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(Circulation. 1996;94:2614-2619.)
© 1996 American Heart Association, Inc.

Articles

Testosterone Induces Dilation of Canine Coronary Conductance and Resistance Arteries In Vivo

Tony M. Chou, MD; Krishnankutty Sudhir, MD, PhD; Stuart J. Hutchison, MD, FRCPC; Eitetsu Ko, MD; Thomas M. Amidon, MD; Peter Collins, MD; Kanu Chatterjee, MB, FRCP

the Cardiovascular Research Institute and Division of Cardiology, University of California at San Francisco (T.M.C., K.S., S.J.H., E.K., K.C.); Overlake Internal Medicine, Bellevue, Wash (T.M.A.); and the Department of Cardiac Medicine, National Heart and Lung Institute, University of London, UK (P.C.).

Correspondence to Tony M. Chou, MD, University of California at San Francisco, Cardiology Division, M1186, Box 0124, San Francisco, CA 94143-0124. E-mail chou@cardio.ucsf.edu.

	Abstract

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Background Although estrogens have been shown to be vasoactive hormones, the vascular effects of testosterone are not well defined. Like estrogen, testosterone causes relaxation of isolated rabbit coronary arterial segments. We examined the vasodilator effects of testosterone in vivo in the coronary circulation and the potential mechanisms of its actions.

Methods and Results Using simultaneous intravascular two-dimensional and Doppler ultrasound, we examined the effect of intracoronary testosterone in coronary conductance and resistance arteries in 10 anesthetized dogs (5 male, 5 female). We also assessed the contribution of NO, prostaglandins, ATP-sensitive K⁺ channels, and classic estrogen receptors to testosterone-induced vasodilation. Testosterone induced a significant increase in cross-sectional area, average coronary peak flow velocity, and calculated volumetric coronary blood flow at the 0.1 and 1 µmol/L concentrations. This effect was independent of sex. Pretreatment with N-nitro-L-arginine methyl ester to block NO synthesis decreased testosterone-induced increase in cross-sectional area, average coronary peak flow velocity, and coronary blood flow. Pretreatment with glybenclamide to assess the role of ATP-sensitive K⁺ channels did not influence testosterone-induced dilation in epicardial arteries but did attenuate its effect in the microcirculation. Pretreatment with indomethacin or the classic estrogen-receptor antagonist ICI 182,780 did not alter testosterone-induced changes.

Conclusions Short-term administration of testosterone induces a sex-independent vasodilation in coronary conductance and resistance arteries in vivo. Acute testosterone-induced coronary vasodilation of epicardial and resistance vessels is mediated in part by endothelium-derived NO. ATP-sensitive K⁺ channels appear to play a role in the vasodilatory effect of testosterone in resistance arteries.

Key Words: testosterone • arteries • vasculature • endothelium

	Introduction

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Epidemiological studies have demonstrated the influence of sex,^{1 2 3} and more specifically, the influence of menopause⁴ and postmenopausal hormone supplementation,^{5 6} on the incidence of CAD in women. These studies suggest an important role for sex steroids in coronary pathophysiology.^{7 8} The suggestion has been made that sex steroids impact on CAD in men and women with opposite effects,⁹ but direct evidence is lacking. Animal^{10 11} and human¹² studies have shown that estrogens have direct effects on the coronary vasculature, and both endothelium-independent¹⁰ and endothelium-dependent^{13 14} mechanisms have been implicated. However, testosterone has also been reported to have antianginal effects,^{15 16 17 18} and both estrogen¹⁹ and testosterone have been shown to improve exercise-induced ST-segment depression in patients with stable CAD.²⁰ The suggestion has been made that testosterone-induced improvement in anginal symptoms and exercise tolerance seen in patients with CAD results from direct coronary vasodilation.^{15 16 17 18} Experimental in vitro studies have shown a vasodilator effect of testosterone in rabbit coronary arteries,²¹ but to date, no direct in vivo studies have been reported.

