(Circulation. 1995;92:1448-1451.)
© 1995 American Heart Association, Inc.
Articles |
Blockade of Vasospastic Attacks by 
2-Adrenergic but Not 1-Adrenergic Antagonists in Idiopathic Raynaud's Disease
From the Departments of Psychiatry (Cellular and Clinical Neurobiology) and Obstetrics and Gynecology (R.R.F.), the Department of Surgery (R.P.B.), and the Department of Internal Medicine (M.D.M.), Wayne State University School of Medicine, Detroit, Mich.
Correspondence to Robert R. Freedman, PhD, C.S. Mott Center, 275 E Hancock, Detroit, MI 48201.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Idiopathic Raynaud's disease is characterized by cold-induced digital vasospasms, but its origin has not been established. Previous research has shown that peripheral vascular
2-adrenergic receptors are hypersensitive to
local cooling in these patients, but the role of
1-adrenergic receptors is not clear. Moreover, the role
of adrenergic receptors in the production of actual vasospastic
symptoms has not been investigated.
Methods and Results We studied 23 patients with idiopathic
Raynaud's disease who were screened using conservative criteria. They
were randomly assigned to receive brachial artery infusions of an
1-antagonist, an
2-antagonist, or both while vasospastic
attacks were induced by cooling in the laboratory. Each patient's
hands were photographed, and the number of attacks in the infused hand
was compared with the number in the contralateral hand. The number of
fingers (mean±SEM) with attacks in infused hands was yohimbine
0.3±0.3, prazosin 2.3±0.3, and both drugs 0.6±0.2. The
difference
between prazosin and the other two drug groups was significant
(P<.001).
Conclusions These findings demonstrate that activation of
2-adrenergic receptors but not
1-adrenergic receptors is necessary for the
production of vasospastic attacks in idiopathic Raynaud's
disease.
Key Words: Raynaud's disease • receptors, adrenergic, alpha • receptors, adrenergic, beta • vasospasm • drug interactions
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Idiopathic Raynaud's disease is characterized by digital vasospastic attacks that are usually provoked by exposure to cold. Although the prevalence of the disease is not known, estimates range from 4.3% of women in the southern United States1 to 19% in the United Kingdom.2
Two main theories have been postulated to explain the pathophysiology of idiopathic Raynaud's disease. Raynaud3 hypothesized that excessive sympathetic nervous system activity caused an increased vasoconstrictive response to cold, whereas Lewis4 hypothesized that a "local fault" caused cold hypersensitivity of the digital arteries.
Recent evidence favors the theory of Lewis. It has been shown that the
vasospastic attacks of Raynaud's disease can be provoked despite
digital nerve blockade5 and that sympathetic nerve impulse
activity in these patients is normal.6 It also has been
shown that vasoconstrictive responses to
intra-arterial clonidine (an 2-adrenergic
agonist) are significantly greater in idiopathic Raynaud's disease
patients than in healthy volunteers.7 8 However, the
role
of 1-adrenergic receptors in Raynaud's disease is
not clear. Whereas some investigations have found increased
vasoconstrictive responses to intra-arterial phenylephrine (an
1-adrenergic agonist) in Raynaud's disease
patients,7 9 others have not.8 Moreover,
the
role of adrenergic receptors in actual vasospastic attacks has not been
studied.
There is considerable evidence that 2-adrenergic
receptors are more important than 1-adrenergic receptors
in agonist-induced and cold-induced vasoconstriction. Coffman and
Cohen10 showed that intra-arterial clonidine
was considerably more potent than intra-arterial
phenylephrine in reducing finger blood flow and that
intra-arterial yohimbine
(2-antagonist) but not prazosin
(1-antagonist) significantly increased
finger blood flow in a cold room. These findings were supported by
subsequent studies showing that an
2-antagonist but not an
1-antagonist abolished cold-induced
vasoconstriction in human finger skin11 and that
2-agonists were more potent than
1-agonists in reducing cutaneous blood
flow.12
To more precisely delineate the pathophysiology of idiopathic
Raynaud's disease we sought to determine whether
1, 2, or both adrenergic
receptor subtypes are necessary to produce vasospastic attacks. We
therefore provoked vasospastic attacks in the laboratory during
brachial artery infusions of selective 1-adrenergic and
2-adrenergic antagonists.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
Twenty-three patients (17 women, 6 men; ages 25 to 57 years old; mean±SD, 41.0±7.7 years old) meeting the Allen and Brown13 criteria for primary Raynaud's disease were examined by a rheumatologist. All were negative for antinuclear and anticentromere antibodies (tested using HEp2 substrate) and had normal nailfold capillaries using the method of Maricq et al.14 Average patient weight and height were 69.5±10.5 kg and 167.6±7.6 cm, respectively. The average duration of Raynaud's disease was 9.2±7.3 years, and patients reported an average of 2.0±1.8 vasospastic attacks per day. None of the patients was taking medication, and all gave written informed consent according to procedures approved by our institutional review board.
