(Circulation. 1995;91:1154-1160.)
© 1995 American Heart Association, Inc.
Articles |
Testosterone Relaxes Rabbit Coronary Arteries and Aorta
From the Department of Cardiac Medicine, National Heart and Lung Institute, London, and the Cardiovascular Research Institute (K.C.), University of California, San Francisco.
Correspondence to Dr Peter Collins, Department of Cardiac Medicine, National Heart and Lung Institute, London SW3 6LY, UK.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Until menopause, women appear to be protected from coronary heart disease. Evidence suggests that estrogen may play a role in the protection of the cardiovascular system by exerting a beneficial effect on risk factors such as cholesterol metabolism and by a direct effect on the coronary arteries. To date there has been no evidence linking testosterone with the occurrence of coronary heart disease. Testosterone may affect the cardiovascular system directly, thus partially explaining the difference in the incidence of coronary artery disease in men and premenopausal women. The purpose of this study was to assess the direct effect of testosterone and a number of testosterone analogues on rabbit coronary arteries and aorta in vitro.
Methods and Results Rings of coronary artery and aorta of
adult male or nonpregnant female New Zealand White rabbits were
suspended in organ baths containing Krebs solution; isometric tension
then was measured. The response to testosterone was investigated in
prostaglandin F2
(PGF2)- and
KCl-contracted rings. The effects of endothelium and nitric oxide
synthase, prostaglandin synthetase, and guanylate cyclase inhibition on
testosterone-induced relaxation were investigated. The effects of
ATP-sensitive potassium channels and potassium conductance were also
assessed. Relaxing responses in the presence of aromatase inhibition
and testosterone receptor blockade were performed. The relaxing
responses to the testosterone analogues etiocholan-3ß-ol-17-one,
epiandrosterone, 17ß-hydroxy-5-androst-1-en-3-one,
androst-16-en-3-ol, and testosterone enanthanate were measured.
Testosterone relaxed rabbit coronary arteries and aorta. There was no
significant difference between the relaxation effect of testosterone
with or without endothelium. Similar results were obtained from male
and nonpregnant female rabbits. The relaxing response of testosterone
in the coronary artery was significantly greater than in the aorta. The
relaxing response of testosterone in the coronary artery was
significantly reduced by the potassium channel inhibitor barium
chloride but not by the ATP-sensitive potassium channel inhibitor
glibenclamide. The relaxing response to testosterone was greater in
PGF2-contracted rings compared with KCl-contracted
rings. Inhibitors of nitric oxide synthase, prostaglandin synthetase,
and guanylate cyclase did not affect relaxation induced by
testosterone. Inhibition of aromatase and testosterone receptors did
not affect relaxation. Testosterone did not shift the rabbit coronary
arterial calcium concentration–dependent contraction curves, whereas
verapamil did. There were, however, significant differences in the
relaxing response to testosterone compared with testosterone analogues.
Testosterone was the most potent relaxing agent, suggesting that there
may be a structure-function relation in the relaxing response.
Conclusions Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.
Key Words: hormones • arteries • endothelium • aorta
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The most important benefit of hormone replacement therapy in postmenopausal women is a reduction of the risk of coronary heart disease.1 A decrease in low-density lipoproteins and an increase in high-density lipoproteins may be an important mechanism by which estrogen reduces coronary heart disease risk.2 Recently, the effect of 17ß-estradiol on endothelium-dependent and endothelium-independent coronary arterial relaxation has been demonstrated.3 4 5 6 Modulation of coronary arterial tone could therefore be another mechanism by which estrogen protects the myocardium from ischemia.7
The fact that postmenopausal women have a lower incidence of coronary heart disease and myocardial infarction than men of a similar age has led to the hypothesis that testosterone may predispose to coronary artery disease. However, there has been no direct evidence linking testosterone administration to an increased incidence of coronary heart disease and myocardial infarction.