In the present study, we assessed the vasodilator effects of acute testosterone administration on both large (epicardial/conductance) and small (resistance/microcirculation) coronary arteries in vivo, using simultaneous 2D and Doppler intravascular ultrasound. Using pharmacological antagonists of several vasodilator pathways, we also examined the relative contribution of endothelium-dependent NO, prostaglandins, and ATP-sensitive K⁺ channels to testosterone-induced vasodilation in vivo. To test the hypothesis that testosterone-induced vasodilation may be mediated via peripheral aromatization to estrogen, we also studied the effect of testosterone after administration of an antagonist to the classic intracellular estrogen receptor.

	Methods

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Ten mongrel dogs (5 male, 5 female; mean weight, 24.6±2.5 kg) were anesthetized with Innovar (0.04 mg/kg SC) and sodium pentobarbital (15 mg/kg IV), with additional doses of sodium pentobarbital as needed to maintain an adequate level of anesthesia. Animals were mechanically ventilated with room air. Heart rate was monitored from the ECG, and blood pressure was monitored from a cannula placed in the right internal carotid artery. All studies conformed to the "Position of the American Heart Association on Research Animal Use" adopted November 11, 1984, by the AHA, and the study protocol was approved by the University of California at San Francisco Committee on Animal Research.

Catheterization Procedures
Under fluoroscopic guidance, the left main coronary artery was cannulated via the transfemoral approach with an 8F canine guiding catheter (Advanced Cardiovascular Systems). Transvenous atrial pacing was used to prevent a fall in heart rate and blood pressure from baseline levels. As previously described,²² a 0.014-in Doppler wire was first introduced through the 8F guiding catheter, after which a 2D imaging catheter was introduced directly over the Doppler wire into the circumflex coronary artery. The Doppler transducer was positioned 2 cm distal to the tip of the 2D imaging catheter²² to preserve Doppler signal without interference from the imaging catheter housing.

Experimental Protocols
Unless otherwise indicated, pharmacological agents were administered directly into the coronary circulation through the guiding catheter in the ostium of the left main coronary artery. While measurements of APV were continuously recorded, measurements of coronary artery CSA were made at 30-second intervals after each administration. Unless otherwise indicated, all drugs were obtained from Sigma Chemical Co. Intracoronary drug infusions were administered over a 1-minute period. Final concentrations in the coronary artery were assessed assuming a flow rate of 80 mL/min, as previously described.^{11 23 24 25}

Testosterone was infused through the guiding catheter into the left coronary artery in concentrations increasing from 1 nmol/L to 1 µmol/L. Concentration-response curves to testosterone were obtained with serial injections, allowing flow to return to baseline before subsequent injection. Epicardial CSA and flow velocity were recorded after each injection. As in previous experience with estrogen,¹¹ it was observed that hormone-induced changes with each dose of testosterone returned to baseline within 5 minutes.

The effects of the following pharmacological interventions on coronary vasodilation induced by testosterone (1 µmol/L) were then determined: (1) inhibition of NO synthesis by intracoronary administration of L-NAME to obtain a final concentration of 100 µmol/L in the coronary artery²⁵ ; (2) inhibition of prostaglandin synthesis by intravenous infusion of indomethacin (Dupont-Merck Pharmaceuticals) 5 mg/kg IV over 5 minutes (previous studies have suggested that this dose is sufficient to block prostaglandin synthesis^{26 27} ); (3) inhibition of ATP-sensitive potassium channels by intracoronary infusion of glybenclamide (10^-5 mol/L)¹¹ ; and (4) blockade of classic estrogen receptors with ICI 182,780 (10^-5 mol/L).²⁸ Each agent was given as a 5-minute infusion before intracoronary infusion of testosterone (1 µmol/L).

