J Appl Physiol
89: 2268–2275, 2000.
Pharmacological characterization of vasomotor activity
of human musculocutaneous perforator artery and vein
JIANRONG ZHANG,1 JOAN E. LIPA,1,2 CLAIRE E. BLACK,1,2 NING HUANG,1
PETER C. NELIGAN,1,2 FRANCIS T. K. LING,1 RONALD H. LEVINE,2
JOHN L. SEMPLE,2 AND CHO Y. PANG1–3
1
Research Institute, Hospital for Sick Children, and Departments of 2Surgery
and 3Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8
Received 23 May 2000; accepted in final form 21 July 2000
tissue transplant; free flap; microvascular surgery; vasospasm; ischemic necrosis
of trauma, congenital malformations, burns, and tumors often produces large,
deep wounds in which vital structures may be exposed.
Failure to close these wounds and achieve wound heal-
SURGERY FOR THE TREATMENT
Address for reprint requests and other correspondence: C. Y. Pang,
The Hospital for Sick Children, 555 Univ. Ave., Toronto, Ontario,
Canada M5G 1X8 (E-mail: [email protected]).
2268
ing may destroy the exposed tissues, such as nerves,
blood vessels, tendons, or bones, resulting in loss of
form and/or function in that part of the body. Autogenous skin or skin and muscle transplantation (i.e.,
cutaneous or musculocutaneous free flap surgery) is
routinely used for wound coverage. Specifically, a cutaneous or musculocutaneous flap is harvested from a
distant donor site of the body and is transferred to
cover the wound, with vascular anastomosis performed
at the recipient site to reestablish blood supply (8).
Despite advances in microsurgical technique, patient
selection, judicious donor site selection, and recipient
site preparation, flap failure associated with vasospasm and thrombosis still occurs at a rate of 5–10%,
even in large medical centers (3). Vasospasm can occur
intraoperatively and shortly after release of the vascular clamp after vascular anastomosis, but vasospasm
can also occur within 48–72 h postoperatively. Vasospasm plays an important role in the pathogenesis of
thrombosis, causing partial or total flap ischemic necrosis (33, 57). Flap failure is time consuming and
costly because it requires additional surgery and a
prolonged period of hospitalization. In the United
States, the operating room costs range from $44,000 to
$68,000 for each total free flap failure (19, 52), and the
additional surgeon reimbursements range from $5,000
to $35,000 (52). Furthermore, repeated reconstructive
surgery may increase donor site deformity and morbidity, which may have a devastating effect on the patient.
Therefore, there is the need to understand the pathophysiology of vasospasm in free flap surgery to develop
an effective pharmacological intervention for prevention and/or mitigation of vasospasm in flap surgery.
The mechanism for vasospasm in free flap surgery is
unclear. It seems that mechanical stretch or trauma
may induce a myogenic response, causing vasospasm.
In addition, surgical trauma may induce local vasospasm by stimulating the sympathetic nerve ending to
release norepinephrine (NE). The synthesis and release of endothelium-derived relaxing factors (EDRFs),
such as prostacyclin (PGI2) and nitric oxide (NO), may
The costs of publication of this article were defrayed in part by the
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8750-7587/00 $5.00 Copyright © 2000 the American Physiological Society
http://www.jap.org
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Zhang, Jianrong, Joan E. Lipa, Claire E. Black, Ning
Huang, Peter C. Neligan, Francis T. K. Ling, Ronald H.
