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Cardiovascular Research 2002 53(3):627-633; doi:10.1016/S0008-6363(01)00498-9
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Copyright © 2002, European Society of Cardiology

Isoproterenol amplifies 17β-estradiol-mediated vasorelaxation: role of endothelium/nitric oxide and cyclic AMP

Hoi Yun Chana, Xiaoqiang Yaoa, Suk Ying Tsanga, Jean-Pierre Bourreaub, Franky Leung Chanc and Yu Huanga,*

aDepartment of Physiology, Chinese University of Hong Kong, Shatin, Hong Kong, China
bDepartment of Physiology, The University of Hong Kong, Hong Kong, China
cDepartment of Anatomy, Chinese University of Hong Kong, Shatin, Hong Kong, China

* Corresponding author. Fax: +852-26-035-022 yu-huang{at}cuhk.edu.hk

Received 18 June 2001; accepted 4 October 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Estrogen exerts cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as β-adrenoceptor agonists. However, little is known whether low concentrations of β-adrenoceptor agonists would reciprocally influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17β-estradiol, and the role of endothelium and cyclic AMP-dependent pathway in this interaction. Methods: Changes in vessel tone of the isolated rat mesenteric artery rings were measured using a force–displacement Grass transducer. Results: In 9,11-dideoxy-11{alpha}, 9{alpha}-epoxy-methanoprostaglandin F2{alpha}-preconstricted endothelium-intact rings, 17β-estradiol induced relaxations with pD2 of 5.06±0.06. Pretreatment of endothelium-intact rings with isoproterenol (1–3x10–9 M, 1 h incubation time) significantly enhanced 17β-estradiol-induced relaxation. This effect was inhibited by Rp-cGMPS triethylamine (3x10–6 M), and abolished in the presence of 3x10–5 M NG-nitro-L-arginine methyl ester or in endothelium-denuded rings. The effect of isoproterenol was antagonized by propranolol (3x10–6 M), ICI 118,551 (3x10–6 M), but not by atenolol (10–5 M). Rp-cAMPS triethylamine (3x10–6 M) abolished the effect of isoproterenol. Besides, exposure to 3x10–9 M forskolin for 1 h also potentiated the relaxant response to 17β-estradiol. Conclusion: In endothelium-intact rat mesenteric arteries pretreatment with low concentrations of isoproterenol enhanced the acute relaxant response to 17β-estradiol. This enhancement was dependent on the presence of endothelium and abolished by L-NAME via a β2-adrenoceptor-mediated cyclic AMP-dependent mechanism.

KEYWORDS Adrenergic (ant)agonists; Arteries; Endothelial function; Hormones; Vasoconstriction/dilation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Gender difference in the incidence of cardiovascular disease is well documented in literature. In the premenopausal reproductive years, women experience a lower risk of coronary heart disease compared with men of the same age. After menopause, this difference significantly narrows unless estrogen replacement therapy is initiated. The epidemiological study demonstrates that the postmenopausal women receiving estrogen therapy have a much lower mortality rate in association with cardiovascular disease, indicating the cardioprotective role of female sex steroid hormones [1,2]. The cardiovascular protective effects of estrogen have also been demonstrated in numerous animal studies [3–6], although the underlying mechanisms are incompletely understood. It is believed that estrogen possesses abilities to lower plasma cholesterol levels [3,7,8] and to exert direct inhibitory effect on the vasomotor activity [9]. Long-term exposure to estrogen attenuates the contractile sensitivity to vasoconstrictors [10–12]. While, estrogen pretreatment enhances endothelium-mediated relaxation [13,14].

Estrogen modulates the adrenergically mediated vascular responses. For example, the depressant effect of estrogen treatment on the relaxant response to noradrenaline in the rabbit femoral artery was prevented by the {alpha}2-adrenergic antagonist, rauwolscine [15]. Noradrenaline-induced relaxation of coronary arteries was enhanced by acute, direct exposure to physiological levels (10–9 M) of 17β-estradiol [16]. On the other hand, estrogen replacement in ovariectomized rats enhanced vasoconstriction induced by endothelial {alpha}2-adrenoceptor activation via an increased release of prostaglandins in mesenteric artery [17].