Maximum Vasodilation Test
All patients received a maximum
vasodilation test to determine
the patency of digital blood vessels. We have used this procedure
before for the same purpose.5 7 9
Patients wearing cotton
hospital scrub suits were supine in a 28°C room. Finger blood flow
was measured three times per minute from both index fingers, using
venous occlusion plethysmography, and recorded on a
polygraph.5 7 9
After 16 minutes, patients were heated ventrally and dorsally with two 91x152-cm circulating water pads maintained at 42°C. The upper extremities were not covered by the pads. After 45 minutes of heating, the peak finger blood flow responses to 2 and 4 minutes of ischemia were measured. Data from these patients were compared with data from 29 healthy volunteers (24 women and 5 men, ages 22 to 66 years old) used in our previous research.9 Data from the two groups were compared using repeated measures ANOVAs.
Procedures
All infusions were performed on a separate day
between 12:00 and
4:30 PM. Patients were seated in a 23°C temperature-
and humidity-controlled room (relative humidity 45% to 50%). A slow
intravenous drip of 0.9% sterile saline solution was
started in one arm. In the opposite arm, a 20-gauge catheter was
inserted percutaneously into the brachial artery, with
lidocaine as the local anesthetic. The catheter was maintained patent
with a 0.75 mL/min infusion of 0.9% sterile saline solution
administered using a Harvard 901 pump.
Patients were randomly assigned
to receive one of three drug
infusions: yohimbine HCl (NIH pharmacy, 70 µg/min,
1.8x10-7 mol/min), prazosin HCl (Pfizer, 6 µg/min,
1.4x10-8 mol/min), or both drugs. The doses of
prazosin and yohimbine were determined in the following manner:
Intra-arterial phenylephrine at 1 µg/min
reduces finger blood flow by 
50% in human subjects.10
This effect is blocked by 6 µg/min prazosin10 but is not
affected by 70 µg/min yohimbine.15 Similarly,
intra-arterial clonidine at 0.2 µg/min reduces blood flow
by 50% in human fingers.10 This vasoconstriction is
blocked by 70 µg/min yohimbine but is not affected by 6 µg/min
prazosin.10 Binding studies have shown that prazosin
(1-adrenergic receptor antagonist) and
yohimbine (2-adrenergic receptor antagonist)
are approximately 104 times more selective than each other
at their respective receptor subtypes, depending on the tissue
used.16 Thus, the antagonists used in the
present study are selective for their respective receptor subtypes
and are equipotent in the doses given. All drugs were dissolved in
0.9% sterile saline solution and infused at a rate of 1.0 mL/min with
a second Harvard 901 pump.
Eight patients were assigned to receive yohimbine, 8 to receive prazosin, and 7 to receive both drugs. There were no differences among these three groups in age, height, weight, sex, duration of disease, reported symptom frequency, or responses to the maximum vasodilation test.
Attack Induction
The drug solution was infused for 10 minutes
with the room at
23°C. The patient's hands were then photographed with a Minolta
Maxxum 7000 automatic camera with a ring flash, macrozoom lens, and
Kodak Ektachrome slide film (ASA 200). As the drug infusion continued,
the room temperature was reduced to 4°C in 10 minutes. The room was
specially constructed with its own cooling and heating
apparatus to accomplish this rapid temperature change. The
patient held a 1000-mL beaker of ice water for 2 minutes, and then
placed the beaker on a table for 2 minutes, during which time the
patient's hands were again photographed. Anterior and posterior views
of the hands were obtained, with a stopwatch in the field of view. We
attempted to capture any discernible color changes. This process was
repeated for 25 to 45 minutes, until an apparent vasospastic attack
occurred. Then the room was rapidly rewarmed, and the catheters were
removed. We have used similar methods previously.5
Determination of Attacks
The slides were processed and
numbered by the same photographic
laboratory, then viewed and rated independently by two raters
experienced in work with Raynaud's disease. The raters were blinded to
the drug used and hand being infused. Each finger in each slide was
scored as to whether a color change had occurred. A vasospastic attack
was defined as two out of the possible three color changes (pallor,
cyanosis, or rubor) in the same finger.5
The number of fingers scored as having an attack was determined by each rater for each patient. The data from the two raters were then averaged. The averaged data were analyzed by two-way (drug by hand) ANOVA with simple effects tests.17 Thus, the number of fingers with an attack in the infused hand was compared with the number in the noninfused (control) hand across the three drug groups.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Data from the maximum vasodilation test are shown in Table 1
. Heating and ischemia produced significant
vasodilation (P<.001), which did not differ significantly
between Raynaud's patients and healthy volunteers.
