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Departments of Anesthesiology and of Physiology and Biophysics, Mayo Clinic and Foundation, Rochester, Minnesota 55905
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Engelke, Keith A., John R. Halliwill, David N. Proctor, Niki
M. Dietz, and Michael J. Joyner. Contribution of nitric oxide and
prostaglandins to reactive hyperemia in the human forearm. J. Appl. Physiol. 81(4):
1807-1814, 1996.
We investigated the separate and combined
contributions of nitric oxide (NO) and vasodilating prostaglandins as
mediators of reactive hyperemia in the human forearm. Forearm blood
flow (FBF) was measured with venous occlusion plethysmography after 5 min of ischemia. In one protocol (n = 12), measurements were made before and after intra-arterial
administration of the NO synthase inhibitor
NG-monomethyl-L-arginine
(L-NMMA) to one forearm. In a
separate protocol (n = 7),
measurements were made before and after systemic administration of the
cyclooxygenase inhibitor ibuprofen and again after
L-NMMA.
L-NMMA reduced baseline FBF at
rest (2.7 ± 0.4 to 1.6 ± 0.2 ml · 100 ml
1 · min1;
P < 0.05) and had a modest
effect on peak forearm vascular conductance and flow (forearm vascular
conductance = 31.1 ± 3.1 vs. 25.7 ± 2.5 ml · min1 · 100 ml
forearm1 · 100 mmHg of perfusion
pressure1 · min1,
P < 0.05; FBF = 26.6 ± 2.9 vs.
22.8 ± 2.6 ml · 100 ml1 · min1,
P = 0.055). Total excess
flow above baseline during reactive hyperemia was unaffected by
L-NMMA (14.3 ± 3.0 vs. 13.1 ± 2.3 ml/100 ml; P < 0.05).
Ibuprofen did not change FBF at rest, reduced peak FBF from 27.6 ± 1.9 to 20.3 ± 2.7 ml · 100 ml1 · min1
(P < 0.05), but had no effect on
total excess flow above baseline. Infusion of
L-NMMA after ibuprofen reduced
FBF at rest by 40%, had no effect on peak flow, but reduced total
excess flow above baseline from 12.0 ± 2.5 to 7.6 ± 1.3 ml/100
ml (P < 0.05). These data
demonstrate that NO synthase inhibition has a modest effect on peak
vasodilation during reactive hyperemia but plays a minimal role later.
Prostaglandins appear to be important determinants of peak flow. The
effects of NO synthase inhibition during reactive hyperemia may also be
potentiated by concurrent cyclooxygenase inhibition.
blood flow; prostaglandins; endothelium; vasodilation
INTRODUCTION AFTER ISCHEMIA caused by arterial occlusion, marked
vasodilation and a transient rise in blood flow are observed in most
tissues (20, 23). This phenomenon, termed reactive hyperemia, is
confined to the previously ischemic vascular bed and does not require
intact innervation of the affected area (7). Myogenic relaxation of the
vessels during the ischemia appears to account for a portion of this
response (23). The remaining vasodilation has been attributed to local
release of mediators and metabolites from the ischemic tissue (23).
However, the identity of these substances remains obscure and it is
unclear whether they account for a majority of the dilation because the
blood flow during the hyperemic period is greater than that required to
repay any metabolic debt (1). Along these lines, the marked rise in
flow at the beginning of the hyperemic period may also remove any
vasodilating metabolites from the tissue, thereby limiting their
contribution later in the hyperemic response (1).
