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Anesth Analg 2000;90:50
© 2000 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

Perinatal Cocaine Exposure Impairs Myocardial ß-Adrenoceptor Signaling in the Neonatal Rat

Lena S. Sun, MD

Department of Anesthesiology and Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York

Address correspondence and reprint requests to Lena S. Sun, MD, Ph 5-544, 630 West 168th St., New York, NY 10032. Address e-mail to LSS4{at}columbia.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Cardiac dysfunction occurs in infants with prenatal cocaine exposure, and gestational cocaine exposure induces presynaptic and postsynaptic changes in the central monoaminergic receptor pathways. The hypothesis of this study is that prenatal cocaine exposure adversely affects the peripheral adrenergic receptor (ßAR) signaling pathway in the neonatal rat heart. Timed pregnant rats received daily intragastric treatment with saline or cocaine 20 mg/kg or 60 mg/kg from Gestational Day 2 until parturition. After birth, nursing mothers either continued to receive the same treatment or received no treatment. Adenylyl cyclase activity, ßAR density, and the amount of immunoreactive G proteins were measured in myocardial membranes obtained from the offspring on Postnatal Day 1 or 7. On Postnatal Day 1, prenatal cocaine exposure increased the ßAR number but did not affect isoproterenol-stimulated adenylyl cyclase activity. On Postnatal Day 7, perinatal cocaine exposure significantly attenuated isoproterenol-stimulated adenylyl cyclase activity in the absence of ßAR up-regulation. Prenatal cocaine exposure also significantly increased Gi protein and reduced GTP-stimulated adenylyl cyclase activity in Postnatal Day 1 cocaine (20 mg/kg) pups compared with saline (P < 0.05). Therefore, perinatal cocaine exposure impaired the myocardial ßAR-cAMP signaling pathway during the first week of postnatal life in the rat.

Implications: This study shows that maternal cocaine use during pregnancy impairs the ß-adrenoceptor signaling pathway in the rat during the first week of life. Abnormal cardiac function in the cocaine-exposed neonate may be related to a defect in ß-adrenoceptors, because they regulate cardiac function.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Of newborns in major urban areas, 10%–15% are affected by maternal cocaine use (1,2). Not only do offspring born to mothers with a history of cocaine abuse have a high incidence of congenital anatomical cardiac and noncardiac malformations, they also show evidence of functional cardiovascular abnormalities, including an altered pattern of heart rate variability, transient myocardial ischemia (3), reduced cardiac output (4), and ventricular dysrhythmias (5). Therefore, these children may be considered at high risk of cardiovascular complications when they present as patients in operating rooms and intensive care units during the neonatal period and early infancy.

Fetal cocaine exposure is associated with both presynaptic and postsynaptic changes in the central monoaminergic receptor pathways (6–8). Peripheral autonomic dysfunction and disruption of ontogeny of cardiovascular autonomic control have been implicated as possible mechanisms for the cardiovascular functional abnormalities (7), although very few studies have specifically examined the peripheral monoaminergic receptor pathway.

The two arms of autonomic control of cardiac function involve stimulation by the sympathetic nervous system and inhibition by the parasympathetic nervous system. Sympathetic stimulation involves the neural release of catecholamines, which in turn stimulate postsynaptic myocardial ß-adrenoceptors (ßAR) to couple to the stimulatory G protein, Gs, and activate adenylyl cyclase, leading to increased intracellular cAMP accumulation (9). In the heart, the stimulation of sympathetic activity is modulated by the parasympathetic nervous system. The release of acetylcholine from vagal nerve endings stimulate postsynaptic muscarinic receptors that are coupled to the inhibitory G proteins, Gi, and inhibit adenylyl cyclase to reduce intracellular cAMP accumulation (9). Although chronic cocaine exposure has been documented to change G-protein expression and the cAMP signaling pathway in the adult central nervous system (CNS) (10–13), little is known regarding the effect of prenatal cocaine exposure on G proteins and cAMP signaling in the neonatal CNS, and even less is known about the peripheral nervous system.

