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(Circulation. 1997;96:3626-3632.)
© 1997 American Heart Association, Inc.

Articles

Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo

Krishnankutty Sudhir, MD, PhD, FRACP; Eitetsu Ko, MD; Christian Zellner, MD; Hubert E. Wong, BS; Stuart J. Hutchison, MD, FRCP(C); Tony M. Chou, MD; ; Kanu Chatterjee, MB, FRCP

From the Vascular Research Laboratory, Cardiology Division, University of California, San Francisco.

Correspondence to Dr K. Sudhir, Box 0124, University of California, 505 Parnassus Ave, San Francisco, CA 94143. E-mail sudhir{at}cardio.ucsf.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Estrogens are cardioprotective hormones and are reported to have antianginal properties. We examined the effect of physiological concentrations of 17ß-estradiol on coronary reactivity in anesthetized female farm pigs.

Methods and Results Epicardial coronary cross-sectional area (CSA) was assessed by two-dimensional intravascular ultrasound, average coronary peak flow velocity (APV) by intravascular Doppler velocimetry, and coronary blood flow (CBF) was calculated. Dose-response curves to intracoronary endothelin-1 (ET-1, 1 pmol/L to 10 nmol/L), the selective ET_B receptor agonist sarafotoxin (1 pmol/L to 10 nmol/L), and serotonin (0.1 nmol/L to 1 µmol/L) were assessed before and after a 10-minute infusion of intracoronary estradiol (1 nmol/L). Before estradiol administration, ET-1 induced significant dose-dependent decreases in CSA, APV, and CBF. Estradiol attenuated ET-1–induced epicardial vasoconstriction (P<.001) as well as ET-1–induced decreases in APV (P=.05) and CBF (P=.012). In an additional five pigs, vehicle (DMSO) had no effect on ET-1–induced coronary vasoconstriction. Before estradiol administration, sarafotoxin induced no net change in CSA but induced increases in APV and CBF, the extent of which did not change significantly after estradiol. Serotonin induced small decreases in CSA but increased APV and CBF. Estradiol did not influence serotonin-induced changes in CSA, APV, or CBF.

Conclusions We conclude that estradiol attenuates ET-1–induced vasoconstriction, possibly through effects on the ET_A receptor, because selective ET_B receptor-induced stimulation with sarafotoxin remained unchanged. Such an effect on the ET_A receptor may relate to the antianginal properties of estrogens.

Key Words: hormones • endothelin • blood flow • angina

	Introduction

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Observational studies of long-term estrogen replacement therapy in postmenopausal women show a significant reduction in the risk of coronary events, lending support to the hypothesis that estrogen may exert cardioprotective effects.¹ While the precise mechanism underlying its benefits are unclear, it has been estimated that estrogen-induced changes in lipoprotein levels account for only 25% to 50% of the observed risk reduction,² suggesting that additional factors may be involved. It is being recognized more often now that some steroid hormones, including estrogens, exert direct effects on the vasculature. Some of these effects might be mediated through receptors for sex steroids that have been identified in the human aorta, left atrial appendage, internal carotid, internal mammary and coronary arteries, and saphenous veins.^{3 4 5} In addition, other rapid nongenomic vascular effects of estrogen on the vasculature have been described.⁶

Estrogen has been shown to induce rapid coronary vasodilation in dogs⁷ and peripheral vasodilation in humans.⁸ In dogs, this vasodilator effect appears to be independent of the classic intracellular estrogen receptor.⁷ Estrogens are reported to have antianginal properties,⁹ and recent studies have shown that acute sublingual estrogen administration improves exercise tolerance in women with coronary artery disease.¹⁰ The mechanisms underlying this antianginal effect are unclear. Endothelin-1 (ET-1) release has been implicated in the pathogenesis of stable and unstable angina,^{11 12 13 14 15} and plasma concentrations are elevated in patients with coronary vasospasm.¹⁶ We hypothesized that physiological concentrations of estrogen might influence ET-1–induced vasoconstriction in the coronary circulation. We examined the effect of short-term administration of estrogen on coronary vasoconstriction induced by ET-1. To differentiate effects on the ET_A and ET_B receptors, we also assessed the effect of estrogen on vasoconstriction induced by the selective ET_B receptor agonist sarafotoxin S6c. Finally, to assess the effect of estrogen on another coronary vasoactive substance that does not act through receptors for endothelin, we examined the effect of estrogen on coronary vasoreactivity in response to serotonin.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Seventeen female pigs 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 the level of anesthesia. They 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 were approved by the UCSF committee on Animal Research.