Prostaglandins, presumably released from the vascular endothelium, have
been shown to contribute to reactive hyperemia in a variety of
experimental models, including the human forearm (2, 3, 12). In these
studies, administration of cyclooxygenase inhibitors reduced peak blood
flow after ischemia and blunted the total excess flow observed in the
minutes after restoration of blood flow. In contrast, the role of the
more recently identified endothelial vasodilating substance nitric
oxide (NO) as a local mediator of reactive hyperemia is unclear. Ward
and colleagues (27) demonstrated that administration of arginine
analogues to inhibit NO synthase reduced both peak and total excess
flow during reactive hyperemia in the canine diaphragm. Along similar lines, O'Leary et al. (19) showed that systemic administration of NO
synthase inhibitors caused a marked rise in arterial pressure and
blunted both the peak and total changes in vascular conductance during
reactive hyperemia in the canine hindlimb circulation. Other studies in
animals and the one study in humans report that NO synthase inhibition
had little effect on the peak flow immediately after the ischemia but
did reduce total excess flow during the hyperemic period (9, 15, 24,
28, 29). However, many of these studies are difficult to interpret
because inhibition of NO synthase frequently reduces baseline blood
flow, which can cloud the interpretation of reactive hyperemia
responses (24).
It also seems reasonable to hypothesize that prostaglandins and NO
might act synergistically to cause vasodilation during reactive
hyperemia. Evidence in vitro suggests that, under certain conditions,
NO and vasodilating prostaglandins interact positively when both
vasodilating systems are activated (4, 11). This means that concurrent
inhibition of cyclooxygenase and NO synthase might result in a greater
blunting of reactive hyperemia than would be predicted on the basis of
the responses seen when each of the systems is inhibited separately.
Additionally, there can be substantial flow-induced release of NO (17,
21). This means that the peak blood flow response, caused in part by
prostaglandins, might evoke substantial flow-induced release of NO.
With this information as a background, we conducted experiments in
which forearm blood flow (FBF) was measured before and after 5 min of
ischemia under four conditions: 1)
control, 2) after local infusion of
the NO synthase inhibitor
NG-monomethyl-L-arginine
(L-NMMA),
3) after systemic treatment with the
cyclooxygenase inhibitor ibuprofen, and
4) after combined administration of
ibuprofen and
L-NMMA. These
interventions allowed us to explore the contribution of NO and
vasodilating prostaglandins in reactive hyperemia. They also allowed us
to test the hypothesis that the combined inhibition of NO synthase and
cyclooxygenase would result in a greater blunting of reactive hyperemia
than would have been predicted based on the individual treatments
alone.
METHODS Experimental Design
Subjects
Twenty-three healthy nonsmokers (18 men, 5 women) between the ages of 18 and 42 yr participated in this investigation. Each female subject had a negative pregnancy test before participation in the study. The subjects were familiarized with the experimental protocols, techniques, and laboratory personnel during an orientation visit before data collection. Studies were performed between 0800 and 1800 with subjects instructed to abstain from large meals for 3 h and caffeine for 6 h before arriving at the laboratory. Room temperature was maintained between 21 and 23°C. The subjects were seated in a reclining chair with the head and chest elevated 30° above the trunk and with the legs at roughly heart level.FBF
FBF was measured in the nondominant forearm by using venous occlusion plethysmography and a mercury-in-Silastic strain gauge with the forearm positioned above heart level (10). The venous collecting pressure was set at 50 mmHg on the basis of the study by Patterson and Whelan (20) that demonstrated that this collecting pressure yields the most accurate measurements of flow during reactive hyperemia. During measurement of FBF, circulation to the hand was arrested by inflation of wrist cuffs to suprasystolic levels. Flow was measured four times each minute for 2 min before forearm ischemia and for 4 min after the occlusion was released during reactive hyperemia. The initial measurement of FBF was recorded within 5 s after release of the arterial occlusion. All FBF values are presented in milliliters per 100 milliliters per minute.Arterial Catheterization
In protocols 2 and 3, a 5-cm 20-gauge catheter was inserted into the brachial artery of the nondominant arm by using aseptic techniques after local anesthesia (5, 6, 8). The catheter was connected to a pressure transducer and continuously flushed at 3 ml/h with saline containing 2 U/ml heparin. A three-port connector was placed in series with the catheter-transducer system to allow for drug infusions and measurement of arterial pressure. In protocols 2 and 3, heart rate and arterial pressure were measured continuously by using the arterial pulse-wave tracing obtained from the catheter. Mean arterial pressure was calculated as one-third pulse pressure plus diastolic pressure.Drug Preparation and Administration