Levine, John L. Semple, and Cho Y. Pang. Pharmacological characterization of vasomotor activity of human musculocutaneous perforator artery and vein. J Appl Physiol 89:
2268–2275, 2000.—Vasospasm is one of the main causes of
skin ischemic necrosis in cutaneous and musculocutaneous
flap surgery, but the pathogenic mechanism is unclear. We
planned to test the hypothesis derived from clinical impression that veins are more susceptible to vasospasm than
arteries in flap surgery and, once established, that venous
vasospasm is difficult to resolve and more detrimental than
arterial vasospasm. To this end, we investigated the differences in sensitivity to vasoconstrictors and vasodilators between the human musculocutaneous perforator (MCP) artery
and vein by measuring the isometric tension of arterial and
venous rings suspended in organ chambers. Vascular contraction was expressed as a percentage of the tension induced
by 50 mM KCl. Relaxation was expressed as a percentage of
contraction induced by a submaximal concentration (3 ⫻
10⫺9 M) of endothelin-1 (ET-1). We observed that the vasoconstrictor potency of norepinephrine was significantly
higher in the MCP vein than in the MCP artery. The vasoconstrictor potency of ET-1 and the thromboxane A2 mimetic
U-46619 were similar in the MCP vein and artery, but the
maximal contraction induced by ET-1 and U-46619 was significantly higher in the MCP vein than in the MCP artery. On
the other hand, the MCP vein was less sensitive than the
MCP artery to the relaxation effect of nitroglycerin, nifedipine, and lidocaine. These differences between the human
MCP artery and vein in response to vasoactive agents lend
support to the clinical impression in flap surgery that veins
appear to be more susceptible to vasospasm than arteries and
venous vasospasm seems to be more difficult to resolve than
arterial vasospasm in cutaneous and musculocutaneous flap
surgery.
REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
MATERIALS AND METHODS
Source of human blood vessels. The skin pannus excised
from patients undergoing abdominoplasty serves no purpose
to the patient and is normally disposed of by incineration. A
clinical protocol was approved to obtain MCP arteries and
veins from the skin pannus after it was excised from the
patient. Another protocol was also approved to obtain MCP
artery and vein specimens (⬃1.0 cm in length) from patients
undergoing transverse rectus abdominis musculocutaneous
flap surgery. Obtaining these vascular specimens did not
affect the procedure or outcome of the surgery. The blood
vessel specimens were wrapped in gauze soaked with isotonic
saline. The specimens were transported to the laboratory at
room temperature. This mimicked the clinical situation in
which the free flap is subjected to ischemia in room temperature during anastomosis at the recipient site. The vascular
specimens were used for experimentation within 45–60 min
after excision. This ischemic period may be slightly shorter
than the ischemic time for free flap surgery in some cases.
The subjects were female (40–60 yr of age) and were not
known to smoke or have any systemic disease.
Preparation of vascular rings and tension recording. The
MCP artery and vein specimens were placed in oxygenated
Krebs-bicarbonate solution at room temperature, cleared of
loose connective tissue, and cut into 4-mm-long rings. The
outer diameter of these vascular rings was 1–2 mm. Two
stainless steel wires were placed through the lumen of each
ring. An arterial and a venous ring were used in each experiment. Each ring was placed in an organ chamber of 25-ml
volume. One wire was anchored to the bottom of the organ
chamber, whereas the other was connected to a Grass FT
0.03 force transducer (Grass Instrument, Quincy, MA) for the
measurement of isometric force. Isometric contractions were
recorded on a Grass model 75 polygraph. The ring was
equilibrated in the organ chamber in Krebs-bicarbonate solution containing (in mM) 118.4 NaCl, 4.7 KCl, 2.25 CaCl2,
1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3, and 11 glucose. The
Krebs-bicarbonate solution was gassed with 95% oxygen-5%
carbon dioxide and maintained at 37°C and pH 7.4. Arterial
and venous rings were equilibrated under resting tensions of
2 and 0.5 g, respectively, which were determined, in a preliminary experiment, to be optimal for maximal tension development by 50 mM KCl. The endothelium was intentionally preserved by cautiously mounting the vascular rings,
and the endothelium-dependent relaxation response of vascular rings to acetylcholine was tested in each experiment.
Clinically, vasospasm in microvascular surgery is probably
caused by a myogenic response induced by mechanical
stretch or trauma and local release of vasoconstrictor substances. In the present studies, vascular contraction was
induced by exogenous vasoconstrictors, which are known to
be associated with experimental skin flap vasospasm.
Protocol 1. Each arterial and venous ring was equilibrated
in Krebs-bicarbonate solution for ⬃30 min with continuous
readjustment of resting tension to 2 g for arterial and 0.5 g
for venous rings. At the end of the equilibration period, the
absolute contract to 50 mM KCl was obtained. After three
washings with Krebs-bicarbonate solution, the ring was allowed to stabilize for at least 30 min before an experiment
was started. Vascular contractions to various vasoconstricting agents were expressed as a percent increase in tension
induced by 50 mM KCl.