Catheterization Procedures
Under fluoroscopic guidance, the left main coronary artery was cannulated through the transfemoral approach with an 8F Amplatz-1 right coronary guiding catheter (Advanced Cardiovascular Systems). As previously described,^{17 18} an 0.014-in Doppler wire (Cardiometrics Inc) was first introduced through the 8F guiding catheter, after which a 3.2F ultrasound imaging catheter (Boston Scientific Corp) 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 imaging catheter.^{17 18} In all animals, transvenous atrial pacing at a rate of 110 bpm was used throughout the study to minimize changes in heart rate.

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. Measurements of coronary artery cross-sectional area and flow velocity were made at 30-second intervals after each administration. Intracoronary drug infusions were over a 1-minute period unless otherwise specified; final concentrations in the coronary artery are indicated, assuming a flow rate of 50 mL/min, as previously described.^{18 19} Except where other sources are stated, all drugs were obtained from Sigma Pharmaceuticals.

The effect of estradiol on coronary vascular responses to the vasoactive agents ET-1, sarafotoxin S6c, and serotonin were assessed in 12 pigs. The order of administration of the three agents was randomized. Intracoronary ET-1 was infused in increasing concentrations (1 pmol/L to 10 nmol/L). (In preliminary studies, infusions of ET-1 in doses >10 nmol/L induced severe degrees of coronary vasospasm, often accompanied by ventricular arrhythmias, and death.) Similarly, intracoronary sarafotoxin S6c (1 pmol/L to 10 nmol/L) and serotonin (100 pmol/L to 1 µmol/L) were administered in increasing doses. A period of at least 45 minutes was allowed between administration of pharmacological agents to allow restoration of baseline.

Intracoronary estrogen was then administered, 1 nmol/L per minute over a 10-minute period. In preliminary studies in 4 animals, such an infusion yielded coronary sinus concentrations of 260±40 pg/mL, which are within the physiological range in women. Second dose-response curves to ET-1, sarafotoxin, and serotonin were obtained, with repeated administrations of estradiol, 1 nmol/L per min over 10 minutes, in between. The order of administration of these agents after estradiol was the same in each animal as before estradiol. In an additional 5 pigs, dose-response curves to ET-1 were obtained before and after a 10-minute infusion of vehicle (dimethylsulfoxide, DMSO) in the same concentration as that accompanying estradiol (1 nmol/L).

Two-dimensional Ultrasound System Description and Image Analysis
The ultrasound catheter (3.2F) has a fixed 30-MHz transducer and a rotating mirror assembly. Images are displayed on a video monitor; axial resolution was 150 µmol/L and lateral resolution 250 µmol/L. 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. 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.

Doppler Ultrasound System Description
Doppler-derived blood flow velocities were measured with a 0.014-in steerable Doppler guidewire (FloWire, Cardiometrics Inc). This guidewire system has a miniature Doppler ultrasound crystal that transmits signals at a carrier frequency of 15 MHz 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) in which dedicated digital signal processing chips perform the fast fourier transformation (FFT) required for the spectral display. The signals are transformed into a gray scale and the resultant spectrum displayed on a monitor. In our study, the ECG and arterial pressure waveform were simultaneously displayed on the monitor. Also displayed were quantitative measurements of average peak velocity (APV) throughout the cardiac cycle. The monitor display was continuously recorded on a VHS videotape for further off-line analysis and comparison with corresponding cross-sectional ultrasound images.

Calculations and Statistical Analysis
Luminal cross-sectional areas (CSA) at baseline and after administration of drugs were determined by computer-assisted planimetry using specialized software. Volumetric coronary blood flow (CBF) was calculated from the relationship CBF=CSAxAPVx0.5, as previously validated.¹⁷ The effects of endothelin, sarafotoxin, and serotonin before and after estrogen administration were compared by two-way repeated-measures ANOVA. Values are expressed as mean±SEM. The null hypothesis was rejected at P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Effect of Endothelin-1 on Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
There were no significant changes in heart rate and blood pressure at the doses of ET-1 administered (Table 1). ET-1 induced dose-dependent decreases in coronary CSA (P=.06), APV (P=.049), and volumetric CBF (P=.001) (Fig 1 and Table 2).

