12–17 slopes) were averaged and represent arterial inflow (in ml·100 ml–1·min–1).
Baseline vascular resistance was calculated by the quotient (Pa – Pv)/arterial inflow, where Pa is arterial pressure and Pv is supine local venous pressure. Pa was assumed to be equal to mean arterial pressure (MAP). For supine Pv, 5 mmHg was used since pilot experiments and previous literature (15) demonstrate that when the limb is above heart level, resting venous pressure varies between 0 and 7 mmHg. During cuff inflation, vascular resistance was estimated from (Pa – Pv)/arterial inflow. Pa was assumed to be equal to MAP, and Pv was equal to the cuff inflation pressure. Experiments in our laboratory, where venous pressure on venous congestion was measured in the vena saphena magna at the ankle in a group of three healthy volunteers, have demonstrated that cuff pressure is a good index for local venous pressure (a cuff pressure of 30 mmHg corresponds with a venous pressure of 27 ± 2 mmHg). This is also in line with previous literature (4, 9, 15). During limb dependency, Pa and Pv were assumed to increase similarly with no change in perfusion pressure (23, 28). In three volunteers, we verified the increase in venous pressure during limb dependency: local venous pressure during limb dependency, measured invasively, with the ankle ranging from 39–54 cm below heart level, increased up to 40 mmHg, which corresponds with the calculated increase in venous pressure based on the height difference between ankle and heart.
Vasoconstriction was quantified by normalizing blood flow and vascular resistance during cuff inflation and limb dependency to baseline values and was presented as percent change from baseline.
Statistical Analysis
All values are reported as means ± SE, unless otherwise indicated. Baseline characteristics were tested using an unpaired t-test. Differences between the groups were analyzed by means of two-way repeated-measures ANOVA, with the pressure (levels of limb dependency or cuff inflation) as within-subject factor and the presence of a SCI as between-subject factor. The pressure factor represents the overall effect of limb dependency or cuff inflation. The pressure by group factor was used to test for differences of limb dependency or cuff inflation between the groups. Statistically significant differences were further analyzed by unpaired t-tests at the highest level of limb dependency or cuff inflation. Statistical significance level was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The two groups did not differ with respect to age, body mass, height, diastolic blood pressure, MAP, and hours of exercise per week. Systolic blood pressure was significantly lower in SCI than in control subjects. Baseline calf and forearm blood flow and vascular resistance did not differ between the groups (Table 2).
Calf: SCI vs. Control Subjects
Cuff inflation. During cuff inflation, calf blood flow decreased with increasing cuff pressure in both groups (Table 3; Fig. 3C). However, calf vascular resistance did not change with increasing cuff pressure (Table 3; Fig. 3D). The responses in both calf blood flow and calf vascular resistance during cuff inflation did not differ between the groups.
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During leg dependency, calf vascular resistance increased with increasing level of dependency (Table 3; Fig. 3B). The relative increase in calf vascular resistance at the different levels of leg dependency was significantly higher in SCI than in controls (2-way repeated measures ANOVA; group x pressure interaction: P = 0.04). With the calf 39 cm below heart level, the percent increase in calf vascular resistance was 186 ± 53% in SCI, which was significantly higher than the 51 ± 17% increase in control subjects (unpaired t-test: P = 0.032).
Forearm: SCI vs. control subjects. During arm dependency, forearm blood flow decreased significantly and forearm vascular resistance increased significantly in both groups. Changes in forearm blood flow and resistance did not differ between both groups (Table 3, Fig. 4). During cuff inflation, forearm blood flow decreased and forearm vascular resistance increased statistically significantly in both groups.