Cumulative concentration response curves for MCP arteries and veins were obtained to the following agents: ET-1
(10⫺10 to 5 ⫻ 10⫺8 M), the stable TxA2 mimetic U-46619
(10⫺9 to 5 ⫻ 10⫺6 M), and NE (10⫺8 to 5 ⫻ 10⫺5 M).
Cumulative concentration-response curves were constructed
by step addition of the constrictor substances to the organ
chamber solution. Each increment was made only after the
response for the preceding concentration of drug had stabilized (40 min for ET-1, 15 min for U-44619 and NE). Each
ring was used to obtain the concentration-response curve for
only one drug. At the end of each experiment, the presence of
functional endothelium in the vascular ring was determined
by testing the relaxation response to 10⫺5 M acetylcholine.
Protocol 2. For relaxation experiments, each MCP artery
and vein was preconstricted with a submaximal dose of ET-1
(3 ⫻ 10⫺9 M). Preliminary experiments indicated that the
onset of contraction to ET-1 was slow and the maximal
contraction was reached at ⬃30 min and sustained for ⬎140
min. Immediately after the maximum contraction was
achieved, the cumulative concentration-dependent relaxation effect of nitroglycerin, papaverine, nifedipine, or lidocaine (Xylocaine) was studied in arterial and venous rings.
Cumulative concentration-response curves were constructed
by addition of the vasodilator drugs to the organ chamber
solution in 0.5-log unit steps. Each step was made only after
the relaxation response had stabilized (⬃15 min). Each arterial and venous ring specimen was used to obtain the relaxation concentration-response curve for one drug only.
Biochemicals. Unless otherwise stated, all chemicals, except for the following, were purchased from Sigma Chemical
(St. Louis, MO): ET-1 from Peptide International (Louisville,
KY), U-46619 from Caymen (Ann Arbor, MI), NE and nitroglycerin from SABEX (Boucherville, Quebec), and lidocaine
from Abbott Laboratory (St. Laurent, Quebec).
ET-1 was dissolved in 0.1% acetic acid and was stored at
⫺70°C for no longer than 30 days before use. To make stock
solutions, NE was dissolved in 5 ml of 5% dextrose at the
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be reduced, or synthesis and release of endotheliumderived contracting factors, such as thromboxane A2
(TxA2) and endothelin-1 (ET-1), may be augmented (4,
8, 41, 42). Last but not least, reduced local blood flow
due to vasospasm may also increase the thrombogenic
nature of the suture lines of the vascular anastomosis.
This may in turn promote platelet release of vasoconstrictive and prothrombotic substances such as NE,
TxA2, and serotonin [5-hydroxytryptamine (5-HT)]
(29). Venous congestion, i.e., “blue flap,” is a common
pathology in skin flap failure and is likely induced by
venous spasm. There is the clinical impression among
surgeons that veins appear to be more susceptible to
vasospasm than arteries in flap surgery and, once
established, venous spasm seems to be more difficult to
resolve than arterial vasospasm (23). In addition, there
is experimental evidence to indicate that venous ischemia is more injurious in flap surgery (26). These
observations imply that venous vasospasm is an important pathogenic mechanism in free flap surgery.
This study was designed to investigate whether indeed
the human musculocutaneous perforator (MCP) vein is
more susceptible to vasospasm than the MCP artery
and whether this susceptibility is related to differences
in sensitivity to vasoactive agents. The MCP artery
and vein were chosen for this study because the MCP
artery supplies blood to the muscle and skin from the
segmental artery and this pattern of blood supply is
relevant to musculocutaneous pedicled and free flap
surgery.
2269
2270
REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
RESULTS
Contractions of the MCP artery and vein. ET-1,
U-46619, and NE elicited cumulative concentrationdependent contraction in MCP arteries and veins (Figs.
1-3, respectively). The order of vasoconstrictor potency
in both MCP arteries and veins as judged by the pD2
values was ET-1 ⬎ U-46619 ⬎ NE (Table 1), and the
Fig. 1. Cumulative concentration-dependent contractions to endothelin-1 in the human musculocutaneous (MC) perforator artery and
vein with intact endothelium. Contractions are expressed as a percentage of the tension induced by 50 mM KCl: 100% ⫽ 4.35 ⫾ 0.11 g
in MC perforator arteries and 1.57 ⫾ 0.11 g in MC perforator veins.