2D Ultrasound System Description and Image Analysis
The 4.3F ultrasound catheter has a fixed 30-MHz transducer and a rotating mirror assembly. Images are displayed on a video monitor; axial resolution was 150 µm and lateral resolution 250 µm (Cardiovascular Imaging Systems). Gain, contrast, and reject settings were adjusted by the operator to yield a well-balanced gray-scale appearance on the video display. Real-time images were stored on high-quality super VHS videotape for subsequent off-line analysis. As previously described, selected portions of the videotape were digitized (12 bits, Rasterops 324) in real time (30 frames per second) and stored on a computer disk for off-line determination of luminal area.²²

Doppler Ultrasound System Description
Doppler-derived blood flow velocities were measured with a steerable Doppler guidewire (FloWire, Cardiometrics Inc). This guidewire system has a miniature Doppler ultrasound crystal that transmits signals at a carrier frequency of 12 or 15 MHz (depending on the guidewire size) and receives pulsed-wave ultrasound signals, sampled at a distance of 5 mm from the guidewire tip. The Doppler signals are analyzed by a FloMap instrument (Cardiometrics Inc) by which dedicated digital signal processing chips perform the fast Fourier transformation required for the spectral display. The signals are transformed into a gray scale, and the resultant spectrum is displayed on a monitor. The ECG, arterial pressure waveform, and quantitative measurements of APV throughout the cardiac cycle were simultaneously displayed on a monitor. The monitor display was continuously recorded on a VHS videotape for further off-line analysis and comparison to corresponding cross-sectional ultrasound images.

Calculations and Statistical Analysis
Coronary APV values were observed after administration of each drug, and maximum change from baseline was taken as the peak response.

Luminal CSAs at baseline and after administration of drug were determined by computer-assisted planimetry. CSA measurements were gated to end diastole and end systole. A mean CSA value was obtained by correcting for the fractional diastolic time interval (fDTI, the duration of diastole as a fraction of the cardiac cycle length) and the fractional systolic time interval (fSTI, the duration of systole as a fraction of the cardiac cycle length) as follows: mean CSA=(fDTIxend-diastolic CSA)+(fSTIxend-systolic CSA). Volumetric CBF was calculated by use of the validated relationship CBF=0.47xCSAxAPV.²² The factor of 0.47 corresponds to the correction for a parabolic velocity profile by compensating for the ratio of spectral peak velocity as measured by the Doppler system and the spatial average velocity required for calculation of volumetric flow.^{22 29} This method assumes a parabolic flow velocity profile, with its peak within the Doppler sample volume throughout the cardiac cycle.

Dose-response relationships with testosterone were analyzed by ANOVA for repeated measures, followed by a post hoc Student-Newman-Keuls test. The effects of L-NAME, indomethacin, glybenclamide, and ICI 182,780 were analyzed with a Student's t test for paired observations. Values are expressed as mean±SEM.

	Results

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Resting Coronary Dimensions and Flow Velocity
Mean resting heart rate, mean arterial pressure, mean resting coronary CSA, APV, and CBF are supplied in the Table. Resting values were greater in male than female dogs with respect to APV (32.8±6.2 versus 21.0±2.5, P=.08) and CBF (116.2±13.1 versus 80.0±6.4, P=.03). Resting coronary CSA was similar in male and female dogs (13.0±2.7 versus 11.9±1.2, P=NS).

View this table: [in this window] [in a new window]   Table 1. Hemodynamic and Coronary CSA and Blood Flow Variables Before and After Administration of Each Pharmacological Agent

Effect of Testosterone on Coronary Artery Dimensions and Flow
At the 10^-7 and 10^-6 mol/L concentrations, testosterone induced a significant increase in CSA, APV, and calculated volumetric CBF (Fig 1). No significant changes in heart rate or systemic pressure were noted. The magnitude of the vasodilator effect was similar in male and female dogs (CSA, 14.0±1.9% versus 13.0±1.8% increase at 10^-6 mol/L [P=NS]; APV, 67.3±12.2% versus 59.4±15.8% increase at 10^-6 mol/L [P=NS]; and CBF, 86.2±19.1% versus 78.3±15.9% increase at 10^-6 mol/L [P=NS] in males and females, respectively). No significant changes in systemic arterial pressure or heart rate were observed with any dose. The peak effect of testosterone on coronary blood flow was seen between 90 and 120 seconds.