The effect of testosterone on the coronary circulation is unknown; however, there have been reports suggesting that testosterone therapy in men has a beneficial effect on angina pectoris8 9 10 11 and on exercise-induced ST segment depression in patients with angina pectoris.12 A double-blind study was carried out in 50 men who had ST segment depression after exercise.12 It was shown that after 4 to 8 weeks of treatment with testosterone or placebo, there was a significant decrease in the exercise-induced extent of ST segment depression in patients treated with testosterone. The mechanisms by which testosterone decreased after exercise ST segment depression were not established. The direct effect of testosterone on the coronary artery and any underlying mechanisms of action are not known. The purpose of this study was to assess the effect of testosterone on isolated rabbit coronary arteries and aorta. We examined the possible role of the endothelium, cyclic GMP (cGMP), vasodilator prostanoids, testosterone receptors, potassium conductance, and calcium influx on testosterone-induced coronary and aortic relaxation. We also examined the effect of a number of testosterone analogues on isolated rabbit coronary arteries.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals and Tissues
Adult male and nonpregnant female New Zealand White rabbits (weight, 2.5 to 3 kg) were killed by an overdose of pentobarbitone (60 mg/kg) and heparin (150 U/kg), in accordance with our institutional guidelines. The hearts were rapidly removed, and the coronary arteries and aorta were dissected free of connective tissue. Arterial rings were prepared, and, in alternate rings, the endothelium was removed by gentle rubbing with a wooden probe. Each ring was suspended horizontally between two stainless steel parallel hooks for the measurement of isometric tension in individual organ baths containing Krebs solution composed of (mol/L) NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, K2PO4 1.2, and glucose 11.1, bubbled with 95% O2 and 5% CO2. Temperature was maintained at 37°C. Isometric tension generated by the vascular smooth muscle was measured using a displacement transducer (model UFI, Devices) and recorded on a pen-chart recorder, as previously described.5
Relaxing Effect of Testosterone on
Precontracted Coronary Arteries
and Aorta
Coronary arteries and aortic rings with or without
endothelium
were stabilized under 1 g of resting tension for 90 minutes before
being contracted with prostaglandin F2
(PGF2, 3 µmol/L). Testosterone (dissolved in
ethanol, 0.1, 1, and 10 µmol/L for coronary rings and 10 and 100
µmol/L for aortic rings) or equivalent ethanol solvent (1 in 1000)
was added 7 minutes after the addition of constrictor agent. In one
group of experiments, the relaxing effects of testosterone (1 and 10
µmol/L) were compared in rings contracted by PGF2 (3
µmol/L) or KCl (30 mmol/L).
Effect of
N
-Nitro-L-Arginine Methyl
Ester and Indomethacin on Testosterone-Induced Relaxation
N-nitro-L-arginine methyl
ester (L-NAME) is an inhibitor of endothelium-derived
relaxing factor (EDRF) synthesis from L-arginine in
vascular endothelial cells.13 L-NAME (100 µmol/L) was
added to coronary arterial and aortic rings with endothelium 20 minutes
before being contracted with PGF2 (3 µmol/L).
Indomethacin, an inhibitor of prostanoid synthesis, was dissolved by
sonication in an Na2CO3 solution. Indomethacin
(10 µmol/L) was incubated with endothelium-intact
rings for 20 minutes before being precontracted with
PGF2. Testosterone (1, 10, and 100 µmol/L) was
subsequently added 7 minutes after the addition of the constrictor
agent.
Effect of Methylene Blue on Testosterone-Induced
Relaxation
To determine the possible involvement of cGMP in the
relaxation
induced by testosterone, coronary arterial and aortic rings without
endothelium were incubated with methylene blue14 (10
µmol/L) for 20 minutes before being contracted with
PGF2 (3 µmol/L). Testosterone (1, 10, and 100
µmol/L) was subsequently added.
