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Cardiovascular Research 2005 67(4):699-704; doi:10.1016/j.cardiores.2005.04.026
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Copyright © 2005, European Society of Cardiology

Role of {alpha}1-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction

Marc Isabelle, Christelle Monteil*, Fabienne Moritz, Brigitte Dautreaux, Jean-Paul Henry, Vincent Richard, Paul Mulder and Christian Thuillez

INSERM U644, Faculté de médecine-Pharmacie de Rouen, UFR de Medecine et de Pharmacie, 22 boulevard Gambetta, 76183 Rouen, France

* Corresponding author. Tel.: +33 2 35 14 84 75; fax: +33 2 35 14 83 65. Email address: christelle.monteil{at}univ-rouen.fr

Received 21 January 2005; revised 5 April 2005; accepted 25 April 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: We assessed whether {alpha}1-adrenoreceptor ({alpha}1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction.

Methods and results: After 7 days of cocaine injection (2 x 7.5 mg/kg/day, i.p., Coc), NADPH activity assessed by chemiluminescence increases as well as phosphorylation of p47phox, one of the cytosolic components of NADPH oxidase. The {alpha}1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 x 1 mg/kg/day, i.p., Coc+Prz), prevents these effects. Moreover, Prz pretreatment reduces left ventricular/body weight (LV/BW) ratio and partially prevents the cocaine-induced alterations in fractional shortening and cardiac index assessed by echocardiography. In order to confirm the involvement of {alpha}1-AR stimulation in NADPH oxidase up-regulation in vivo, we used phenylephrine (Phe) administration with the same protocol of injections as that used with cocaine (2 x 5 µg/kg/day, i.p.). After Phe administration, as expected, NADPH oxidase activity increases as well as phosphorylation of p47phox. These effects occur in the absence of sustained hemodynamic changes.

Conclusion: This study demonstrates the involvement of the {alpha}1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that {alpha}1-AR stimulation, at least in part via NADPH oxidase induction, plays a critical role in the events leading to the cardiomyopathy observed after cocaine abuse.

KEYWORDS {alpha}1-Adrenoreceptor; Cocaine; Free radicals; Ventricular function; Superoxide; Hypertrophy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The effects of repeated cocaine administration on the cardiac function are numerous. These include myocardial ischemia, myocardial infarction, arrhythmia, development of atherosclerosis and cardiomyopathy [1]. However, the molecular mechanisms of cocaine cardiotoxicity are not fully understood.

The two main pharmacological mechanisms of cocaine consist in its ability to block sodium-channels in cell membranes and to inhibit the presynaptic reuptake of catecholamines [2]. The interference with monoamine reuptake systems results in an increase in plasma catecholamines which plays a significant role in the hemodynamic responses to cocaine [3]. Moreover, it has been suggested that catecholamines accumulation into myocardium may result in free radicals production, that could promote the development and progression of cardiomyopathies [2]. Previous studies have reported signs of oxidative stress in the myocardium of cocaine-treated rats [4–6]. We have further shown that oxidative stress is an early triggering event of cocaine-induced myocardial injury and hypertrophy [6]. However, the contribution of catecholamines in cocaine-induced oxidative stress is yet to be determined. Catecholamines autooxidation may represent an important source of oxidative metabolites such as aminochromes and reactive oxygen species (ROS) [7]. Beside this direct production of free radicals, catecholamines may also contribute to the production of ROS through {alpha}- and β-adrenergic stimulations [8–10]. In adult rat ventricular myocytes, direct β-adrenergic stimulation causes a ROS-dependent apoptosis [8] whereas {alpha}1-adrenergic stimulation leads to an increase in hypertrophy [9]. This ROS-dependent hypertrophic response also appears to mediate {alpha}1-adrenoreceptor-stimulated hypertrophy in vascular smooth muscle cells [10].