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Results of the infusions are shown in Table 2.
Vasospastic attacks occurred in 21 of 23 (91.3%) patients. The ANOVA
showed significant effects for hand (P=.0001) and for the
hand by drug interaction (P<.0012). For the group treated
with yohimbine, significantly fewer attacks occurred in the infused
hand than in the noninfused hand (P<.001). In the group
treated with prazosin, there was no significant difference between the
two hands (P=.74). For the group treated with both yohimbine
and prazosin there were significantly fewer attacks in the infused than
the noninfused hand (P<.001). However, there was no
additional effect of prazosin compared with that of yohimbine
alone.
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Complete prevention of attacks in the infused arm occurred in 6 of 8 yohimbine group patients, 0 of 8 prazosin group patients, and 5 of 7 yohimbine plus prazosin patients. There was no significant difference (P>.3) among the three groups in the amount of time the ice beaker was held (mean±SEM, 11.4±0.7 minutes). The 2 yohimbine group patients who had attacks held the beaker for 14 and 13 minutes.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present investigation, yohimbine but not prazosin significantly blocked vasospastic attacks associated with idiopathic Raynaud's disease. These data provide strong evidence that activation of
2-adrenergic receptors but not
1-adrenergic receptors is necessary for
production of these symptoms. We previously demonstrated that
local cooling augments 2-adrenergic vasoconstriction in
fingers of patients with Raynaud's disease but produces the opposite
effect in healthy female volunteers.7 Additionally, there
is considerable evidence from animal studies that
peripheral vascular 2-adrenergic receptors
are thermosensitive.18 19 20 Thus, it is
likely that
cold-induced sensitization of peripheral vascular
2-adrenergic receptors triggers the vasospastic attacks
of idiopathic Raynaud's disease. Other studies have shown increased
numbers of platelet 2-adrenergic receptors in
Raynaud's disease patients, suggesting the possibility of a
generalized 2-adrenergic receptor abnormality in this
group.21 22 23 However, further research
is needed to support
this hypothesis.
The present study found that prazosin had no effect in attenuating
the vasospastic attacks, demonstrating that 1-adrenergic
receptor stimulation is not necessary for symptom production.
These data are consistent with previous findings that local
cooling did not affect 1-adrenergic vasoconstriction in
Raynaud's disease patients.7 Evidence of increased
1-adrenergic responsiveness in Raynaud's disease may
explain the lower finger blood flows sometimes found at comfortable
ambient temperatures in these patients.24 However,
1-adrenergic responses do not appear to be necessary to
trigger the vasospastic attacks.
We considered the possibility that the lack of effect of prazosin was
due to an insufficient dose. However, previous research using similar
methods showed that our dose produced significantly increased finger
blood flow in a cold room in primary Raynaud's patients8
and was sufficient to block the vasoconstrictive
effects of intra-arterial phenylephrine
(1-agonist).10 Thus, it is highly likely
that an 1-antagonist effect was produced by
the dose of prazosin in the present study. Even if we had achieved
partial 1-adrenergic blockade, one would have expected
prazosin to cause some reduction in the number of attacks, albeit less
than that of yohimbine. However, we did not obtain that result.
Each patient served as his or her own control in the present study, since we compared attacks in the infused hand with those in the contralateral hand. Thus, hormonal effects cannot explain our findings. Moreover, because our patients were conservatively classified and showed normal responses to a maximum vasodilation test, it is unlikely that our results are due to vascular wall hypertrophy in some fingers.
In conclusion, the present study demonstrates that
2-adrenergic receptor but not
1-adrenergic receptor activation is necessary to induce
vasospastic attacks in idiopathic Raynaud's disease. Future research
should attempt to determine the causes of this
2-adrenergic receptor abnormality and to develop
effective therapeutic interventions to ameliorate it.
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Acknowledgments |
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This work was supported by research grant HL-30604 from the National Heart, Lung, and Blood Institute. We thank Janice Rodriguez for technical assistance; Daniel Colaluca, PharmD, for preparing the drugs; Dena Norton for analyzing the data; Helen Brewster for preparing the manuscript; and Pfizer Inc for donating the prazosin.
Received February 14, 1995; accepted March 27, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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