All drugs given via the brachial catheter were formulated by using aseptic techniques and delivered through the catheter at a rate of 4 ml/min by a syringe pump. When appropriate, saline was also infused at 4 ml/min when drugs were not being administered to control for the effect of infusion volume on FBF. Before this study was begun, permission was obtained from the United States Food and Drug Administration to administer L-NMMA to humans. L-NMMA (Calbiochem, La Jolla, CA) was infused at 4 mg/min for 10 min to inhibit NO synthase with the wrist cuff inflated to 250 mmHg (5). This was followed by an infusion of 2 mg/min for 5 min. To test the efficacy of the NO synthase inhibition with L-NMMA, acetylcholine (ACh; IOLAB Pharmaceuticals, Claremont, CA) was infused at 64 µg/min via the brachial artery before and after L-NMMA administration. ACh stimulates muscarinic receptors on the vascular endothelium and causes NO release. A marked blunting of the vasodilator response to ACh is consistent with inhibition of NO synthase in the vascular endothelium (25). Intra-arterial infusion of sodium nitroprusside (NTP; Elkins-Sinn, Cherry Hill, NJ) at 10 µg/min was used to determine whether L-NMMA administration had any nonspecific effects on forearm vasodilation (5, 6, 8, 25). To inhibit cyclooxygenase and attenuate formation of prostaglandins, 1,200 mg of ibuprofen (Motrin IB, Upjohn, Kalamazoo, MI) were administered orally. This dose was selected on the basis of previously published studies demonstrating that it caused a marked blunting of the FBF responses during reactive hyperemia (2, 3).Specific Protocols
Protocol 1. The purpose of this protocol was to demonstrate the reproducibility of our reactive hyperemia procedure for use in subsequent protocols. Three reactive hyperemia trials, each separated by ~15 min, were conducted on six subjects (all men). Protocol 2. This protocol was designed to investigate the role of NO in reactive hyperemia. Twelve subjects (9 men, 3 women) were studied. Five of these were recruited because they had participated in previous studies that used L-NMMA to block NO synthase, and in these studies L-NMMA caused marked (~70% or more) reductions in their vasodilator responses to ACh. The brachial artery was cannulated, and the forearm was then instrumented to measure FBF and a reactive hyperemia trial performed. ACh and NTP were then administered. When baseline FBF returned to normal, a second reactive hyperemia trial was performed to control for any residual effects of ACh and NTP on FBF responses to forearm ischemia. After this procedure, L-NMMA was administered for 10 min at a rate of 4 mg/min. A second infusion of ACh was then given to test the level of NO synthase inhibition. After additional L-NMMA was infused (~5 min at 2 mg/min), the third reactive hyperemia trial was performed. NTP was then administered to confirm the ability of the forearm vessels to dilate after L-NMMA infusion. Protocol 3. To investigate the relative roles of prostaglandins and NO during reactive hyperemia, seven additional subjects (4 men, 3 women) were studied. First, a noninvasive component of the study was performed in which the FBF response during reactive hyperemia was recorded in a manner similar to protocol 1. Within 72 h of completing this study, subjects returned to the laboratory and ingested 1,200 mg of ibuprofen. Subjects were then instrumented as in protocol 2, and a reactive hyperemia trial was conducted 60-75 min after ingestion of the ibuprofen. Acetylcholine (64 µg/min), NTP (10 µg/min), and L-NMMA (4 mg/min) were then infused as in protocol 2 and the reactive hyperemia protocol was repeated.Calculations and Statistics
A FBF-time curve was constructed for each reactive hyperemia trial. Baseline FBF was estimated as the mean of eight flow measurements recorded during 2 min before forearm ischemia. Total excess flow was defined as the area under the FBF-time curve after baseline flow was subtracted (16). The highest FBF value observed after release of occlusion was chosen as representative of the peak postischemic flow. Because L-NMMA can reduce baseline FBF, the results were analyzed as both absolute flow values and increases in flow above baseline. Values of total excess flow above baseline are given as milliliters per 100 ml tissue (referring to the entire 4-min period after release of occlusion). The entire 4-min period after ischemia was included in the calculation of total excess flow on the basis of pilot work, indicating that FBF did not return to baseline for up to 3-4 min in a few subjects. Forearm vascular conductance (FVC) was calculated as the ratio of FBF and mean arterial pressure and is expressed as arbitrary units [ml · min1 · 100 ml
forearm1 · 100 mmHg of perfusion
pressure1 · min1
(units)]. Data are expressed as means ± SE,
except for protocol 1 (reproducibility) where means ± SD are reported. Intraclass correlation coefficients and coefficients of variation were calculated to determine the reproducibility of blood flow responses in
protocol 1. When appropriate,
comparisons among baseline, peak, and total excess flow were made with
a paired t-test, a one-way analysis of
variance (ANOVA) for repeated measures, or a two-way ANOVA (treatment × time).