Effect of Glibenclamide
and Barium Chloride on Testosterone-Induced
Relaxation
To examine the possible role of ATP-sensitive potassium
channels
and potassium conductance on testosterone-induced coronary relaxation,
glibenclamide (3 µmol/L), an inhibitor of ATP-sensitive potassium
channels,15 or barium chloride (3 mmol/L), a nonspecific
inhibitor of potassium channels,16 was added to coronary
artery rings without endothelium 20 minutes before being contracted
with PGF2 (3 µmol/L). The relaxation to testosterone
(1, 10, and 100 µmol/L) or equivalent concentrations of ethanol
solvent was measured.
Effect of Aminoglutethimide and
Flutamide on Testosterone-Induced
Relaxation
Aromatase is a tissue enzyme that converts testosterone to
estrogen.17 To examine the possible role of aromatase and
testosterone receptors on testosterone-induced coronary relaxation,
aminoglutethimide (50 µmol/L), an inhibitor of aromatase, or
flutamide (10 µmol/L), a testosterone receptor
antagonist,18 was added to
endothelium-denuded coronary artery rings 20 minutes
before contraction with PGF2 (3 µmol/L). The
relaxation response to testosterone (1 and 10 µmol/L) then was
measured.
Effect of Testosterone and Verapamil on Calcium
Concentration–Dependent Contractile Responses in Rabbit Coronary
Arteries
Rabbit coronary arterial rings without endothelium were
incubated in calcium-free solution containing 0.5 mmol/L EGTA for 10
minutes. Afterward, calcium concentration–dependent contraction curves
were performed in K+ depolarization medium
(K+=100 mmol/L). Rings were readjusted in modified
Krebs
for 20 minutes before being incubated in calcium-free solution
containing EGTA (0.5 mmol/L) for a further 10 minutes. Subsequently,
rings were incubated with testosterone (1 and 10 µmol/L) or verapamil
(1 and 10 µmol/L) or the same concentration of ethanol solvent for 30
minutes. The calcium concentration–dependent contraction curves then
were repeated.
Effect of Testosterone Analogues on
Precontracted Coronary
Arteries
Coronary artery rings were stabilized under 1 g of resting
tension for 90 minutes before being contracted with PGF2
(3 µmmol/L). Testosterone analogues etiocholan-3ß-ol-17-one,
epiandrosterone, 17ß-hydroxy-5-androst-1-en-3-one,
androst-16-en-3-ol, and testosterone enanthanate (dissolved in ethanol,
1 and 10 µmol/L) were added 7 minutes after the addition of
constrictor agent.
Drugs
The following drugs were used: testosterone
(4-androsten-17ß-ol-3-one), etiocholan-3ß-ol-17-one
(5ß-androstan-3ß-ol-17-one), epiandrosterone
(3ß-hydroxy-17-androstanone), 17ß-hydroxy-5-androst-1-en-3-one,
androst-16-en-3-ol (3-hydroxy-5-androst-16-ene), testosterone
enanthanate (17-[(1-oxoheptyl)oxy]-androst-4-en-3-one), L-NAME,
indomethacin, methylene blue, barium chloride,
PGF2, pentobarbitone, aminoglutethimide,
flutamide (all supplied by Sigma), and glibenclamide (a gift from
Hoechst). All drugs were Analar grade.
Data Analysis
All results are expressed as mean±SEM.
Relaxation is expressed
as percentage relaxation of contraction induced by PGF2
(3 µmol/L) or KCl (30 mmol/L). The results were analyzed with a
Student's t test for paired and unpaired observations. Each
group was compared with the time-matched ethanol solvent control. A
probability level of less than .05 was considered significant. For the
analogue data, an ANOVA with repeated measurements was used. If a
significant F value was found, Scheffé's test for multiple
comparisons was used to identify differences among groups. n indicates
the number of animals.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Relaxing Effect of Testosterone on Precontracted Coronary Arteries and Aorta
PGF2
(3 µmol/L) and KCl (30 mmol/L)
induced
comparable contractile responses in coronary arterial rings with and
without endothelium (0.7±0.1, 0.7±0.1 g and 0.7±0.05,
0.7±0.05 g,
respectively, P>.05). Likewise, PGF2 (3
µmol/L) induced comparable contractile responses in rabbit aortic
rings with and without endothelium (1.12±0.1 and 1.13±0.05 g,
respectively). Testosterone (0.1 µmol/L) had no effect on
PGF2-precontracted (3 µmol/L) rabbit coronary arterial
rings (Fig 1
). However, 1 and 10 µmol/L of
testosterone induced significant concentration-related relaxation of
contracted rings with or without endothelium from male or female
rabbits (compared with time-matched ethanol solvent controls, all
P<.01, Fig 1). There were no differences between
the
relaxation of arteries from male and female rabbits to testosterone 1
and 10 µmol/L (23±5, 74±6 versus 25±5, 71±6,
all
P>.05, n=8). There were no differences between groups with
and without endothelium (P>.05, Fig 1).