[M], molar concentration. Values are means ⫾ SE; n ⫽ 5 experiments.
Fig. 2. Cumulative concentration-dependent contractions to
U-46619 in human MC perforator artery and vein with intact endothelium. Contractions are expressed as a percentage of the tension
induced by 50 mM KCl: 100% ⫽ 4.28 ⫾ 0.10 g in MC perforator
arteries and 1.54 ⫾ 0.11 g in MC perforator veins. Values are
means ⫾ SE; n ⫽ 5 experiments.
differences were significant (P ⬍ 0.05). The order of
maximal contraction induced by these vasoconstrictors
was U-46619 ⬎ ET-1 ⫽ NE for MCP arteries and
U-46619 ⫽ ET-1 ⬎ NE for MCP veins (Table 2), and the
differences were also significant (P ⬍ 0.05).
Comparison of contractions between the MCP artery
and vein. The vasoconstrictor potency of ET-1 and
U-46619 as judged by pD2 values (Table 1) was similar
between the MCP artery and vein. However, the maximal contraction elicited by ET-1 was 56% higher in the
MCP vein compared with the MCP artery and for
U-46619 was 38% higher in the MCP vein than MCP
artery (Figs. 1 and 2; Table 2). The vasoconstrictor
potency of NE was twofold higher (P ⬍ 0.05) in the
MCP vein compared with the MCP artery (Table 1), but
the maximal contraction induced by NE was similar
between the MCP artery and vein (Table 2).
Relaxations of the MCP artery and vein. Nitroglycerin, papaverine, nifedipine, and lidocaine elicited concentration-dependent relaxation in MCP arteries and
veins preconstricted with 3 ⫻ 10⫺9 M ET-1 (Fig. 4). The
order of relaxation potency as judged by the pD2 values
was nitroglycerin ⬎ papaverine ⫽ nifedipine ⫽ lidocaine for MCP arteries and nitroglycerin ⬎ papaverine ⬎ nifedipine ⫽ lidocaine for MCP veins (Table 3),
and the differences were significant (P ⬍ 0.05). Next to
nitroglycerin, papaverine was the most effective vaso-
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concentration of 6 ⫻ 10⫺3 M. Papaverine and nifedipine were
dissolved in 0.5 ml of DMSO at the concentration of 10⫺2 M.
Injectable lidocaine was dissolved in perfusion solution.
Krebs-bicarbonate solution and all drug stock solutions were
made in the morning of each experiment day and were kept
at 4°C. Various concentrations of drugs were made with 37°C
Krebs-bicarbonate solution during the experiment. The
quantity of acetic acid, dextrose, and DMSO used for dissolving drugs did not affect the isometric tension of the arterial
and venous rings tested (n ⫽ 3).
Data processing and statistical analysis. Vascular contractions were expressed as a percentage of the tension induced
by 50 mM KCl. Vascular relaxations were expressed as a
percentage of contraction induced by 3 ⫻ 10⫺9 M ET-1. The
concentration of a drug exhibiting 50% of the maximal contraction or relaxation (EC50) was calculated for each arterial
or venous ring. Apparent affinity (pD2) was calculated as
negative log molar concentration of EC50.
All values are expressed are means ⫾ SE. One-way analysis of variance followed by Duncan’s multiple-range test was
used for comparison of mean values. Student’s t-test was
used for comparison of two mean values. Statistical significance was set at P ⬍ 0.05 for all tests. The number (n) of
observations indicates the number of blood vessels obtained
from different patients.
2271
REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
Table 2. Maximal contraction effect of endothelin-1,
U-46619, and norepinephrine in the human
musculocutaneous perforator artery and vein
Maximal Contraction Effect (%
response to 50 mM KCl)
Drug
Artery
Vein
Endothelin-1
U-46619
Norepinephrine
104 ⫾ 2
123 ⫾ 4a
112 ⫾ 3b
b
162 ⫾ 8*a
170 ⫾ 8*a
114 ⫾ 7b
Values are means ⫾ SE; n ⫽ 5 experiments. a,b Within-group
means without a common letter are significantly different (a ⬎ b),
P ⬍ 0.05 (1-way ANOVA followed by Duncan’s multiple comparisons of means). * Venous mean value significantly different from
arterial in endothelin-1 and U-46619 treatment, P ⬍ 0.05 (Student’s
t-test).