In these models, NADPH oxidase appeared to be the intracellular source of the ROS in response to a direct {alpha}1-adrenoreceptor stimulation [9,10]. Activation of NADPH oxidase is a multistep process, initiated by serine phosphorylation of p47phox, that facilitates association of the membrane-bound and cytoplasmic subunits of the enzyme [11]. A plethora of stimuli elicits activation of non phagocytic NADPH oxidase, particularly activators of G-protein coupled receptors such as {alpha}1-AR [10,12]. Since we have previously observed that cocaine administration induces an increase in NADPH oxidase activity, the aim of the present study was to elucidate whether catecholamines via {alpha}1-AR stimulation, contribute to cocaine-induced activation of NADPH oxidase and to cardiac dysfunction in a rat model.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.1. Dose selection and study design
All rats were maintained for 2 weeks before the beginning of protocols, at room temperature (21 °C) and humidification temperate (26%) with a 12 h light/dark cycle. They had free access to food and water.

To perform this study, we used two different protocols.

2.1.1. Protocol 1
Forty male Wistar rats (325–350 g, Iffa-Credo, L'Arbresle, France) were randomly divided into four groups: control, cocaine, cocaine plus prazosin (Coc+Prz) and prazosin (Prz). The animals in the control group received intraperitoneal injections of saline. In both cocaine and Coc+Prz groups, rats were injected with cocaine hydrochloride (2 x 7.5 mg/kg/day, i.p.) for 7 days [6]. Prazosin was administered 1 h before each cocaine injection (2 x 1 mg/kg/day, i.p.), as previously described [13].

2.1.2. Protocol 2
Twenty male Wistar rats (325–350 g, Iffa-Credo, L'Arlesle, France) were allocated in two groups to receive saline (control group) or phenylephrine hydrochloride (2 x 5 µg/kg/day, i.p., phe group) for 7 days. The pressor response produced by 5 µg/kg, i.p., was similar to those observed after cocaine injection as assessed in separate series of rats (n = 6) instrumented for pressure measurements by telemetry (data not shown).

On day 8, animals from each group were anaesthetised (Midazolam 0.5 mg/kg, Ketamine 130 mg/kg, i.p.) 3 h after a single saline, cocaine or phenylephrine injection in order to evaluate cardiac function by echocardiography and to perform hemodynamic measurements. The heart was removed from the chest and weighed. Left ventricle (LV) was dissected on ice, weighed and the LV was cut in three sections then frozen for biochemical analysis.

2.2. Echocardiographic and hemodynamic evaluations
Echocardiographic measurements were performed blinded to the animal groups using an echocardiograph (HDI 5000, ATL, 8.5 MHz transducer). M-mode tracings were recorded from a 2-dimensional short-axis view obtained at the level of the LV papillary muscle. LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) were measured and used to calculate fractional shortening (FS) using the equation FS=[(LVEDDLVESD)/LVEDD] x 100. The velocity-time integral (VTI) was measured by pulsed-wave Doppler to calculate cardiac index (CI), CI=[VTIaortic x {pi} x (Daortic2/4) x heart rate]/Body Weight.

After the echocardiographic measurements, cardiac hemodynamics were determined as previously described [14]. In brief, the right carotid artery was cannulated with a micromanometer-tipped catheter (SPR 407, Millar Instruments) for the recording of systolic blood pressure (SBP, mm Hg), diastolic blood pressure (DBP, mm Hg) and heart rate (HR, beats per minute). Then the catheter was introduced into the LV to assess the maximal rate of rise (dP/dtmax, mm Hg/s) and decrease (dP/dtmin, mm Hg/s) of LV pressure.