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Testosterone (1 µmol/L) had no effect on PGF2-
precontracted (3 µmol/L) rabbit aortic rings. However, 10 and 100
µmol/L of testosterone induced significant concentration-related
relaxation of contracted rings with and without endothelium from male
or female rabbits (compared with time-matched ethanol solvent controls,
all P<.01, Fig 2). There were no differences
between coronary arteries from male and female rabbits (10±3,
40±3
versus 10±1, 31±7, all P>.05, n=8). There
were no
differences between groups with and without endothelium
(P>.05, Fig 2).
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Testosterone (1 and 10
µmol/L) induced significantly greater
relaxation in rabbit coronary arterial rings than in rabbit aortic
rings (P<.05). Testosterone (1 and 10 µmol/L) induced
significantly greater relaxation in coronary arterial rings
precontracted with PGF2 (3 µmol/L) than rings
precontracted with KCl (30 mmol/L) (P<.01, Fig 3).
Representative traces are shown in Fig 4.
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Effect of N-Nitro-L-Arginine
Methyl Ester and Indomethacin on Testosterone-Induced Relaxation
Incubation with L-NAME (100 µmol/L) did not inhibit relaxation
induced by testosterone (1 and 10 µmol/L) in either rabbit coronary
arterial rings (14±2 versus 23±5 and 55±8 versus
74±6,
respectively, P>.05) or rabbit aortic rings (12±1 versus
12±5 and 37±3 versus 32±6, respectively,
P>.05) with
endothelium. Incubation with the prostaglandin synthetase inhibitor
indomethacin (10 µmol/L) did not affect the relaxation induced by
testosterone (1 and 10 µmol/L) in rabbit coronary arterial rings
(14±2 versus 23±5 and 62±9 versus 74±6,
respectively,
P>.05) or aortic rings (11±1 versus 12±5 and
40±3 versus
32±6, respectively, P>.05) with endothelium.
Effect of Methylene Blue on Testosterone-Induced Relaxation
Incubation with methylene blue (10 µmol/L) for 20 minutes before
contraction with PGF2 (3 µmol/L) had no effect on
relaxation induced by testosterone (1 and 10 µmol/L) in rabbit
coronary arterial rings (15±3 versus 23±5 and 68±7 versus
74±6,
respectively, P>.05) or testosterone (10 and 100 µmol/L)
in aortic rings (11±3 versus 12±5 and 30±7 versus
32±6,
respectively, P>.05) without endothelium.
Effect of Glibenclamide and Barium Chloride on Testosterone-Induced
Relaxation
Glibenclamide (3 µmol/L) did not affect the relaxing
effect of
testosterone. Barium chloride (3 mmol/L) partially but significantly
reduced testosterone-induced relaxation in rabbit coronary arterial
rings without endothelium (n=8, P<.05, Fig
5).
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Effect of Aminoglutethimide and Flutamide on Testosterone-Induced
Relaxation
Aminoglutethimide (50 µmol/L) did not affect the
relaxing effect
of testosterone (10 µmol/L) in coronary arterial rings (68±7% and
70±7% before and after aminoglutethimide, respectively, n=6,
P>.05). Flutamide (10 µmol/L) did not influence
testosterone-induced (1 and 10 µmol/L) relaxation in coronary
arterial rings without endothelium (17±3, 72±7 and 16±3,
71±3
before and after flutamide, respectively, n=6, P>.05).