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Heart rate did not change during limb dependency or during cuff inflation. During forearm and leg cuff inflation, MAP did not change in either group. During both arm and leg dependency, MAP increased in both groups (P = 0.012 for arm, and P < 0.001 for leg) (Table 3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Venous Congestion by Cuff Inflation
Limb blood flow in response to venous congestion by cuff inflation decreased. Interestingly, the increase in limb vascular resistance on cuff inflation was less marked; in the forearm an increase in vascular resistance was observed, whereas in the calf the increase in vascular resistance did not reach statistical significance. The consistency of this finding is underlined since it was found in both controls and SCI individuals. It was previously described that the reduction in blood flow within human skeletal muscle when subjected to venous congestion was attributed to a local vasoconstrictor mechanism, the VAR, which is elicited when venous transmural pressure exceeds 25 mmHg (18). To assess vasoconstriction on venous congestion, in the present and former studies (25–27), changes in perfusion pressure have been taken into account to calculate limb vascular resistance. The observations are ambiguous. In the cutaneous circulation of the human finger, vascular tone did not change on venous congestion, indicating that a VAR mechanism is not operative in that specific region (27). However, this is in contrast to an increase in vascular resistance on venous congestion in the human forearm and calf skin (25). There are several reasons for this striking difference. First, regulation of blood flow in the finger (apical skin) and forearm (nonapical skin) is different; sympathetic tone in the apical skin in a thermoneutral environment at rest is substantial, whereas nonapical skin at rest demonstrates little vasoconstrictor activity. Thus the vasoconstrictor effect of the VAR in the preconstricted finger skin vascular bed may be marginal. Second, calculation of perfusion pressure differed between the studies. To calculate perfusion pressure, Richardson et al. (27) used capillary pressure, which is higher than venous pressure that was used in the present study and the study by Okazaki et al. (25). The consequent underestimation of vascular resistance may explain the lack of increase in vascular tone on venous congestion in the study by Richardson et al. (27). However, calculation of vascular resistance in the present study, which is similar to that used by Okazaki et al. (25), cannot explain the attenuated increase in vascular resistance on venous congestion. Using venous occlusion plethysmography to measure blood flow, a previous study (31) described that a venous congestion of 40 mmHg caused an increase in calf vascular resistance of 25%. Although a venous pressure of 25–30 mmHg used in the present study exceeds the threshold to elicit the VAR, it may explain the less marked increase in vascular resistance on venous congestion. Therefore, up to a venous congestion pressure of 30 mmHg, the present study casts doubt on a leading role of an active venoarteriolar vasoconstriction mechanism in the arm or leg vascular bed. In other words, the reduction in limb blood flow on venous congestion up to 30 mmHg seems to be mostly a passive effect caused by a reduced arteriovenous pressure difference, with a minor role of additional active vasoconstriction mechanism.
Limb Dependency
On forearm and calf dependency, limb blood flow decreased in both groups. In contrast to the observations during cuff inflation, limb dependency resulted in a marked increase in limb vascular resistance. On limb dependency, the increase in vascular tone is elicited by 1) the myogenic response via an increase in arteriolar pressure, and it was assumed that 2) the increase in venous pressure will activate the VAR. However, taking into account the vascular responses during cuff inflation, one may question to what extent the venoarteriolar response contributes to the increase in limb vascular resistance on depending a limb, since local venous pressure on cuff inflation matches local venous pressure on limb dependency and results in a local venous pressure of 25–30 mmHg. Hence, the increase in vascular resistance on limb dependency in the present study seems to be predominantly due to arterial myogenic vasoconstriction, which has been suggested before (5).
Leg cuff inflation induced similar changes in calf vascular tone in SCI and controls. However, on leg dependency, SCI showed a more pronounced increase in calf vascular resistance than controls, where no differences in forearm vascular responses were observed between the groups on arm dependency. Since calf blood flow tended to be higher in the SCI group, a larger vasoconstrictor reserve in the SCI than in the control group could have influenced the results of the study. Therefore, results of matched supine blood flows of a subgroup of five SCI individuals and five control subjects are presented in Fig. 5. Using these subgroups of subjects, the trend toward an enhanced vasoconstriction during leg dependency in SCI is evident. In addition, the decrease in calf blood flow on venous congestion in the subgroup of subjects is equal in both groups. This underlines our conclusion that local vasoconstriction on leg dependency is enhanced in SCI individuals; and so an exaggerated myogenic response, below the level of the spinal lesion, could explain the disparity in vascular responses found in the calf on leg dependency between SCI and controls.