Fig. 3. Cumulative concentration-dependent contractions to norepinephrine in the human MC perforator artery and vein with intact
endothelium. Contractions are expressed as a percentage of the
tension induced by 50 mM KCl: 100% ⫽ 4.44 ⫾ 0.10 g in MC
perforator arteries and 1.60 ⫾ 0.11 g in MC perforator veins. Values
are means ⫾ SE; n ⫽ 5 experiments.
dilator observed in the present study. Specifically, the
relaxation potency of papaverine was similar between
nifedipine and lidocaine in the MCP artery but was
significantly higher (P ⬍ 0.05) than nifedipine and
lidocaine in the MCP vein (Table 3). The maximal
relaxation effect was similar among nitroglycerin, papaverine, and nifedipine in that they all completely
mitigated ET-1-induced contraction in both MCP arteries and veins (Fig. 4). However, the maximal relaxTable 1. Vasoconstrictor potency of endothelin-1,
U-46619, and norepinephrine in the human
musculocutaneous perforator artery and vein
pD2
Drug
Artery
Vein
Endothelin-1
U-46619
Norepinephrine
8.852 ⫾ 0.614*
7.862 ⫾ 0.075†
6.138 ⫾ 0.018‡
8.946 ⫾ 0.060*
7.805 ⫾ 0.078†
6.490 ⫾ 0.001‡,§
Values are means ⫾ SE; n ⫽ 5 experiments. pD2, apparent
affinity. *,†,‡ Within-group mean values are significantly different,
P ⬍ 0.05 (* ⬎ † ⬎ ‡); 1-way ANOVA followed by Duncan’s multiple
comparisons of means. § Venous mean value significantly different
from arterial value in norepinephrine treatment, P ⬍ 0.05.
DISCUSSION
The present study demonstrated for the first time
some differences in the responsiveness of the human
peripheral artery and vein to vasoactive agents. Specifically, we observed that the vasoconstrictor potency
of NE was higher in the MCP vein than in the MCP
artery. Although the vasoconstrictor potency of ET-1
and U-46619 was similar between the MCP artery and
vein, their maximal contraction effect was higher in
the MCP vein than in the MCP artery. More importantly, MCP veins preconstricted with a submaximal
concentration of ET-1 were less sensitive to the relaxation effect of nitroglycerin, nifedipine, and lidocaine
than MCP arteries preconstricted with the same concentration of ET-1.
Explanation for differences in contraction between
the human MCP artery and vein. In this study, we did
not plan to investigate the mechanism responsible for
the differences in sensitivity to the vasoconstrictor
effects of NE, ET-1, and U-46619 between the human
MCP artery and vein. These vasoconstrictors were
used because there is experimental evidence to indicate that they most likely contribute to the pathogenesis of vasospasm in flap surgery (4, 41–43). Other
investigators have observed that large canine veins
were more sensitive to the vasoconstrictor effect of
ET-1 than were their paired arteries (7, 35) and the
human internal mammary vein was more sensitive to
the vasoconstrictor effect of NE (31) and ET-1 (6, 32,
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ation achieved by lidocaine was only 48% in the MCP
artery and 49% in the MCP vein (Fig. 4).
Comparison of relaxation between the MCP artery
and vein. MCP veins preconstricted with ET-1 were
less sensitive to the relaxation effect of vasodilators
than MCP arteries preconstricted with the same concentration of ET-1. Specifically, the relaxation potency
of nitroglycerin, nifedipine, and lidocaine, as judged by
their pD2 values, was lower (P ⬍ 0.05) in the MCP vein
than in the MCP artery by 2.4-, 4.7-, and 5.8-fold,
respectively (Table 3). However, the relaxation potency
of papaverine was similar between the MCP artery and
vein.
2272
REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
59) than was its corresponding artery. It was suggested
that the greater vasoconstrictor effect of ET-1 and NE
in the human internal mammary vein than the artery
may be related to a greater vasoconstrictor effect of
these vasoconstrictors on venous smooth muscle cells,
less release of EDRFs, or less responsiveness to EDRFs
in the vein than in the artery (31, 32). Further study is
required to determine which of these factors is responsible for the difference in responsiveness to vasoconstrictors between the MCP artery and vein.