Effect of Testosterone and Verapamil on Calcium
Concentration–Dependent Contractile Responses in Rabbit Coronary
Arteries
The calcium concentration–dependent contraction curves
in
K+ depolarization medium were not affected by testosterone
(1 and 10 µmol/L) in rabbit coronary arterial rings without
endothelium. The -log EC50s of calcium in control rings
and after incubation with testosterone (1 and 10 µmol/L) for 30
minutes were 3.8±0.2, 3.5±0.2, and 3.6±0.15, respectively
(Fig 6). In contrast, the concentration-dependent contraction
curves in K+ depolarization medium were shifted to the
right in a dose-dependent manner after incubation with verapamil (1 and
10 µmol/L) in rabbit coronary arterial rings without endothelium.
Maximal contraction was reduced to 52±9% and 18±5%,
respectively.
The -log EC50s of calcium in control and after incubation
with verapamil (1 and 10 µmol/L) for 30 minutes were 3.7±0.1,
2.8±0.18, and 1.8±0.1, respectively (Fig 7).
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Indicates control;
, 1 µmol/L testosterone; and 
, 10 µmol/L testosterone.
Data are expressed as percentage of maximal contraction induced by
calcium in controls (mean±SEM, n=8 in each group).
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Effect of Testosterone Analogues on Precontracted Coronary
Arteries
There were significant differences in the relaxing potency of
testosterone analogues (1 and 10 µmol/L) on precontracted rabbit
coronary arterial rings (Fig 8). There were no
significant differences between the relaxation induced by testosterone
(1 and 10 µmol/L), etiocholan-3ß-ol-17-one, and epiandrosterone;
however, there were significant differences between
testosterone-induced relaxation and that induced by
17ß-hydroxy-5-androst-1-en-3-one, androst-16-en-3-ol, and
testosterone enanthanate.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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We have demonstrated that testosterone (1, 10, and 100 µmol/L) induces relaxation in precontracted rabbit coronary arteries and aorta with or without endothelium. No difference was seen between arteries from male and female rabbits. Barium chloride partially inhibited the relaxation, and the relaxing response to testosterone was greater in PGF2
-contracted rings compared with KCl-contracted
rings. Neither L-NAME, methylene blue, indomethacin, animoglutethimide,
flutamide, nor glibenclamide affected this relaxation. Testosterone did
not shift the calcium concentration–dependent contraction curve in
high K+ solution (100 mmol/L) in rabbit coronary artery
preparations. Early studies from the 1940s assessed the effect of intramuscular testosterone, usually 25 mg given 2 to 5 times per week, on a variety of clinical parameters including anginal symptoms and crude ECG assessments.8 9 10 These studies suffer from the fact that the numbers of patients studied were small (7, 9, and 20, respectively), there was no documentation of coronary artery disease, and very few patients received placebo. A later study by Lesser11 reported marked clinical improvement of angina pectoris in 91 out of 100 patients treated with 15 to 25 intramuscular injections of 25 mg of testosterone propionate given over periods varying from several months to 5 years. Again, this study provided no objective evidence of a benefit in myocardial ischemia and no documentation of coronary artery disease. In this study, 5 patients were given six consecutive injections of sesame oil as control, and none of these patients showed any change in symptoms. One of the commonly cited theoretical mechanisms of the beneficial effect of testosterone on anginal symptoms in these studies was coronary vasodilatation.8 10 11 In a later study, testosterone treatment for several weeks reduced objective evidence of exercise-induced myocardial ischemia in patients with angina pectoris.12 Possible mechanisms discussed for this beneficial effect included an improvement of oxygen-carrying capacity of red cells19 and an increase in blood hemoglobin levels.20 Dilatation of the coronary arteries or their collaterals also was suggested to account for the beneficial effect; however, this hypothesis has never been tested. Testosterone is highly protein bound in plasma21 ; 98% of testosterone is bound to sex hormone–binding globulin, albumin, and other proteins. This may result in substantially different concentrations at different sites, including the smooth muscle of arteries, in vivo. Physiological effects may therefore occur despite lower plasma concentrations of the hormone.