The hypothesis of this study is that chronic perinatal cocaine exposure reduces the myocardial (ßAR)-G protein-cAMP signaling pathway in the neonatal rat. An established pregnant rat model of perinatal drug exposure was used to determine myocardial adenylyl cyclase activity, ßAR density, and G-protein expression in neonatal rats on Postnatal Day 1 or day 7. The results indicate that perinatal cocaine exposure significantly impairs the myocardial ßAR-cAMP signaling pathway on Postnatal Days 1 and 7.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by the institutional animal care and use committee at the College of Physicians and Surgeons of Columbia University. Timed-pregnant (Gestational Day 0–1) female Sprague-Dawley rats, 90–110 days of age, were purchased and housed individually in a temperature/humidity-controlled room on a 12/12-hour light/dark cycle with ad libitum access to laboratory rodent chow and drinking water. On arrival in the animal care facility, the rats were weighed and transferred to a maternal cage within the first-24 h. Weights were obtained on Gestational Days 7, 14, and 21.

Saline (control) or cocaine 20 mg/kg (C20) or 60 mg/kg (C60) in equal volume was given once a day beginning on Gestational Day 2 by intragastric administration. These doses and the intragastric route of administration simulate the plasma and tissue concentrations achieved in human cocaine abusers (14). Moreover, these doses cause minimal changes in maternal weight gain and fetal wastage (14). After birth, neonatal animals were divided into two groups: those that were nursed by mothers that continued to receive drug treatment until Postnatal Day 7 and those that were nursed by mothers that were not receiving cocaine. Animals were killed on Day 1 (D1) or Day 7 (D7) of postnatal life. The experimental protocol is outlined in Table 1.


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  		Table 1. Experimental Protocol
 
Sarcolemmal preparations used for all of the studies were obtained as follows, according to previously described methods (15). Heart tissues were placed in ice-cold saline and rinsed clean of any obvious blood, blotted dry, quickly frozen in liquid nitrogen, and stored at -70°C. Tissues were minced in six volumes of a solution containing 50 mM EDTA, 0.1 mM PMSF, 250 mM sucrose, and 30 mM histidine (pH 7.4), on ice, then homogenized with a polytron with three 15-s bursts. The homogenate was centrifuged at 15,000g for 15 min at 0°C; the resultant supernatant was centrifuged at 105,000g for 45 min. The pellet was resuspended and centrifuged again for an additional 45 min at 105,000g. The final pellet was resuspended in four volumes of the homogenizing buffer, except that EDTA was deleted. Membrane preparations were immediately used for enzyme assays or stored at -70°C for later use in binding and immunoblot assays. Protein determination was performed immediately before each experiment according to the method of Bradford (16), using bovine serum albumin as the standard.

Adenylyl Cyclase Assay
For adenylyl cyclase assays, membranes (10 µg of protein) were incubated in triplicate at 37°C for 15 min in a final volume of 100 µL containing the following reaction mixture (final concentration): 1 mM IBMX, 3 mM MgSO4, 50 mM Tris (pH 7.5), 0.2 mM ATP, an ATP regenerating system (creatine phosphate 10 mM and 50 U/mL CPK), with and without isoproterenol (ISO), and/or 200 µM GTP. For basal activity, GTP was deleted. The reaction was stopped by the addition of 50 µL of 1% sodium dodecyl sulfate (SDS). After centrifugation at 1000g for 15 min., the cAMP generated was determined by radioimmunoassay. Separate groups of adenylyl cyclase assays were performed to evaluate ßAR- and GTP-stimulated adenylyl cyclase activity. Three different concentrations of ISO were used—0.1, 1, and 10 µM—to evaluate the response to ßAR stimulation. GTP 200 µM was used to assess postreceptor-mediated, G-protein–stimulated adenylyl cyclase activity.