Relaxation mechanism. Nitroglycerin, papaverine,
nifedipine, and lidocaine are common spasmolytic
drugs (15–17, 51). Nitroglycerin releases NO, which
interacts with soluble guanylate cyclase to raise the
intracellular concentration of cGMP, which in turn
mediates vascular smooth muscle relaxation (44, 45).
There is evidence to indicate that cGMP may act to
reduce intracellular Ca2⫹ concentration ([Ca2⫹]i) (1,
22) and modulate the Ca2⫹ contractile apparatus in
smooth muscle cells (2, 25).
Papaverine is known to inhibit oxidative phosphorylation (50) and increase intracellular accumulation of
cAMP and cGMP in vascular smooth muscle cells by
inhibition of cAMP and cGMP degradation by cyclic
nucleotide phosphodiesterases (10, 28, 37). The accumulated cAMP and cGMP decrease [Ca2⫹]i and the
sensitivity of contractile activity in vascular smooth
muscle cells (5).
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Fig. 4. Cumulative concentration-dependent relaxations to nitroglycerin, papaverine, nifedipine, and lidocaine in
the human MC perforator artery and vein with intact endothelium and preconstricted with 3 ⫻ 10⫺9 M
endothelin-1. Relaxations are expressed as a percentage of the contraction induced by 3 ⫻ 10⫺9 M endothelin-1:
100% ⫽ 1.40 ⫾ 0.05 g in MC perforator arteries and 0.67 ⫾ 0.02 g in MC perforator veins. Values are means ⫾ SE;
n ⫽ 4 experiments (nitroglycerin and papaverine) and n ⫽ 5 experiments (nifedipine and lidocaine).
REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
Table 3. Relaxation potency of nitroglycerin,
papaverine, nifedipine, and lidocaine in the human
musculocutaneous perforator artery and vein
preconstricted with 3 ⫻ 10⫺9 M endothelin-1
pD2
Drug
Nitroglycerin
Papaverine
Nifedipine
Lidocaine
n
Artery
Vein
4
4
5
5
5.852 ⫾ 0.063
5.330 ⫾ 0.017b
5.470 ⫾ 0.103b
5.547 ⫾ 0.094b
a
5.442 ⫾ 0.015*a
5.270 ⫾ 0.049b
4.757 ⫾ 0.044*c
4.768 ⫾ 0.043*c
Values are means ⫾ SE; n, no. of experiments. a,b,c Within-group
means without a common letter are significantly different (a ⬎ b ⬎ c),
P ⬍ 0.05; 1-way ANOVA followed by Duncan’s multiple comparisons of means. * Venous mean value is significantly different from
arterial in nitroglycerin, nifedipine, and lidocaine treatments, P ⬍
0.05; Student’s t-test.
postoperatively, and the effectiveness of nitroglycerin
for prevention and/or treatment of postoperative vasospasm is unclear. Specifically, there are positive (9, 13,
43, 47, 51, 56) and negative (14, 39, 54) results in the
therapeutic effect of nitroglycerin in augmentation of
skin flap viability in laboratory animals. These controversial results may be attributed to differences in flap
models, dosage, and method of drug administration.
Nitroglycerin is a safe and inexpensive drug that can
be administered topically in cutaneous and musculocutaneous flaps. Therefore, there is the need to elucidate
the efficacy of nitroglycerin for the prevention and/or
treatment of intraoperative and postoperative vasospasm in flap surgery.
The relaxation mechanism of nitroglycerin and an
L-type Ca2⫹ channel blocker are different; therefore,
the combined use of nitroglycerin and an L-type Ca2⫹
channel such as nifedipine may potentially produce an
additive effect against vasospasm (15, 17). Theoretically, topical nitroglycerin in combination with oral
treatment of an L-type Ca2⫹ channel blocker would
provide optimal prevention and/or treatment against
intraoperative and postoperative vasospasm in flap
surgery. However, similarly to nitroglycerin, the experimental evidence concerning the efficacy of L-type Ca2⫹
channel blockers for augmentation of skin flap viability
is equivocal at the present time (21, 24, 34, 38, 56). The
dose-response effect of L-type Ca2⫹ channel blockers on
skin hemodynamics and viability in flap surgery has
yet to be investigated. It has been demonstrated that
the vasoconstrictor effect of ET-1 is mediated by ETA
receptors, with little participation from ETB receptors
(30). Therefore, selective ETA-receptor antagonists
may also be used as a combined treatment for skin flap
vasospasm. Papaverine is also a potent vasodilator in
human MCP arteries and veins. However, there is the
suspicion that papaverine may not be a drug of choice
because commercially available papaverine solution is
highly acidic (pH 3.0–4.5) and can be potentially damaging to endothelial cells. Papaverine is relatively unstable in nonacidic solution (17, 49). In addition, papaverine is not used systemically; thus the use of
papaverine for the prevention and/or treatment of postoperative vasospasm in flap surgery may be limited.