2.3. Myocardial NADPH oxidase activity
NADPH oxidase activity was measured by superoxide-dependent lucigenin chemiluminescence as described previously [6]. Myocardial tissues were minced and homogenized on ice with a tissue homogenizer (Ultraturax) in buffer A containing 50 mM monobasic potassium phosphate pH 7.0, 250 mM sucrose and protease inhibitors (1 µg/ml aprotinin, 0.5 µg/ml leupeptine, 87 µg/ml phenylmethylsulfonyl fluoride). Microsomal fractions were obtained from 100000 x g pellets. Microsomal fraction (30 µg of protein) was added to a glass scintillation vial in 50 mM monobasic potassium phosphate pH 7.0, containing 5 µM lucigenin. Reaction was started by the addition of 500 µM NADPH to the incubation medium as a substrate for O2– production. Luminescence was measured in a dark room with a scintillation counter (Wallac 1410). Measurements were integrated for a 1 min period and the cycle repeated three times. Background counts were determined by NADPH-free incubation. NADPH oxidase was expressed as cpm/min/30 µg proteins.

2.4. Quantification of p47phox phosphorylation by Western blot analysis
P47phox phosphorylation was examined by western blot analysis. LV tissue was homogenised in buffer A on ice with a tissue homogenizer (ultraturax) and a Dounce homogenizer. Fifty micrograms of proteins were incubated with protein A/G (Santa Cruz, 1 h at 4 °C). The sample was centrifuged (30 s at 700 x g) and the supernatant was incubated with anti-p47phox primary antibody (Santa Cruz, 6 µg for 1 h at 4 °C), then with protein A/G (1 h at 4 °C). The sample was centrifuged (30 s at 700 x g), the pellet was washed (4 x buffer A) and the resulting pellet was resuspended with buffer sample (60 mM tris pH 6.8, 2% sodium dodecyl sulfate, 1% saccharose, 1% bromophenol blue, 5% β-mercaptoethanol). After boiling for 5 min, proteins were separated by 10% SDS-polyacrilamide gels (Bio-Rad) for 1 h at 100 V and transferred to nitrocellulose membrane (45 min at 100 V). To ensure equivalent quantitative transfer efficiency of proteins, the nitrocellulose membrane was stained with a Ponceau solution. For blocking, the membrane was incubated in a buffer containing (6% milk, Phosphate Buffer Saline (PBS), 0.1% tween-20) for 2 h at room temperature. The phosphorylated form was detected with a antibody against phosphorylated serine residues (P-serine) (Alexis, 1:500, overnight at 4 °C). The result is expressed as P-serine/p47phox ratio.

2.5. Statistical analysis
All results are expressed as mean ± SEM. Data were analysed by an analysis of variance (ANOVA) for multiple comparisons followed by the post hoc Tukey's test (protocol 1) and a Student's test for unpaired data (protocol 2), using SYSTAT software. Differences were considered to be statistically significant at p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Effects of an {alpha}1-adrenoceptor antagonist on cocaine-induced cardiac dysfunction, hypertrophy and NADPH oxidase
3.1.1. Cardiac functional parameters and hypertrophy
Results on echocardiography assessments of the left ventricular function are shown in Table 1. Compared with controls, cocaine significantly decreases FS and CI, by 21 and 17%, respectively (p<0.05). Prazosin pretreatment prevents these decreases. Similarly, left ventricular end-diastolic and end-systolic diameters are increased after cocaine administration by 17 and 25% (p<0.05), respectively, and are normalized by prazosin.


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  		Table 1 Functional parameters and hypertrophy after cocaine administration with or without prazosin

 
LV weight is increased by 14% (p<0.05) after cocaine. This parameter is normalized with prazosin pretreatment.

There are no differences between groups in blood pressure and heart rate. However, a slight decrease in dP/dtmin and dP/dtmax is observed after cocaine administration.

3.1.2. NADPH oxidase
Cocaine administration increases myocardial NADPH oxidase activity compared to the control group: 14600 ± 654 vs. 9999 ± 1025 cpm.min–1.30 µg proteins–1 (p<0.05). This NADPH-dependent superoxide anion production is significantly decreased by prazosin: (10977 ± 774 cpm min–1 30 µg proteins–1, p<0.05 vs. cocaine) (Fig. 1A).