Some of the increased risk for coronary heart disease in men has been attributed to differences in lipoprotein levels; in particular, high-density lipoprotein cholesterol (HDL-C), a protective factor, is higher in women. There are some reports that testosterone substitution in men is associated with decreased serum HDL-C levels.22 23 However, the data are by no means consistent, since testosterone replacement in elderly men caused a decrease in total cholesterol without a change in HDL-C cholesterol,24 and testosterone treatment may have other beneficial effects on cardiovascular and diabetic risk factors such as insulin resistance.25 The effect of physiological levels of testosterone in the control of lipoproteins and cardiovascular risk also is not clear. Some studies suggest a suppressive effect on HDL-C,26 whereas other studies suggest that testosterone levels are favorably associated with cardiovascular risk.27 28 It also has been shown that hypotestosteronemia is associated with an adverse cardiovascular risk29 30 and that testosterone replacement in such men reverses this adverse risk.31 The data on the unfavorable effect of testosterone replacement on cardiovascular risk are therefore not established or clear.
Acetylcholine induces endothelium-dependent vascular relaxation mediated by the release of EDRF.32 We have demonstrated that testosterone induced an equal degree of relaxation in rabbit coronary arteries and aorta with and without endothelium. L-NAME, an inhibitor of EDRF synthesis,13 did not affect the relaxation by testosterone. Methylene blue, an inhibitor of EDRF- induced increase of cGMP,14 also had no effect on relaxation induced by testosterone. Our results suggest that the in vitro acute relaxation of rabbit coronary arteries and aorta by testosterone is independent of EDRF.
Indomethacin inhibits the synthesis of prostaglandins.33 34 Indomethacin markedly inhibits the transient relaxation induced by arachidonic acid in rabbit coronary arteries.4 However, indomethacin did not affect testosterone-induced relaxation in endothelium-intact coronary arteries. These results indicate that the release of vasodilator prostanoids is not involved in testosterone-induced coronary relaxation in vitro.
Glibenclamide, an inhibitor of ATP-sensitive potassium
channels,15 did not affect testosterone-induced
relaxation. Barium chloride, a nonspecific inhibitor of potassium
channels,16 did attenuate the relaxing response to
testosterone in rabbit coronary arteries, suggesting that alterations
of potassium conductance may be involved partially in the mechanism of
relaxation. At concentrations less than those used in this study,
barium chloride has been shown to reverse the nonendothelium
vasorelaxing actions of the potassium channel–opening drugs diazoxide,
cromakalim, and pinacidil in norepinephrine-contracted (10
µmol/L) rabbit mesenteric artery rings.15 Testosterone
is much more effective in relaxing PGF2-contracted
tissues than those contracted with high concentrations of potassium.
The reason for this difference is not clear, but similar differences
have been demonstrated for the relaxing responses to potassium channel
openers such as pinacidil.35 This differential effect is
indicative of potassium channel opening36 and supports the
possibility that the testosterone-induced relaxation may involve
potassium channel opening, since the relaxation was partly inhibited by
barium chloride.
There is no evidence that testosterone receptors exist in vascular or cardiac tissues. We did assess the effect of the nonsteroidal antiandrogen flutamide18 on testosterone-induced relaxation. The other potential relaxing mechanism of testosterone is by its conversion to estradiol via the aromatase pathway.17 Therefore, we investigated the relaxing effect in the presence of aminoglutethimide, which is a competitive nonsteroidal aromatase inhibitor. This substance blocks the conversion of androgenic prohormones to estrogen.17 Neither aminoglutethimide nor flutamide affected the relaxation responses to testosterone, suggesting that neither the testosterone receptor nor its conversion to estrogen is involved in the mechanism of smooth muscle relaxation.