The effect of cyclooxygenase products on skin flap
viability is unclear. It was observed that intravenous
infusion of prostacyclin (PGI2) did not increase skin
flap distal perfusion or viability in the pig (11). There
were two clinical cases in which aspirin and iloprost (a
stable analog of PGI2) were used as antithrombotic
drugs for salvage of failing flaps (46, 53), but the
efficacy of these drugs for prevention and/or treatment
of skin flap thrombosis has yet to be documented clinically. It is important to point out that there are potential complications of postoperative bleeding and hematoma formation with the use of antithrombotic agents
in flap surgery.
In summary, using the vascular ring perfusion technique, we demonstrated for the first time that the
vasoconstrictor potency of NE is higher in the human
MCP vein than artery and the maximal contractions
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Nifedipine causes vasodilation by blocking entry of
extracellular Ca2⫹ from L-type Ca2⫹ channels (20).
The mechanism of action of lidocaine is unclear. Its
vasodilator effect may be partly due to its inhibitory
effect on local sympathetic nerves and blocking of Na⫹
channels, thus leading to a decrease in intracellular
Na⫹ concentration, which in turn reduces [Ca2⫹]i, resulting in vasodilation (27).
Limitations of the present findings. Experimental
evidence presented thus far seems to indicate that
ET-1-preconstricted human MCP veins are less sensitive to vasodilators such as nitroglycerin, nifedipine,
and lidocaine than are MCP arteries. However, further
studies are required to demonstrate that these differences between human MCP arteries and veins in their
response to the relaxation effect of these spasmolytic
drugs are not limited to ET-1-induced vasoconstriction.
Specifically, Miller and Vanhoutte (36) observed that
the ability of NO donors to inhibit contractions in
canine femoral arteries and veins varied with the
agent used to activate the contraction. For example, it
was reported that, when ET-1 was used to contract the
canine femoral arteries and veins, 3-morpholinosydnonimine was more potent in relaxing arteries than
veins, but this difference was not seen when these
blood vessels were contracted with NE. It has been
demonstrated previously that 5-HT and TxA2 (18, 40),
but not NE (12), are likely to be involved in the pathogenesis of vasospasm and thrombosis in skin flap surgery. Therefore, future study with human MCP arteries and veins is required to clarify the relaxation effect
of vasodilators on 5-HT- and TxA2-induced vascular
contractions.
Clinical perspectives. The effective agents for prevention and/or treatment of flap vasospasm remain elusive. Results obtained from this study certainly indicate that nitroglycerin is a potent vasodilator for
resolving vasospasm in both MCP arteries and veins
intraoperatively. However, it is of interest to investigate whether nitroglycerin can also be used as a prophylactic agent for the prevention of perioperative vasospasm. More importantly, it is well known that
vasospasm and thrombosis can occur within 24–48 h
2273
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REACTIVITY OF MUSCULOCUTANEOUS ARTERY AND VEIN
elicited by ET-1 and U-46619 are higher in the human
MCP vein than artery. On the other hand, the human
MCP vein is less sensitive to the relaxation effect of
nitroglycerin, nifedipine, and lidocaine than the MCP
artery. These differences in sensitivity to vasoconstrictors and vasodilators between the human MCP artery
and vein lend support to the clinical impression that, in
cutaneous and musculocutaneous flap surgery, veins
appear to be more susceptible to vasospasm than do
arteries and, once established, venous vasospasm
seems to be more difficult to resolve than arterial
vasospasm.
The authors thank Tina Ferri for word processing in preparation
of this manuscript.
This research project was supported by an operating grant (MT
8048) to C. Y. Pang from the Medical Research Council of Canada.
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