Figure 1
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  		Fig. 1 Effect of cocaine with or without prazosin (Prz) treatment on myocardial NADPH oxidase. (A) NADPH oxidase activity in LV homogenates measured by lucigenin chemiluminescence. (B) Detection of p47phox and phosphorylated serine residues by immunoprecipitation, expressed as P-serine/p47phox ratio. Bar graphs are summary data of normalized densitometric ratios (n = 5 per group). *p<0.05 vs. control, {dagger}p<0.05 vs. cocaine.

 
Because serine phosphorylation of p47phox is a key event in NADPH oxidase activation, we investigated whether this process is influenced by cocaine. The phosphorylation of p47phox in myocardial homogenates is analyzed by detecting phosphorylation of serine residues after p47phox immunoprecipitation. Western blot analysis indicates that cocaine treatment enhances phosphorylation of the NADPH oxidase subunit p47phox as assessed by the increase in P-serine/p47phox ratio, compared to the control group (1.61 ± 0.31 vs. 0.52 ± 0.20, respectively, p<0.05). Pretreatment with Prz prevents this effect (Fig 1B).

3.2. Effects of phenylephrine on myocardial NADPH oxidase and heart function
3.2.1. Hypertrophy and functional parameters
The LV/BW ratio is slightly increased by 9.6% (p<0.05) after phenylephrine administration. However, there are no differences between groups in mean arterial pressure, heart rate, dP/dtmin or dP/dtmax (Table 2).


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  		Table 2 Hypertrophy and functional parameters after phenylephrine administration

 
Echocardiographic assessments of left ventricular function are shown in Table 2. Fractional shortening, cardiac index, left ventricular end systolic and diastolic diameters (LVESD and LVEDD) are not altered after phenylephrine.

3.2.2. NADPH oxidase
As shown in Fig. 2A, NADPH oxidase activity is significantly increased in the phenylephrine group compared to the control group: 10807 ± 769 vs. 9001 ± 290 units, respectively, p<0.05.


Figure 2
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  		Fig. 2 Effect of phenylephrine (Phe) on myocardial NADPH oxidase. (A) NADPH oxidase activity in LV homogenates measured by lucigenin chemiluminescence. (B) Detection of p47phox and phosphorylated serine residues by immunoprecipitation, expressed as P-serine/p47phox ratio. Bar graphs are summary data of normalized densitometric ratios (n = 5 per group). *p<0.05 vs. control.

 
As shown in Fig. 2B, phosphorylation of p47phox is significantly increased in the myocardium of rats treated for 7 days by phenylephrine. The P-serine/p47phox ratio is increased by 90% compared to the control group.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We demonstrated that blockade of {alpha}1-AR by prazosin prevents cocaine-induced increase in NADPH oxidase activity, LV dysfunction and hypertrophy. We also showed that specific {alpha}1-AR stimulation increases NADPH oxidase activity and cardiac hypertrophy, independently of sustained hemodynamic changes. These observations clearly demonstrate that the cardiac effects of cocaine are mediated by {alpha}1-AR and that NADPH oxidase-mediated ROS production may represent an important effector.

An excessive amount of circulating catecholamines is known to induce cardiomyopathy through cardiac adrenergic receptors and also possibly by increasing production of reactive oxygen species (ROS) [15]. Recent studies suggested that catecholamines, through {alpha}1-AR stimulation, may activate NADPH oxidase-dependent generation of superoxide and secondarly of hydrogen peroxide, involved in the hypertrophic response of vascular wall cells [10] and cardiomyocytes [12]. As cocaine leads to an excess level of catecholamines, we hypothesized that it may also increase NADPH oxidase via {alpha}1-AR stimulation. After cocaine, we observed an increase in NADPH oxidase activity, accordingly to our previous results [6]. However, systemic administration of the {alpha}1-AR antagonist, prazosin, prevented this increase. In order to assess more precisely the contribution of {alpha}1-adrenoreceptor in the activation of myocardial NADPH oxidase in vivo, we used phenylephrine as a specific {alpha}1-AR agonist. We demonstrated that phenylephrine induced an increase in NADPH oxidase activity. It is possible that this effect is simply a concomitant phenomenon to a functional response but not directly related to {alpha}1-AR activity. However, we noted that (1) this effect occurred in the absence of sustained hemodynamic changes and without cardiac dysfunction after Phe administration, in our experimental conditions and (2) we have previously shown that an early increase in NADPH oxidase may also occur after a short-term cocaine administration and that it precedes the myocardial dysfunction observed after a chronic cocaine use [6]. These observations strongly indicate the direct cause–effect relationship between catecholamines via {alpha}1-AR stimulation and activation of NADPH oxidase.