RESULTS
Protocol 1
Baseline, peak, and total excess hyperemia were not different among the three trials and were highly reproducible (Table 1).
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Protocol 2
Baseline blood flow and dilator response to ACh and NTP. In the forearm that received L-NMMA, baseline FBF was 2.7 ± 0.4 ml · 100 ml1 · min1
before drug infusion and was reduced 38% to 1.6 ± 0.2 ml · 100 ml1 · min1
(P < 0.05) after
L-NMMA. Because mean arterial
pressure was unchanged (88 ± 3 vs. 90 ± 3 mmHg) after
L-NMMA, this corresponded to a decrease in FVC from 2.9 ± 0.4 to 1.8 ± 0.2 units
(P < 0.05) in the forearm that
received L-NMMA. The peak FBF
observed after ACh infusion in the control condition was reduced after
L-NMMA from 20.7 ± 2.8 to
10.4 ± 1.8 ml · 100 ml1 · min1
(P < 0.05). NTP infusion caused FBF
to increase from 14.9 ± 1.2 before to 14.7 ± 1.2 ml · 100 ml1 · min1
after L-NMMA administration.
Reactive hyperemia.
Figure 1 is an individual record from one
subject, and Fig. 2 shows the mean reactive
hyperemia responses before and after L-NMMA. Peak FBF during reactive
hyperemia tended to decrease from control after NO synthase inhibition
(26.6 ± 2.9 vs. 22.8 ± 2.6 ml · 100 ml1 · min1;
P = 0.055; Fig. 2). Because mean
arterial pressure was slightly higher when peak flow was measured after
release of ischemia after L-NMMA
(85 ± 2 vs. 88 ± 3 mmHg; P < 0.05), peak FVC was reduced after NO synthase inhibition (31.1 ± 3.1 vs. 25.7 ± 2.5 units; P < 0.05). Because L-NMMA caused a
reduction in baseline FBF, the data were also analyzed after this value
was subtracted (Fig. 2B). When this
analysis was performed, peak change in FBF after L-NMMA infusion was unchanged
from control (24.0 ± 2.7 vs. 21.2 ± 2.5 ml · 100 ml1 · min1)
and change in FVC was also unaffected (28.1 ± 3.1 vs. 24.0 ± 2.4 units; P > 0.05). Additionally,
L-NMMA reduced the FBF values in
the first minutes after release of ischemia, but this reduction was
similar in magnitude to the decrease in resting FBF caused by
L-NMMA. One minute after release
of ischemia, FVC was reduced (P < 0.05) from 6.8 ± 1.6 before to 4.7 ± 0.4 units after
L-NMMA. However, the rise in FVC
above baseline was similar at 1 min when differences in baseline
conductance were eliminated (3.4 ± 1.2 vs. 2.7 ± 0.8 units; P = 0.29). Total excess flow
above baseline was also unchanged after
L-NMMA (14.3 ± 3.0 vs. 13.1 ± 2.3 ml/100 ml).
) and after (
)
administration of NO synthase inhibitor L-NMMA.