View this table: [in this window] [in a new window]   Table 1. Effects of Endothelin-1, Sarafotoxin, and Serotonin on Mean Arterial Pressure and Heart Rate Before and After Administration of Estradiol

View larger version (13K): [in this window] [in a new window]   Figure 1. Changes in epicardial coronary cross-sectional area (CSA), average coronary peak flow velocity (APV), and volumetric coronary blood flow (CBF) in response to increasing doses of endothelin-1 before and after acute intracoronary administration of 17ß-estradiol (1 nmol/L).

View this table: [in this window] [in a new window]   Table 2. Effects of Endothelin-1, Sarafotoxin, and Serotonin on Coronary CSA, APV, and CBF Before and After Administration of Estradiol

Effect of Estrogen on Endothelin-1–Induced Changes in Coronary Cross-sectional Area, Flow Velocity, and Volumetric Flood Flow
Estrogen (1 nmol/L) did not induce any changes in blood pressure, heart rate, or CBF (Table 1). Estrogen significantly attenuated endothelin-induced decreases in CSA (P<.001), APV (P=.05), and volumetric CBF (P=.012) (Fig 1 and Table 2).

Effect of Vehicle on Endothelin-1–Induced Changes in Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
Vehicle (DMSO) administered in the same dilution as that accompanying estradiol (1 nmol/L) did not induce any changes in blood pressure, heart rate, or CBF (Table 3). Vehicle also had no effect on endothelin-induced decreases in CSA, APV, and volumetric CBF (Table 3).

View this table: [in this window] [in a new window]   Table 3. Effect of Vehicle on Hemodynamic and Coronary Vascular Responses to Intracoronary Administration of Endothelin-1

Effect of Sarafotoxin on Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
Sarafotoxin did not induce any significant change in coronary CSA but significantly increased APV (P>.05) and volumetric coronary blood flow (P>.05) (Fig 2 and Table 2). There were no significant changes in heart rate and blood pressure at the doses of sarafotoxin administered (Table 1).

View larger version (14K): [in this window] [in a new window]   Figure 2. Changes in epicardial coronary cross-sectional area (CSA), average coronary peak flow velocity (APV), and volumetric coronary blood flow (CBF) in response to increasing doses of sarafotoxin S6C before and after acute intracoronary administration of 17ß-estradiol (1 nmol/L).

Effect of Estrogen on Sarafotoxin-Induced Changes in Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
Estrogen did not significantly influence sarafotoxin-induced increases in APV or volumetric CBF, nor was there any significant effect on coronary CSA (Fig 2 and Table 2).

Effect of Serotonin on Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
Serotonin caused a small but significant decrease in coronary CSA (P=.01) but significantly increased APV (P=.02), resulting in a tendency to an increase in volumetric CBF (P=.09) (Fig 3 and Table 2). There were no significant changes in heart rate and blood pressure at the doses of sarafotoxin administered (Table 1).

View larger version (14K): [in this window] [in a new window]   Figure 3. Changes in epicardial coronary cross-sectional area (CSA), average coronary peak flow velocity (APV), and volumetric coronary blood flow (CBF) in response to increasing doses of serotonin before and after acute intracoronary administration of 17ß-estradiol (1 nmol/L).

Effect of Estrogen on Serotonin-Induced Changes in Coronary Cross-sectional Area, Flow Velocity, and Volumetric Blood Flow
Estrogen did not significantly influence either serotonin-induced decrease in coronary CSA or serotonin-induced increases in APV or volumetric CBF (Fig 3 and Table 2).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates that acute administration of physiological concentrations of estradiol attenuates endothelin-1–induced vasoconstriction in porcine coronary conductance and resistance arteries in vivo. The effect of estradiol appears to be selective to the ET_A receptor, since estradiol had no effect on sarafotoxin-induced increase in CBF. Further, since serotonin-induced epicardial coronary vasoconstriction was unchanged by estradiol, it would appear that its attenuation of ET-1–induced vasoconstriction is not a nonspecific effect.

Plasma endothelin concentrations are raised in patients with stable angina,¹¹ unstable angina,^{13 15} and myocardial infarction,¹⁵ suggesting a role for endothelin in coronary syndromes. Lerman et al²⁰ have demonstrated a correlation between plasma ET-1 levels and the extent of atherosclerosis, implying participation of the peptide in the atherogenic process. Estrogens have been shown to reduce coronary mortality in epidemiological studies,¹ and there is recent evidence suggestive of a protective effect of this hormone in myocardial ischemia.²¹ Female sex hormone therapy appears to induce a fall in plasma ET-1 concentrations,^{22 23} and in vitro studies in rabbit aortic rings have suggested that 17ß-estradiol attenuates rabbit coronary artery contraction induced by ET-1.²⁴ These observations suggest a possible link between endothelins and the vascular effects of estrogens.