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Clinical Relevance
In SCI individuals, the importance of local vasoconstriction in withstanding orthostatic tolerance has been emphasized by former research (1, 12, 13, 30, 32). The uniqueness of the present study is that mechanisms of local vasoconstriction were investigated without interference of baroreflex-mediated vasoconstriction by limb dependency and during venous congestion above and below the level of the spinal lesion. No differences between the groups were found in changes of calf blood flow and calf vascular resistance on venous congestion, indicating that the reduction in blood flow on venous congestion relies on a change in perfusion pressure and to a minor extent on the VAR, which are equal in both groups. On leg dependency, however, changes in calf blood flow and calf vascular resistance were more pronounced in the SCI group. This supports the idea that the enhanced local vasoconstriction in the paralyzed legs of SCI individuals is most likely due to the myogenic mechanisms.
Limitations
The mechanisms of local vasoconstriction are investigated by both limb dependency and cuff inflation. This approach is based on several assumptions. We do not exactly know how arteriolar pressure is changed on cuff inflation and limb dependency. Nonetheless, it may be possible for these two models to demonstrate differences that may reasonably be attributed to different mechanisms. For example, on cuff inflation, back pressure from the increased local venous pressure does exert some unknown influence on arteriolar pressure. These unknown mechanisms, however, do not differ between the control and SCI group and do, therefore, not influence the observations in the present study. To verify the assumptions made in the present study, leg venous pressure under different conditions was measured invasively by canulation of the vena saphena magna at the ankle in a group of three healthy volunteers. Like previous studies (4, 15), where venous pressure was measured invasively, these experiments demonstrated that cuff pressure is a good index for local venous pressure (a cuff pressure of 30 mmHg corresponds with a venous pressure of 27 ± 2 mmHg).
We did not measure arterial pressure during venous congestion and assumed that arterial pressure remained similar to the period just before venous congestion, and so perfusion pressure is calculated as MAP minus cuff pressure. As confirmed in three volunteers with invasive venous pressure measurements, leg dependency results in an increase in local venous pressure that corresponds with the calculated hydrostatic pressure gradient (see METHODS). We assumed that the hydrostatic pressure gradient causes a similar increase in the arteries (28) and that, therefore, perfusion pressure was not affected by limb dependency. This is confirmed in a study where arterial and venous pressure, both measured in the depending limb, changed linearly with the height of the column of blood (23).
Conclusions
On arm dependency above the level of the spinal lesion, both groups exhibited similar vasoconstriction responses. However, on leg dependency, vasoconstriction was more pronounced in the paralyzed legs of SCI than in the legs of controls. No differences between the groups were observed on cuff inflation, where the myogenic response is not involved. Thus most likely the myogenic response is responsible for the augmented vasoconstriction on leg dependency in SCI. Therefore, the myogenic response may play a pivotal role in the orthostatic tolerance in SCI, where sympathetic baroreflex control of the leg vasculature is absent.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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  J. T. Groothuis, F. Poelkens, C. W. Wouters, M. Kooijman, and M. T. E. Hopman Leg intravenous pressure during head-up tilt J Appl Physiol, September 1, 2008; 105(3): 811 - 815. [Abstract] [Full Text] [PDF]
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Pa-v=). Thus limb blood flow decreases by eliciting the venoarteriolar reflex (VAR) via an increase in Pv and the arteriolar myogenic response via an increase in Pa. B: limb cuff inflation impedes venous return, resulting in venous congestion. Subsequently, Pv rises, whereas inflation of the cuff minimally affects Pa. Therefore, arteriovenous pressure difference is decreased (
), resulting in a decrease in driving pressure. Since Pa is minimally affected, the arteriolar myogenic response is not likely to be activated. Thus during cuff inflation limb blood flow decreases by a decrease in driving pressure (