B: change in forearm blood flow above
baseline flow, which demonstrates that effects of
L-NMMA on reactive hyperemia
were not solely due to reductions in baseline flow.
L-NMMA did not alter peak
hyperemia. Values are means ± SE.
Because the degree of NO synthase inhibition (as determined by the blunting of the vasodilator responses to ACh) can vary among the subjects, we further analyzed a subgroup of seven subjects who showed the greatest reductions in ACh-mediated vasodilation after L-NMMA (Fig. 3). Resting FBF fell from 2.9 ± 0.6 to 1.5 ± 0.2 ml · 100 ml
1 · min1
(P < 0.05) in this subgroup, and the
peak FBF responses after ischemia were 28.3 ± 4.3 before vs. 25.9 ± 3.8 ml · 100 ml1 · min1
after L-NMMA
(P > 0.05). When the changes in
baseline were analyzed, peak change in FBF was 25.3 ± 3.9 vs. 24.4 ± 3.7 ml · 100 ml1 · min1.
When FVC was considered L-NMMA
reduced the peak response from 31.8 ± 4.1 to 27.8 ± 3.5 units
(P < 0.05). However,
this response was not significant when only peak changes in FVC above
baseline were considered (28.7 ± 3.4 vs. 26.2 ± 5.5 units).
Protocol 3
Ibuprofen. After oral administration of 1,200 mg ibuprofen, baseline FBF was not different from control (2.2 ± 0.4 vs. 2.0 ± 0.3 ml · 100 ml1 · min1).
On release of arterial occlusion, peak vasodilation was reduced 22%
after ibuprofen from 27.6 ± 1.9 to 20.3 ± 2.7 ml · 100 ml1 · min1
(P < 0.05; Fig.
4), but total excess flow was unchanged.
This similarity resulted from higher blood flow values during the 2nd min of the reactive hyperemia (Fig. 4).
, change.
Ibuprofen + L-NMMA. Infusion of L-NMMA reduced baseline FBF 40% from 2.0 ± 0.3 to 1.2 ± 0.2 ml · 100 ml
1 · min1
(P < 0.05; Fig. 4). The increase in
FBF observed after ACh infusion in the control condition was reduced
after L-NMMA from 15.4 ± 1.9 to 9.3 ± 2.0 ml · 100 ml1 · min1
(P < 0.05). FBF rose to a similar
level with NTP infusion before and after
L-NMMA administration (11.6 ± 0.8 vs. 12.5 ± 1.0 ml · 100 ml1 · min1).
Mean arterial pressure was also unchanged by local administration of
L-NMMA (84 ± 3 vs. 86 ± 3 mmHg; P > 0.05).
Reactive hyperemia.
Peak FBF was unchanged after
L-NMMA administration (27.6 ± 1.9 vs. 23.1 ± 2.5 ml · 100 ml1 · min1;
Fig. 4). When the reduction in baseline FBF evoked by
L-NMMA infusion was considered,
peak hyperemic flow remained unchanged from control (25.0 ± 1.9 vs.
21.6 ± 2.4 ml · 100 ml1 · min1).
Total excess flow was reduced by 37% from 12.0 ± 2.5 to 7.6 ± 1.3 ml · 100 ml1 · min1
in the combined presence of ibuprofen and
L-NMMA (Fig. 4).
DISCUSSION
The major finding of this study is that inhibition of cyclooxygenase augments the effects of NO synthase inhibition on the FBF responses during reactive hyperemia. NO synthase inhibition alone caused modest reductions in peak flow and vascular conductance after ischemia but had little effect on total excess flow after ischemia. Inhibition of prostaglandin synthesis reduced peak blood flow and did not change total excess flow after ischemia. By contrast, combined cyclooxygenase and NO synthase inhibition caused a marked reduction in total excess flow after forearm ischemia.