The {alpha}1-ARs are Gq-coupled receptors and stimulation of the receptors leads to activation of mitogen-activated protein kinases (MAPK) and one or more isoforms of protein kinase C which play a role in hypertrophic response of catecholamines [16–19]. Additional experiments [9,10,12] revealed that these {alpha}1-AR-induced hypertrophic effects involve reactive oxygen species and NADPH oxidase as a critical player. Consistent with these observations, we showed that phenylephrine-induced LV hypertrophy is associated with increased NADPH oxidase activity. Moreover, cocaine-induced cardiac hypertrophy and NADPH oxidase activity are prevented by prazosin. These observations confirm that cocaine-induced hypertrophy is mediated predominantly by {alpha}1-AR and that NADPH oxidase up-regulation may represent an important step in the signaling pathway. Potential mechanisms through which NADPH oxidase is increased include transcriptional up-regulation of oxidase components and post-translational modifications such as p47phox phosphorylation that facilitates association of the membrane-bound and cytoplasmic subunits of the enzyme [11]. In the present study, at least part of the mechanism underlying the increased NADPH oxidase is an increase in phosphorylation of p47phox subunit. It would be interesting to conduct another study in order to understand the integrated signaling mechanisms leading to the activation of NADPH oxidase after {alpha}1-AR stimulations.

Another new finding of this study is the prevention of cocaine-induced LV dysfunction by prazosin. Indeed, the decrease in fractional shortening and cardiac index and increases in systolic LV diameters, as already described [6], were prevented by prazosin. These beneficial effects of prazosin on cardiac dysfunction clearly demonstrate the role of {alpha}1-adrenoreceptor in cardiac effects associated with repeated cocaine use. The role of {alpha}1-adrenoreceptors in mediating acute hemodynamic responses to cocaine has been well described in different vascular beds [20–24] and it is easy to speculate that the blockade of vascular adrenoreceptor would prevent systemic vasoconstriction that could affect cardiac function. However, considering the modest and transient increase in arterial pressure after cocaine administration noted in many studies [3], it is unlikely that the hemodynamic improvement occurs secondary to changes in afterload. As described above, a contribution of a direct {alpha}1-AR stimulation on NADPH oxidase-ROS production could participate to this cardiac dysfunction. This participation appears to be important and may run in synergy with other systems activated by cocaine as, e.g. cholinergic responses. Indeed, muscarinic receptors also contribute to the hemodynamic responses to cocaine because atropine prevented the decrease in cardiac output [25]. Knuepfer [26] has also demonstrated muscarinic cholinergic and β adrenergic contribution to cardiac responses to cocaine.

Based on our present results and others, we speculate that the increased O2.– production by NADPH oxidase after {alpha}1 stimulation contributes to initiate a cascade of events leading to cocaine-induced cardiotoxicity. Although the exact contribution of NADPH oxidase needs further investigation, these observations outlined its role in cocaine-induced cardiac dysfunction.

The present study clearly demonstrate the role of {alpha}1-adrenoreceptors in cocaine-induced cardiotoxicity. The evidence we present here for the adrenergic dependent pathway on myocardial NADPH oxidase up-regulation, together with the effects of prazosin on cardiac function, supports the hypothesis that a direct action of catecholamines on {alpha}1-AR contributes to cocaine-induced impairment of cardiac function, probably through a NADPH oxidase-dependent ROS production.


   Acknowledgement
 
The authors would like to thank the "Société Française de Réanimation en Langue Française" for their financial help.


   Notes
 
Time for primary review 23 days


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

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