The relaxation induced by isoproterenol was impaired in ovariectomized rats and estrogen substitution restored β-adrenergically-mediated relaxation [18]. Estrogen sensitized the isoproterenol-induced rat aortic relaxation probably through nitric oxide- and cytochrome P450-dependent metabolites [19]. β-Adrenoceptor-mediated relaxation was mediated via cyclic AMP-dependent mechanisms [20–22] or by an endothelium-dependent pathway [23–25]. Estrogen-induced vasorelaxation may also involve cyclic AMP-mediated pathway [26]. In the cardiac myocytes, a low concentration of 17β-estradiol (10–9 M) reduced isoproterenol-induced increase in the whole-cell L-type voltage-dependent Ca2+ current [27]. It remains, however, elusive whether estrogen potentiation of the isoproterenol-induced relaxation is due to synergistic interaction on cyclic AMP-dependent mechanism or on up-regulation of β-adrenoceptors in vascular smooth muscle cells. If there is an interaction between different intracellular signaling pathways activated by estrogen and β-adrenoceptor agonists, it is reasonable to hypothesize that isoproterenol may be also able to amplify the relaxant response to 17β-estradiol.

The purpose of the present study was therefore to evaluate (1) the potentiating effect of low concentrations (1–3x10–9 M) of isoproterenol on 17β-estradiol-induced vasorelaxation; (2) involvement of endothelial nitric oxide; and (3) contribution of β-adrenoceptor subtypes. In addition, we also wanted to test the effect of forskolin on the arterial response to 17β-estradiol. The most important finding of this study was that cyclic AMP-dependent endothelial nitric oxide-forming pathway is likely involved in isoproterenol enhancement of 17β-estradiol-induced relaxation through activation of β2-adrenoceptor subtype.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Arterial ring preparation
All experimental protocols were approved by the Ethical Committee on the Use of Experimental Animals, Chinese University of Hong Kong. This investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996). Male Sprague–Dawley rats weighing ~250–300 g were killed by cervical dislocation and bled. The superior branch of the mesenteric artery was excised. After the connective tissue was carefully removed each artery was cut into two 3-mm-wide ring segments. Each ring was dispensed between two stainless metal hooks in a 10 ml organ bath. The upper wire was connected to a force–displacement transducer (Grass Instruments FT03C, USA) and the lower one was fixed at the bottom of the organ bath. The organ bath was filled with Krebs solution of the following composition (mM): NaCl 119, KCl 4.7, NaHCO3 25, CaCl2 2.5, MgCl2 1, KH2PO4 1.2, and D-glucose 11. The bath solution was continuously oxygenated with a gas mixture of 95% O2 plus 5% CO2, and kept at 37°C (pH {approx}7.4). The rings were placed under an optimal resting tension of 5 mN, which had been determined by length–tension relationship experiments. Changes in isometric tension were continuously measured with the force transducer connected via an interface to a computer system. The Maclab software (version 3.0) was used for real-time data acquisition, display and analysis. Some 30 min after being set up in organ baths, rings were first contracted with a single concentration of phenylephrine (3x10–7 M) to assess the contractile capacity, thereafter they were rinsed with pre-warmed and oxygenated Krebs solution several times until a stable baseline tone was restored. The rings were then allowed to equilibrate for additional 60 min. Baseline tone was readjusted to 5 mN when necessary. In some arterial rings the endothelial layer was mechanically disrupted by gently rubbing the luminal surface of a ring back and forth several times with plastic tubing. Endothelium integrity or functional removal was confirmed by the presence or absence, respectively, of the relaxant response to 10–6 M acetylcholine. Each experiment was carried out on the rings prepared from different rats. Sixty-nine rats in total were used in this study.