Technical Limitations
Quantification of reactive hyperemia involves measurement of a peak flow immediately after release of ischemia followed by serial measurements of flow as the hyperemia decays (Fig. 1). In protocol 1, baseline, peak, and total excess blood flow across three trials of reactive hyperemia were highly reproducible, indicating that the differences seen with the experimental intervention in protocols 2 and 3 were due to the intervention and not a result of inherent variation in the blood flow responses after ischemia.Another important issue in the analysis of these data is how to account for the lower baseline FBF values after treatment with L-NMMA. When only changes in flow above baseline were considered, NO synthase inhibition had little or no effect on peak blood flow, peak vascular conductance, or total excess flow above baseline after ischemia. Finally, the similarity of the blood flow responses during NTP administration before and after L-NMMA indicate that the L-NMMA selectively inhibited NO synthase in the forearms (5, 6, 8, 25). This means that any changes in flow or conductance after L-NMMA were not due to a nonspecific vasoconstricting effect of the L-NMMA.
One continuing problem associated with L-NMMA use in the human forearm is the inability to blunt completely the rise in FBF during an ACh infusion. Additionally, in the present study and others that have used L-NMMA, we have observed marked subject-to-subject variability with this compound (5, 6, 8). In all of the subjects we have studied (>100), L-NMMA has caused a marked (~25-50%) reduction in baseline FBF. In many subjects, it reduces the vasodilator responses to ACh at 16 to 64 µg/min by 50% or more. However, in a few subjects (~10%) L-NMMA causes the normal reduction in baseline FBF but has little or no impact on the dilator responses to ACh. Along similar lines, L-NMMA causes marked increases in hindlimb vascular resistance in the rabbit but has little impact on ACh-mediated vasodilation (18). This means that ACh-mediated vasodilation in the human forearm may be a less than perfect test for the inhibition of NO synthase as a result of 1) subject-to-subject variability, 2) ACh-mediated release of another vasodilating factor, or 3) ACh-mediated presynaptic inhibition of norepinephrine release (22, 23, 25).
With the above concepts as a background, we recruited a number of experienced subjects whose vasodilator responses to ACh were markedly blunted by L-NMMA in our previous studies (5, 6, 8). We also analyzed the response of these subjects separately (Figs. 1 and 3, A and B). The key point from this analysis is that the responses in these subjects were similar to the group as a whole. This suggests that inadequate inhibition of NO synthase (as tested by ACh responses) cannot explain our failure to observe a major effect of L-NMMA on reactive hyperemia responses in the human forearm. It also supports our conclusion that NO does not play an essential role in the peak blood flow or vasodilator responses during reactive hyperemia in the human forearm after 5 min of ischemia or in the FBF responses later after release of ischemia.
Reactive Hyperemia and NO
We observed that peak flow or conductance after 5 min of forearm ischemia was not markedly reduced after selective intra-arterial infusion of L-NMMA. This observation suggests that NO does not play a major role in causing maximal vasodilation during peak reactive hyperemia in the human forearm. These findings are in agreement with the observation that NO synthase inhibition did not alter peak dilation during reactive hyperemia in either the human forearm (i.e., primarily muscle and skin) (24) or rat skeletal muscle (28). These observations are consistent with the concept that peak hyperemic flow is mediated primarily by a myogenic mechanism, which reduces vascular tone in vessels that are mechanically unloaded during the ischemia (14, 16). Presumably, the reduction in smooth muscle tone is similar before and after inhibition of NO synthase. Along these lines, inhibition of NO synthase in the coronary circulation of guinea pigs (15) and dogs (9, 29) did not affect maximal blood flow after a brief period of occlusion. However, reactive hyperemia in the coronary circulation is difficult to compare with other tissues because the heart continues to beat during the ischemia. In contrast to these findings, NO synthase inhibition blunted the peak vasodilatory responses during reactive hyperemia in the canine hindlimb and diaphragmatic circulations (19, 27).NO synthase inhibition did not cause large reductions in total excess flow above baseline in the human forearm, indicating that NO plays at best a modest role in maintaining the vasodilation observed after the peak responses (Figs. 1, 2, 3, 4). Similar observations from other studies demonstrate that inhibition of NO synthesis reduced the total excess flow (or calculated vasodilation) in coronary, mesenteric, hindlimb, and diaphragmatic arterial beds in experimental animals (9, 14, 15, 19, 29) and also in the human forearm (24). However, these responses are also less dramatic when changes in baseline flow are considered. Additionally, in isolated vessels and in the rat cremaster muscle, physical or chemical impairment of the vascular endothelium had no impact on the increase in blood vessel diameter when perfusion pressure was reduced, but it did blunt flow-induced vasodilation and reactive hyperemia (14, 16). On the basis on these observations, it appears that NO is not essential to observe reasonably normal reactive hyperemia responses after 5 min of ischemia in the human forearm.