Potential sensitive calcium channels are activated by depolarization of the plasma membrane when the extracellular K+ concentration is increased. Incubation with testosterone did not shift the calcium concentration–dependent contraction curves to the right in high K+ depolarization medium in rabbit coronary arteries without endothelium. These results suggest that testosterone does not have a calcium-antagonistic property in these vascular preparations.
The concentrations that induce relaxation of rabbit coronary arterial
preparations in vitro (1 and 10 µmol/L) are approximately 50 and 100
times greater than those found in normal male volunteers (21±1 nmol/L)
and approximately 10 times greater than those found in New Zealand
White rabbits (77±2 to 638±11 nmol/L).37 However,
the
concentrations of testosterone produced by intramuscular injections of
25 mg of the hormone produce supraphysiological peak blood levels in
hypogonadal men.38 These levels are approximately 10 times
less than those used in this in vitro study, which induced coronary
relaxation. The plasma levels achieved in those normal men treated by
Jaffe12 may have been equivalent to concentrations used in
this study. Direct coronary relaxation therefore may have been one of
the mechanisms of the beneficial effect of testosterone on angina in
those patients as hypothesized in this article.12 It is
well recognized that discrepancies exist between the concentration of
agents that induce in vivo changes and those that induce in vitro
smooth muscle–relaxing responses in the organ bath. Examples would be
calcium channel blockers39 and potassium channel–opening
agents.40 Cromakalim, a potassium channel opener, has been
shown acutely to reduce systolic arterial pressure and systemic
vascular resistance in patients with angina pectoris at plasma
concentrations of 2 to 3x10-8 mol/L,41
whereas relaxing effects of cromakalim in phenylephrine contracted
rat aorta in vitro only occurred at 10-6 and
10-5 mol/L concentrations.42 Likewise,
cromakalim-induced relaxation of PGF2-contracted (10
µmol/L) pig coronary arteries in vitro occurred only at
10-6 and 10-5 mol/L. These data would be
analogous to the discrepancy between the concentration of testosterone
required to induce relaxation of coronary arteries in vitro and those
concentrations found in vivo.
The testosterone analogues used in this study were chosen on the basis
of previous work demonstrating a nongenomic structure-activity relation
of testosterone analogues in a New Zealand White rabbit model of a
thyroid hormone–responsive membrane calcium-ATPase.43
This sex steroid–thyroid hormone interaction at or near the
calcium-ATPase site in the rabbit reticulocyte is novel in that it is
at the cell membrane and represents a previously unrecognized
ability of steroids to directly modulate the thyroid hormone. It was
demonstrated that 5ß-androstanes were active, whereas
5-androstanes were less active. Within the 5ß-androstanes,
activity was dependent on at least one hydroxyl group at the C3 or C17
position. In a similar way, we have demonstrated that the presence of a
hydroxyl group at the 17ß position may be important, since those
analogues with no hydroxyl group (androst-16-en-3-ol) or with
esterification of the 17ß-hydroxyl group (testosterone enanthanate)
result in a significant decrease in relaxing potency. It was also found
that, compared with testosterone, analogues derived by oxidation,
substitution, or deletion at the C3, C17, or C19 positions were less
active.43 The reason for this was unclear but does suggest
a structure-activity relation. It is interesting to note that the
5ß-configuration results in a marked angulation of the A-ring
relative to the plane of the remaining rings of the steroid. The flat
steroid conformation made by the
all-trans–anti-trans ring junctures would appear
to decrease activity, since the 5-androstane analogue
(17ß-hydroxy-5-androst-1-en-3-one) resulted in less coronary
artery relaxation. These data would suggest that testosterone is
interacting with the plasma membrane and may be affecting potassium
conductance by an interaction with the potassium channel. The time
course of the relaxing response and the inability of the testosterone
receptor antagonist to affect the relaxation would also support a
nongenomic mechanism of relaxation. The mechanism of such an
interaction is undetermined; however, hydrophobic hormone or drug
molecules may be orientated selectively in the lipid bilayer to enhance
the efficacy of binding of such molecules to cell membrane receptor
sites. Such a novel action may account for a nonconformity of such
molecules to traditional binding kinetics, as previously
postulated.43
Conclusions
We have demonstrated that testosterone induces
endothelium-independent relaxation in isolated rabbit
coronary artery and aortic preparations. The mechanism may involve, in
part, the vascular smooth muscle potassium channel. Testosterone may
play a role in the regulation of coronary tone, and this may be one of
the explanations as to why testosterone has previously been shown to
demonstrate beneficial effects on anginal symptoms and on parameters of
myocardial ischemia in patients treated with this hormone. Further work
will be required to establish if this vascular effect has any
therapeutic potential in patients with coronary heart disease.