2.2. Experimental protocol
Relaxations induced by 17β-estradiol were studied in rings preconstricted by U46619 [GenBank] , the concentration of which (1–3x10–8 M) was titrated for each vessel to give a contraction of similar magnitude. Once stable vessel tone was obtained, 17β-estradiol was applied cumulatively (10–7–10–4 M) to the bath solution to determine concentration–response relationships. The time-matched vehicle control experiments showed that dimethyl sulfoxide (DMSO) did not affect U46619 [GenBank] -induced tension during the duration of the experiments. To evaluate the potential modulation by β-adrenoceptor activation of 17β-estradiol-induced relaxant response, the concentration-dependent relaxing effect for isoproterenol was determined. The isoproterenol concentration (1–3x10–9 M) that caused less than 10% of the maximum relaxation was used.

In the first series of experiments, the rings were exposed to isoproterenol for 1 or 2.5 h before addition of U46619. [GenBank] Some experiments was designed to examine the possible involvement of endothelial nitric oxide, the effect of isoproterenol was investigated in endothelium-intact rings pretreated with NG-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase, 3x10–6 M), Rp-cGMPS triethylamine (an inhibitor of cyclic GMP-dependent protein kinase, 3x10–6 M), or in endothelium-denuded rings. The inhibitor was added to the bathing solution 10 min prior to application of 10–9 M isoproterenol. In the second set of experiments, the endothelium-intact rings were exposed to Rp-cAMPS triethylamine (an inhibitor of cyclic AMP-dependent protein kinase, 3x10–6 M) for 10 min before addition of isoproterenol. The effect of forskolin (3x10–9 M) was also tested on the 17β-estradiol-induced relaxation in endothelium-intact rings following 60 min exposure. In the last group of experiments, the rings were incubated with the β1- or β2-adrenoceptor antagonist for 10 min before addition of 10–9 M isoproterenol. The relaxant effect of 17β-estradiol was then examined. All experiments were carried out in the presence of 10–5 M indomethacin to exclude contribution of vasorelaxing prostanoids. The U46619 [GenBank] -induced tone did not significantly decline within 4 h.

2.3. Drugs
Drugs used in the present study included: phenylephrine hydrochloride, acetylcholine hydrochloride, 9,11-dideoxy-11{alpha},9{alpha}-epoxy-methanoprostaglandin F2{alpha} (U46619 [GenBank] ), NG-nitro-L-arginine methyl ester (L-NAME), 17β-estradiol, (±)-isoproterenol hydrochloride, forskolin, indomethacin (Sigma, St Louis, MO, USA). Propranolol, ICI 118,551 hydrochloride, (±)-atenolol, Rp-cGMPS triethylamine, Rp-cAMPS triethylamine (RBI. USA). U46619 [GenBank] , 17β-estradiol, forskolin, Rp-cGMPS triethylamine and Rp-cAMPS triethylamine were dissolved in DMSO. All other drugs were dissolved in double-distilled water. Stock solution of the each compound was stored at –20°C. Necessary dilution was made in Krebs solution shortly before the experiment commenced. DMSO at 0.2% did not influence the U46619 [GenBank] -induced tone.

2.4. Analysis of the results
Data are presented as means±S.E.Ms and n refers to the number of arterial rings examined. The relaxant responses to 17β-estradiol are expressed as percentage reversal of the U46619 [GenBank] -induced contraction. pD2 is the negative logarithm (–log) of the concentration of a dilator required to produce 50% the maximal relaxation calculated by non-linear regression curve fitting (Graphpad Prism Software, version 3.0, USA). Statistical analysis was performed by using Student's t-test or analysis of variance (ANOVA) followed by Newman–Keul's test. a P-value <0.05 was taken to indicate a significant difference.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Isoproterenol potentiation of 17β-estradiol-induced relaxation
17β-Estradiol induced concentration-dependent relaxations to a similar extent in both endothelium-intact and -denuded rat mesenteric artery rings (pD2 values: 5.06±0.06, n=8 with endothelium and 5.17±0.07, n=7 without endothelium). Full relaxation could be obtained with 17β-estradiol in both types of artery rings. Low concentrations of isoproterenol produced a slight relaxant response (3.3±2.9% and 7.6±3.3% relaxation, respectively in 10–9 M and 3x10–9 M isoproterenol, n=4) without an effect on baseline tone. The trace in Fig. 1b shows that following 60 min pretreatment of endothelium-intact rings with low concentrations of isoproterenol, the relaxant response to 17β-estradiol was significantly enhanced (compared to the control trace in Fig. 1a). The pD2 values were 5.97±0.14, n=9 for 10–9 M isoproterenol; 6.18±0.28, n=5 for 3x10–9 M isoproterenol (P<0.05 compared with control). The effect of isoproterenol (10–9 M) was not different in rings that had been exposed for 2.5 h (pD2 value: 5.85±0.22, n=7, P>0.05 compared with that obtained in 1 h incubation time, data not shown).