Reactive Hyperemia and Prostaglandins
In addition to myogenic mechanisms, prostaglandins appear to play a role in mediating peak vasodilation after arterial occlusion. Several investigations have demonstrated that inhibition of cyclooxygenase production had no effect on baseline blood flow but resulted in reduced peak and total reactive hyperemia (2, 3, 12). This suggests that vasodilating prostaglandins formed during the ischemic period contribute to vasodilation after reestablishment of flow. We noted similar effects of cyclooxygenase inhibition on baseline and peak hyperemia. However, the total excess flow in our study after ibuprofen was not different from control as a result of higher FBF values later during reactive hyperemia (Fig. 4). This observation is surprising because our protocol for ibuprofen administration was similar to that used previously (2, 3). These differences may be protocol or subject dependent because some of the subjects in previous studies on this issue appear to have had very high baseline FBF values (2, 3). Additionally, the previous studies used relatively high venous- collecting pressure (60-70 mmHg) during their measurements of FBF (2, 3).A potential physiological explanation for our findings is that vasodilating prostaglandins contributed to the initial rise in flow after ischemia and that vasoconstricting prostaglandins can play a role in the decay of flow observed later in the reactive hyperemia. If this were the case and ibuprofen inhibited production of both types of prostaglandins, then FBF might be lower immediately after the release of ischemia but higher later during the hyperemia.
Reactive Hyperemia, NO, and Prostaglandins
Administration of L-NMMA in the presence of ibuprofen had no additional effect on peak hyperemia, but it reduced total excess blood flow above baseline by 37% in comparison to the ibuprofen-only condition. We initially hypothesized that combined inhibition of both NO synthase and cyclooxygenase would cause a greater blunting of reactive hyperemia responses than that seen when only one endothelial vasodilating system is inhibited. This hypothesis was based on observations in vitro that show that cyclooxygenase and NO can interact synergistically when both vasodilating systems are activated (11). Our findings support this concept because total excess flow was much lower after combined cyclooxygenase inhibition and NO synthase inhibition than after NO synthase inhibition alone.How then do the endothelial vasodilating factors fit into the emerging picture of the mechanisms that govern reactive hyperemia? Based on our findings and those of others, it seems reasonable to suggest that peak flow seen after 5 min of ischemia is mediated primarily by myogenic factors and vasodilating prostaglandins (1, 2, 14, 16). Metabolites and other dilating factors such as free radicals released by the ischemic tissue might also play a minor role in the initial responses (13). Because the initial rise in flow is typically far more than required to repay the metabolic debt and probably also removes any locally acting factors that accumulate during ischemia, it is unlikely that these mechanisms contribute to the vasodilation seen later during reactive hyperemia (1, 2, 23). In this context, it seems reasonable to suggest that flow-mediated release of NO might contribute modestly to vasodilation later in reactive hyperemia, especially after inhibition of cyclooxygenase (14, 16).
In summary, endothelial factors can contribute to reactive hyperemia in the human forearm. However, these factors probably only explain a modest portion of the rise in blood flow and vasodilation seen during reactive hyperemia.
ACKNOWLEDGEMENTS
The authors thank Cathy Nelson and Janet Beckman for their assistance in the preparation of the manuscript and the subjects for their cheerful cooperation.
FOOTNOTES
Address for reprint requests: M. J. Joyner, Dept. of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Received 9 November 1995; accepted in final form 13 May 1996.
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