View larger version (12K): [in this window] [in a new window]   Figure 1. Effect of increasing concentrations of testosterone on coronary CSA (top), Doppler-derived APV (middle), and calculated CBF (bottom). *Significant increase at P<.05.

Effect of L-NAME on Testosterone-Induced Coronary Vasodilation
After pretreatment with L-NAME 100 µmol/L IC, there was a tendency toward a decrease in CSA (P=.08) but no significant change in APV or CBF. After pretreatment with L-NAME, there were attenuations of the testosterone-induced increase in CSA (P=.06), APV (P=.06), and CBF (P=.04) (Fig 2, Table).

View larger version (17K): [in this window] [in a new window]   Figure 2. Testosterone-induced increase in CSA, APV, and calculated CBF before (open bars) and after (solid bars) administration of L-NAME, 100 µmol/L, showing a reduction in testosterone-induced increase in CSA (P=.06), APV (P=.06), and CBF (P=.04) after L-NAME.

Effect of Indomethacin on Testosterone-Induced Coronary Vasodilation
Pretreatment with indomethacin 5 mg/kg IV caused no significant change in CSA, APV, or CBF. Testosterone-induced increases in CSA, APV, and CBF remained unchanged after indomethacin pretreatment (Fig 3, Table).

View larger version (18K): [in this window] [in a new window]   Figure 3. Testosterone-induced increase in CSA, APV, and calculated CBF before (open bars) and after (solid bars) administration of indomethacin, 5 mg/kg IV, showing no change in testosterone-induced coronary vasodilation induced by indomethacin.

Effect of Glybenclamide on Testosterone-Induced Coronary Vasodilation
After infusion of glybenclamide 10^-5 mol/L, there was no significant change in coronary artery CSA, but coronary blood flow velocity did decrease significantly (P<.05), and there was a tendency for CBF to fall. The magnitude of testosterone-induced increase in epicardial coronary CSA was not attenuated by glybenclamide. However, testosterone-induced increases in APV (P=.03) and CBF (P=.02) were significantly attenuated after glybenclamide pretreatment (Fig 4, Table).

View larger version (17K): [in this window] [in a new window]   Figure 4. Testosterone-induced increase in CSA, APV, and calculated CBF before (open bars) and after (solid bars) administration of glibenclamide, 10 µmol/L, showing an attenuation in testosterone-induced increase in APV (P=.03) and CBF (P=.02) induced by glybenclamide.

Effect of ICI 182,780 on Testosterone-Induced Coronary Vasodilation
CSA, APV, and CBF remained unchanged after pretreatment with selective estrogen receptor antagonist ICI 182,780 pretreatment. The magnitudes of the testosterone-induced increase in CSA, APV, and CBF were unchanged by ICI 182,780 (Fig 5, Table).

View larger version (18K): [in this window] [in a new window]   Figure 5. Testosterone-induced increase in CSA, APV, and calculated CBF before (open bars) and after (solid bars) administration of intracoronary ICI 182,780, 10 µmol/L, showing no change in testosterone-induced coronary vasodilation induced by ICI 182,780.

	Discussion

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The present study demonstrates that testosterone induces a significant sex-independent vasodilation in coronary conductance and resistance arteries. Inhibition of NO synthesis decreased testosterone-induced epicardial and microvascular vasodilation. Pharmacological antagonism of ATP-sensitive K⁺ channels did not attenuate testosterone-induced dilation in epicardial arteries, although it did in the microcirculation.