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Acknowledgments |
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This study was supported by a grant from the British Heart Foundation.
Received September 8, 1994; accepted September 23, 1994.
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G. M. C. Rosano, F. Leonardo, P. Pagnotta, F. Pelliccia, G. Panina, E. Cerquetani, P. L. della Monica, B. Bonfigli, M. Volpe, and S. L. Chierchia Acute Anti-Ischemic Effect of Testosterone in Men With Coronary Artery Disease Circulation, April 6, 1999; 99(13): 1666 - 1670. [Abstract] [Full Text] [PDF]
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V. E. Laubach, P. L. Foley, K. S. Shockey, C. G. Tribble, and I. L. Kron Protective roles of nitric oxide and testosterone in endotoxemia: evidence from NOS-2-deficient mice Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2211 - H2218. [Abstract] [Full Text] [PDF]
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R. J. McCredie, J. A. McCrohon, L. Turner, K. A. Griffiths, D. J. Handelsman, and D. S. Celermajer Vascular reactivity is impaired in genetic females taking high-dose androgens J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1331 - 1335. [Abstract] [Full Text] [PDF]
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M. Christ and M. Wehling Cardiovascular steroid actions: swift swallows or sluggish snails? Cardiovasc Res, October 1, 1998; 40(1): 34 - 44. [Abstract] [Full Text] [PDF]
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 T. J. K. Toung, R. J. Traystman, P. D. Hurn, and V. M. Miller Estrogen-Mediated Neuroprotection After Experimental Stroke in Male Rats • Editorial Comment Stroke, August 1, 1998; 29(8): 1666 - 1670. [Abstract] [Full Text] [PDF]
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M. Kahonen, J.-P. Tolvanen, K. Sallinen, X. Wu, and I. Porsti Influence of gender on control of arterial tone in experimental hypertension Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H15 - H22. [Abstract] [Full Text] [PDF]
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S. M. Herman, J. T.C. Robinson, R. J. McCredie, M. R. Adams, M. J. Boyer, and D. S. Celermajer Androgen Deprivation Is Associated With Enhanced Endothelium-Dependent Dilatation in Adult Men Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 2004 - 2009. [Abstract] [Full Text]
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B. Bruck, U. Brehme, N. Gugel, S. Hanke, G. Finking, C. Lutz, N. Benda, F. W. Schmahl, R. Haasis, and H. Hanke Gender-Specific Differences in the Effects of Testosterone and Estrogen on the Development of Atherosclerosis in Rabbits Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 2192 - 2199. [Abstract] [Full Text]
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T. M. Chou, K. Sudhir, S. J. Hutchison, E. Ko, T. M. Amidon, P. Collins, and K. Chatterjee Testosterone Induces Dilation of Canine Coronary Conductance and Resistance Arteries In Vivo Circulation, November 15, 1996; 94(10): 2614 - 2619. [Abstract] [Full Text]
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J. Alfie, G. D. Waisman, C. R. Galarza, M. I. Magi, F. Vasvari, L. M. Mayorga, and M. I. Camera Relationship Between Systemic Hemodynamics and Ambulatory Blood Pressure Level Are Sex Dependent Hypertension, December 1, 1995; 26(6): 1195 - 1199. [Abstract] [Full Text]
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D. Pratico and G. A. FitzGerald Testosterone and Thromboxane : Of Muscles, Mice, and Men Circulation, June 1, 1995; 91(11): 2694 - 2698. [Full Text]
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