Figure 1
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  		Fig. 1 Representative records showing the concentration-dependent relaxant responses to 17β-estradiol in endothelium-intact rat mesenteric arteries in control (a) and in the ring pretreated with 10–9 M isoproterenol (b).

 
3.2. Role of endothelium/nitric oxide
Pretreatment with 3x10–6 M L-NAME abolished the effect of isoproterenol (Figs. 2a and 5aGo). Treatment with Rp-cGMPS triethylamine (3x10–6 M), the cyclic GMP-dependent protein kinase inhibitor, partially but significantly, attenuated the effect of isoproterenol (pD2 value: 5.52±0.08, n=7, P<0.05 compared with the value obtained with isoproterenol alone, Fig. 2a). The enhancing effect of isoproterenol on 17β-estradiol-induced relaxation was abolished in the endothelium-denuded rings (pD2: 5.18±0.08, n=7 in control and 5.32±0.16, n=8 in 10–9 M isoproterenol, P>0.05, Fig. 2b). Both inhibitors had no effect on baseline tone or the maximal relaxation induced by 17β-estradiol.


Figure 2
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  		Fig. 2 (a) Effect of 3x10–5 M L-NAME on isoproterenol enhancement of 17β-estradiol-induced relaxation in endothelium-intact rings ({circ}, n=8 in control; bullet, n=8 in 10–9 M isoproterenol; and {square}, n=7 in L-NAME plus 10–9 M isoproterenol; {diamond}, n=7 in 3x10–6 M Rp-cGMPS triethylamine plus 10–9 M isoproterenol). (b) Lack of effect of 10–9 M isoproterenol on 17β-estradiol-induced relaxation in endothelium-denuded rings ({circ}, n=6 in control; bullet, n=8 in isoproterenol). Data are means±S.E.Ms of n different rings.

 

Figure 5
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  		Fig. 5 pD2 values were calculated as the negative logarithm of the 17β-estradiol concentration that produces 50% the maximal relaxation following various pharmacological interventions in the isolated rat mesenteric artery rings. Data are means±S.E.Ms of n different rings. A significant difference (P<0.05) is indicated by a between treatment and control and b between treatment and isoproterenol groups.

 
3.3. Role of cyclic AMP
Pretreatment with Rp-cAMPS triethylamine (3x10–6 M), the cyclic AMP-dependent protein kinase inhibitor significantly inhibited the effect of isoproterenol (pD2 value: 5.25±0.11, n=6, P<0.05, compared with the value obtained with isoproterenol alone, Figs. 3a and 5aGo). Pretreatment of endothelium-intact rings with 3x10–9 M forskolin also amplified the relaxation induced by 17β-estradiol (Fig. 3b). Co-treatment with forskolin and isoproterenol did not have additive effect (pD2 values: 5.38±0.09, n=6 for forskolin and 5.71±0.09, n=6 for forskolin plus isoproterenol, P>0.05, Figs. 3b and 5aGo). Neither Rp-cAMPS nor forskolin at concentrations used affected baseline tone.