Edwards and colleagues³⁰ first described the effects of testosterone on the vasculature in 1939. Using spectrophotometry, they demonstrated an impaired arterial supply to the skin of castrated men that was improved by administration of testosterone. They also observed symptomatic improvement of intermittent claudication in a series of seven patients. After this, there were several reports of the use of testosterone to treat essential hypertension, angina pectoris, and peripheral vascular disease.^{15 16 17 18 31}

Although testosterone-induced coronary vasodilation appears to be a favorable effect, the literature reveals numerous deleterious cardiovascular associations of androgenic steroid use and of steroid abuse, including reducing serum HDL and HDL/LDL ratios,³² thromboxane-induced vasoconstriction in guinea pigs³³ and monkeys,³⁴ and increasing thromboxane excretion and thromboxane receptors in cultured rat aortic cells.³⁵ Reports of an increase in the incidence of myocardial infarction³⁶ and stroke³⁷ in anabolic steroid users suggests an adverse vascular effect from such steroids.

By contrast, in a retrospective study of men with premature myocardial infarction,³⁸ serum dehydroepiandrosterone sulfate levels were inversely related to premature myocardial infarction in men, and the association was independent of the effects of several known risk factors. In another study, 55 men undergoing angiography who had not previously had a myocardial infarction³⁹ were found to have serum levels of testosterone (r=-.36, P=.008) and free testosterone (r=-.49, P<.001) that correlated inversely with the degree of CAD after age and body mass index were controlled for. These suggest that hypotestosteronemia in men may be a risk factor for coronary atherosclerosis.

The facts that estrogen and testosterone both have coronary vasodilating properties and both share some common molecular structural properties suggest a shared nonspecific steroid mechanism(s) of action. Acetylcholine induces endothelium-dependent vascular relaxation mediated by the release of NO.⁴⁰ In vitro studies have shown that testosterone relaxes rabbit coronary arteries acutely via what appears to be an endothelium-independent mechanism to a degree similar to acetylcholine-induced dilation.²¹ Yue et al²¹ found that L-NAME did not affect acute testosterone-induced vasorelaxation in vitro, nor did methylene blue, an inhibitor of NO-induced increase of cGMP. In that study, the effect in coronary arteries appeared to be greater than relaxation seen in the aorta. In our study, there was an attenuation of testosterone-induced vasorelaxation after L-NAME pretreatment at both the epicardial and microvascular levels. The reasons for the differences between our study and those of Yue et al are unclear but may relate to differences between the in vivo environment, in which blood, circulating vasoactive factors, and neural influences are present, and the organ bath, in which tissues are studied in isolation.

Glybenclamide is a potent inhibitor of ATP-sensitive potassium channels. In previous in vitro studies, glybenclamide did not inhibit testosterone-induced changes.²¹ In our study, glybenclamide pretreatment resulted in a significant attenuation in testosterone-induced vasorelaxation in the microcirculation but not in the epicardial coronary arteries. It is possible that glybenclamide may also have an inhibitory effect at the epicardial level as well but to a lesser degree that does not reach significance in this study. Again, variations between the in vitro and in vivo models may explain the discrepancy between our study and that of Yue et al.²¹ In the present study, testosterone-induced vasorelaxation in resistance arteries may be mediated via more than one mechanism, namely NO release and opening of ATP-sensitive potassium channels.

Indomethacin inhibits the synthesis of prostaglandins and transiently inhibits relaxation induced by arachidonic acid in rabbit coronary arteries.¹⁰ However, indomethacin pretreatment did not affect testosterone-induced relaxation in vitro in previous studies²¹ or in vivo in the present study. Thus, release of vasodilator prostanoids does not appear to be involved in testosterone-induced coronary vasorelaxation.