In this study, we have confirmed that ET-1 constricts large and small coronary arteries, since it induces decreases in both coronary CSA and CBF. The effects of ET-1 at both levels of the coronary circulation (large and small arteries) are significantly attenuated by short-term administration of estradiol. Endothelin reportedly potentiates myofilament calcium sensitivity in vascular smooth muscle.²⁵ Estrogen has been shown to reduce calcium influx into cells,²⁶ a possible mechanism underlying the rightward shift in the ET-1 dose-response curve observed in previous in vitro studies,²⁴ as well as in the current in vivo study. Barber et al²⁷ have reported that endogenous fluctuations in estrogen influence affinity of an endothelin receptor in coronary arterial smooth muscle from female pigs; the relationship of their observations to our acute studies is unclear. Our data suggest that attenuation of ET-1–induced vasoconstriction by estradiol occurs through a nongenomic pathway, since the effect is rapid. We have previously shown that in canine coronary arteries, acute estrogen-induced vasodilation is independent of the estrogen receptor(s) because it is not blocked by the receptor antagonist ICI 182,780.⁷ We have also recently shown that this rapid vasodilatory effect of estradiol is preserved in a patient with estrogen resistance caused by a disruptive mutation in the estrogen receptor gene.²⁸

Sarafotoxin S6c is a selective ET_B receptor agonist that reportedly evokes both vasopressor and vasodepressor effects, presumably mediated through stimulation of receptors located on vascular smooth muscle and endothelial cells, respectively.²⁹ Warner et al³⁰ have suggested that there may be two subtypes of ET_B receptors, one mediating vasoconstriction and the other mediating vasodilation through endothelium-derived growth factor (EDRF) release. In our study, sarafotoxin did not induce epicardial vasoconstriction (possibly because of equipotent effects on ET_B receptors mediating vasoconstriction and vasodilation) but caused an increase in CBF velocity and absolute CBF. Thus stimulation of ET_B receptors on porcine coronary resistance arteries causes vasodilation in vivo, possibly through release of EDRF, as previously described.³⁰ ET_B receptor–mediated vasodilation in coronary resistance arteries was not influenced by estrogen in the current study. This suggests that the increase in nitric oxide release reportedly induced by estradiol in previous studies^{31 32} is unlikely to be mediated by ET_B receptor stimulation. Our finding of a lack of epicardial vasoconstriction observed in response to sarafotoxin in this study is at variance with previous observations in dogs;³³ species differences in the distribution of ET_B receptors may explain this finding. Our observations also suggest that attenuation of ET-1–induced coronary vasoconstriction by estradiol occurs through ET_A receptors, since estradiol does not influence the effect of sarafotoxin on the coronary circulation.

In pig coronary arteries, serotonin induces vasoconstriction³⁴ through 5-HT₂ receptor stimulation³⁵ or vasodilation by activation of 5-HT₁ receptors on endothelial cells³⁶ and subsequent nitric oxide release.³⁷ In basilar artery rings from rabbits, estrogen and progesterone withdrawal have been shown to selectively increase vasoreactivity to serotonin.³⁸ In the present study, serotonin was a weak vasoconstrictor in the epicardial coronary arteries, much less potent than ET-1. However, the degree of epicardial coronary vasoconstriction induced by serotonin was unchanged by estradiol, suggesting that estradiol-induced attenuation of epicardial vasoconstriction caused by ET-1 is not a nonspecific effect occuring with all vasoconstrictors. Serotonin, like sarafotoxin, increased CBF velocity and absolute CBF, suggesting a vasodilator effect in coronary resistance arteries, possibly by activation of endothelial 5-HT₁ receptors, and subsequent nitric oxide release.³⁷ As with sarafotoxin, serotonin-induced increases in coronary blood flow were unchanged after administration of estradiol.

Conclusions
Acute administration of estradiol, given to achieve physiological concentrations of the hormone in the coronary circulation, attenuates ET-1–induced vasoconstriction through an effect on ET_A receptors. Such an effect, if present in human subjects, might contribute to the beneficial effects of estrogen in ischemic syndromes.

	Acknowledgments

 
Dr Sudhir was funded in part by the Foundation for Cardiac Research, Cardiology Division, UCSF. Dr Zellner was partially funded through a grant from Philips Corp. Dr Hutchison was funded in part by the R.S. McLaughlin Foundation, Toronto, Canada.

Received April 21, 1997; revision received June 30, 1997; accepted July 15, 1997.

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