Figure 3
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  		Fig. 3 (a) The effect of Rp-cAMPS triethylamine on isoproterenol enhancement of 17β-estradiol-induced relaxation in endothelium-intact rings ({circ}, n=8 in control; bullet, n=8 in 10–9 M isoproterenol; and {square}, n=6, Rp-cAMPS triethylamine plus 10–9 M isoproterenol). (b) The effect of 3x10–9 M forskolin on 17β-estradiol-induced relaxation in endothelium-intact rings ({circ}, n=8 in control; bullet, n=6 in forskolin, and {square}, n=6, forskolin plus 10–9 M isoproterenol). Data are means±S.E.Ms of n different rings.

 
3.4. Effects of β-adrenoceptor antagonists
Pretreatment with 3x10–6 M propranolol, the non-selective β-adrenoceptor antagonist partially inhibited the effect of isoproterenol (Figs. 4a and 5bGo). ICI 118,551 at 3x10–6 M almost abolished the effect of isoproterenol (pD2 values: 5.99±0.14, n=8 for isoproterenol and 5.29±0.14, n=6 for ICI 118,551 plus isoproterenol, P<0.05, Figs. 4b and 5bGo). In contrast, 10–5 M atenolol, the β1-adrenoceptor antagonist had no effect (Fig. 4c). None of three blocking agents influenced baseline tone or the relaxant response to 17β-estradiol (n=4–8, Figs. 4 and 5Gob).


Figure 4
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  		Fig. 4 Effects of β-adrenoceptor antagonists on isoproterenol enhancement of 17β-estradiol-induced relaxation in endothelium-intact rings. (a) The effect of 3x10–6 M propranolol ({circ}, n=8 in control; bullet, n=8 in 10–9 M isoproterenol; {square}, n=6 in propranolol plus isoproterenol; {diamond}, n=8 in propranolol). (b) The effect of 3x10–6 M ICI 118,551 ({circ}, n=8 in control; bullet, n=8 in 10–9 M isoproterenol; {square}, n=6 in ICI 118,551 plus isoproterenol; {diamond}, n=5 in ICI 118,551). (c) The effect of 10–5 M atenolol on 17β-estradiol-induced contraction ({circ}, n=8 in control; bullet, n=8 in 10–9 M isoproterenol; {square}, n=6 in atenolol plus isoproterenol; {diamond}, n=6 in atenolol). Data are means±S.E.Ms of n different rings.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The main objective of this study was to investigate the synergistic interaction between isoproterenol and 17β-estradiol, and the role of endothelium and cyclic AMP-dependent pathway in this interaction. Our results provide evidence for the enhanced relaxant response to 17β-estradiol in the isolated rat mesenteric artery rings pretreated with low concentrations of isoproterenol, the non-selective β-adrenoceptor agonist. It appears that this enhancing effect is dependent on the presence of functional endothelium since removal of endothelium or inhibition of nitric oxide synthase by L-NAME abolished the effect of isoproterenol. Moreover, pretreatment with Rp-cGMPS triethylamine also significantly attenuated the isoproterenol-induced potentiation. Rp-cGMPS was less effective than L-NAME in inhibiting the effect of isoproterenol; this is probably due to an endothelial nitric oxide-mediated cyclic GMP-independent vascular effect, which is insensitive to protein kinase G inhibitors. On the other hand, the endothelium was not involved in 17β-estradiol-induced relaxation in the same preparation [28]. The role of endothelial nitric oxide in isoproterenol-induced relaxation was demonstrated in rat mesenteric arteries [23,25] and rat aorta [20,21]. L-NAME or methylene blue (an inhibitor of guanylyl cyclase) significantly reduced the relaxant response to β-adrenoceptor agonists or forskolin, an adenylyl cyclase inhibitor in these blood vessels. Forskolin also induced endothelium-dependent aortic relaxation [20,29], indicating a role of endothelial nitric oxide in relaxation initiated by cyclic AMP-elevating dilators.