The hormonal effects of steroids typically are mediated by a family of intracellular receptors⁴¹ and depend on a genomic mechanism by which activation leads to transcription, translation, and ultimately protein synthesis. Thus, steroid hormone–induced responses typically take 1 to 2 hours to occur. Recent evidence has suggested that nongenomic pathways of steroid hormone action exist.⁴² Rapid effects of estrogen have been described in endometrial,⁴³ pituitary,⁴⁴ and central nervous tissue.⁴⁵ Recent work with aldosterone has demonstrated membrane receptors distinctly different from the known intracellular receptors.^{46 47} This "two-step" model for sequential nongenomic and genomic steroid hormone action is increasingly being accepted.^{42 48 49} We have demonstrated that the classic intracellular estrogen receptor antagonist ICI 182,780 did not attenuate vasorelaxation induced by estrogen¹¹ or in the present study by testosterone. This confirms in vitro studies in the rabbit aorta and coronary arteries.²¹ In addition, as in our previous observations with estrogen,¹¹ the magnitude of testosterone-induced vasodilation was similar in male and female dogs. Both these hormones thus induce rapid effects that appear to represent acute nongenomic effects, possibly transmitted by membrane receptors different from the classic intracellular sex steroid receptors.

The testosterone concentrations that result in statistically significant vasodilation in the coronary vasculature (0.1 mmol/L [100 nmol/L]) are slightly higher than those found in normal male volunteers (21±1 nmol/L)⁵⁰ but certainly are within the range of concentrations achieved via injections of 25 mg IM in hypogonadal men⁵⁰ and in other settings in which human subjects are treated with exogenous testosterone. Organ bath studies demonstrate effects at only supraphysiological levels.²¹ This study lends support to the hypothesis that direct coronary vasodilation may be responsible for the improvement in symptoms of angina and improved exercise tolerance seen in previous studies.^{15 16 17 18 20}

Limitations of This Study
The measurement of absolute coronary blood flow using combined 2D and Doppler ultrasound may have some inaccuracy inherent in the technique.²² As previously described, the CSA of the epicardial coronary artery was measured 2.5 cm proximal to the site of measurement of flow velocity distal to the flow-wire tip.²² However, all of our inferences are based on within-animal comparisons and paired data, and the final emphasis is on change from baseline rather than on absolute values. So it is unlikely that the interpretation of our data was influenced by the measurement technique.

It is possible that the epicardial coronary vasodilator effects of testosterone could have been, in part or in total, a consequence of shear stress from the increased flow⁵¹ caused by testosterone-induced vasodilation in coronary resistance arteries. Our data do not exclude such a possibility.

Conclusions
We conclude that acute testosterone administration induces epicardial and resistance coronary artery dilation in vivo at concentrations of 0.1 mmol/L. Acute testosterone-induced coronary vasodilation is mediated in part by endothelium-derived NO. In addition, ATP-sensitive K⁺ channels appear to play a role in its effect on resistance arteries. The vasomotor response to testosterone is a possible explanation for its effects seen on myocardial ischemia. Like estrogen, testosterone may play a role in the regulation of coronary tone in health and in disease. Although it is clear that estrogen and testosterone induce coronary vasodilation, it is unclear whether the effects on the coronary vasculature observed with long-term administration of sex hormones are brought about through genomic or nongenomic mechanisms. The clinical importance and any potential therapeutic application of estrogen and testosterone in regulating coronary flow will require further work.

	Selected Abbreviations and Acronyms

 

2D = two-dimensional APV = average coronary peak flow velocity CAD = coronary artery disease CBF = coronary blood flow CSA = cross-sectional area L-NAME = N-nitro-L-arginine methyl ester

	Acknowledgments

 
This study was supported in part through funds from the Foundation for Cardiac Research, Cardiology Division, University of California, San Francisco (UCSF). Dr Chou was partially funded by a grant from Devices for Vascular Intervention and by NIH grant F32-HL-090969-01. Dr Sudhir was funded as a C.J. Martin Fellow by the National Health and Medical Research Council of Australia and as a Postdoctoral Fellow by the American Heart Association, California Affiliate. Dr Hutchinson was funded as an R.J. McLaughlin Travelling Fellow, McLaughlin Foundation, Toronto, Canada. We are indebted to Jim Stoughton for his technical assistance in the UCSF Animal Care Facility.

	Footnotes

 
Portions of this study were presented at the Scientific Sessions of the American College of Cardiology, New Orleans, La, March 19, 1995.

Received March 4, 1996; revision received June 25, 1996; accepted July 8, 1996.

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