Our data demonstrate that isoproterenol-induced potentiation of 17β-estradiol-induced relaxation is abolished by Rp-cAMPS triethylamine, a membrane permeable protein kinase A inhibitor. Pretreatment with low concentration of cyclic AMP-elevating agent, forskolin, also amplified the relaxant effect of 17β-estradiol in endothelium-intact rings. These results suggest that the effect of isoproterenol may be mediated through cyclic AMP-dependent mechanism in the endothelium. Both isoproterenol and forskolin stimulated production of cyclic AMP and cyclic GMP in endothelium-intact rat aortic ring [20].

In rat aortic rings, the relaxant response to isoproterenol or dibutyryl AMP was inhibited by L-NAME. Isoproterenol-induced relaxation was associated with increases in tissue cyclic AMP and cyclic GMP contents. L-NAME reduced isoproterenol-induced increase in cyclic GMP but not cyclic AMP levels [22]. It seems that the relaxant response of rat aorta to cyclic AMP-mediated vasodilators is mediated at least in part through nitric oxide production in endothelium and subsequent increase in cyclic GMP in vascular smooth-muscle cells. Our results indicate that isoproterenol-induced increase in endothelial cyclic AMP level may enhance the basal nitric oxide production and release, which subsequently interacts synergistically with 17β-estradiol to produce greater relaxation. Therefore, the amplifying effect of isoproterenol could be mimicked by forskolin and abolished by the inhibitors of either protein kinase A or nitric oxide synthase. To a certain degree our data support a previous study in which histamine-induced nitric oxide release was significantly reduced by Rp-cAMPS, suggesting that in porcine aortic endothelial cells, nitric oxide-mediated vasodilation might be caused by production of cyclic AMP initiated through the histamine H-receptor [30].

Both β1 and β2-adrenoceptor agonists produced endothelium-dependent and -independent relaxation in rat mesenteric arteries [24,25] and in rat aorta [22]. Stimulation of cyclic AMP formation in the endothelium by isoproterenol, leading to direct or indirect release of nitric oxide, was reported by Gray and Marshall [20]; however, the subtype of the β-adrenoceptors involved was not further determined. Our data show that isoproterenol-induced enhancement is partially antagonized by propranolol, a non-selective β-adrenoceptor antagonist, but almost completely inhibited by ICI 118,551, a selective β2-adrenoceptor antagonist [31]. In contrast, atenolol, a selective β1-adrenoceptor antagonist [31] did not influence the effect of isoproterenol. These results clearly point to a primary role of β2-adrenoceptors in an enhanced relaxation to 17β-estradiol in isoproterenol-treated rings. Our results support a recent in vivo study with perfused rabbit femoral artery [32]. Isoproterenol decreased prefusion pressure via stimulation of β2-adrenoceptor subtype. Injection of L-NAME abolished the pressure response to isoproterenol and significantly suppressed the pressure response to forskolin and dibutyryl cyclic AMP [32]. These results together with our findings again indicate that β2-adrenergic stimulation and cyclic AMP elevation activate nitric oxide-producing system in mammalian arteries in vitro and in vivo.

In conclusion, we have provided novel mechanistic evidence for the isoproterenol potentiation of 17β-estradiol-induced relaxant response in rat mesenteric arteries. Isoproterenol may stimulate endothelial β2-adrenoceptors to elevate basal nitric oxide release via a cyclic AMP-dependent mechanism on the endothelium. This increased level of nitric oxide then interacts synergistically with cellular mechanisms initiated by 17β-estradiol. This study used the superior mesenteric arteries that are considered rather large arteries while it is likely that the cardio-protective effects of estrogen lie with the resistance arteries. If our results can apply to the smaller, resistance-sized vessels, synergistic interaction between β-adrenoceptor agonists and 17β-estradiol would play a significant role in the regulation of vessel tone and blood pressure.

Time for primary review 22 days.


   Acknowledgements
 
This work was supported by grants from Hong Kong Research Grants Council and UPGC Direct Allocation. HYC and SYT were supported by Chinese University of Hong Kong Postgraduate Studentships.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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