ß Adrenoceptor Radioligand Binding Experiments
Saturation experiments were performed in duplicate using the radiolabeled antagonist (-)-125I-iodocy-anopindolol (ICYP) to determine total ßAR density. Membranes (25–40 µg of protein) were incubated with 8–11 concentrations of 125I-ICYP in the absence (total binding) and presence of 10 µM propranolol (nonspecific binding) in the saturation binding studies. In all experiments 125I-ICYP 2, 4, 8, 16, 32, 64, 128, and 160 pM were used. In some experiments, additional concentrations of ICYP (12, 24, and 48 pM) were included. After incubation for 1 h at 37°C, the reaction was terminated by rapid vacuum filtration over glass fiber filters, followed by three washings with 5 mL of ice-cold 50 mM Tris buffer (pH 7.5). All filters had been presoaked in 0.5% polyethylenimine. Filters were then counted in a gamma counter at 70% efficiency.

Immunoblot Analysis
Sarcolemmal membrane proteins were subjected to SDS-polyacrylamide gel electrophoresis (12%) according to the method of Laemmli, and protein was transferred electrophoretically to a nitrocellulose membrane. Gel was soaked overnight in phosphate-buffered saline containing 0.05% Tween 20 and 5% nonfat dry milk in the refrigerator. The membrane was then incubated for 90 min with the primary antibodies (anti-Gi{alpha} 1&2 or anti-Gs{alpha}) at 1:1000 dilution. After four 10-min washes with phosphate-buffered saline containing 0.05% Tween 20, the gel was incubated for 45 min with horseradish peroxidase-conjugated goat anti-rabbit immunoglobin G as the secondary antibody at 1:3000 dilution. This was followed by four 15-min washes. The immunoreactive bands were visualized using a Western blot analysis reagent system. Bands obtained from the chemiluminescence films were quantified by densitometry.

Data Analysis
Adenylyl cyclase assays and ßAR binding data obtained from D7 animals were initially analyzed to assess whether there was any effect of postnatal cocaine treatment. There was no difference in animals nursed by mothers that did or did not continue to received cocaine; therefore, all of the data for D7 animals with and without postnatal cocaine exposure were combined and are reported as one group. The saturation binding experiments were analyzed by performing Scatchard analysis to determine the apparent affinity (Kd) of the ligand for the ßAR and the apparent maximal number of binding sites (Bmax) (bound versus bound/free ligand and using least square linear regression) (16). The negative reciprocal of the slope of the best fit yields the Kd, and the x intercept yields the Bmax. Bmax was used as an index of ßAR density. Analysis of variance (ANOVA) for repeated measures was used to assess the concentration-response effect of ISO within each group, followed by Bonferroni’s modified t-test, if needed. The interaction of cocaine exposure and dose was examined by using ANOVA (17). Significant differences in Kd, Bmax, and the amount of immunoreactive G proteins among groups were assessed by using factorial ANOVA. Data are expressed as means ± SEM. P < 0.05 was deemed significant.

Materials
Anti-Gs, anti-Gi antibodies, and creatine kinase were purchased from Calbiochem Biolabs (Beverly, MA); 125ICYP was purchased from New England (Lã Jolla, CA); Western blot analysis reagent system was purchased from Amersham (Arlington Heights, IL), and all other chemicals were purchased from Sigma Chemical Company, St. Louis, MO.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Maternal weight gain, litter size, and birthweights were comparable among the three groups (data not shown).

Myocardial Adenylyl Cyclase Activity in Neonatal Rats
In myocardial membranes from D1 animals, basal adenylyl cyclase activity was similar in rats that had received intrauterine saline (CTL), cocaine 20 mg/kg (C20), or cocaine 60 mg/kg (C60) treatment [in pmoles] cAMP/mg protein per minute: 18.8 ± 3.1, 20 ± 2.7, or 17 ± 1.5, respectively). ISO increased adenylyl cyclase activity at all three concentrations and was comparable among the three groups (Figure 1A) (CTL n = 8; C20 n = 6; C60 n = 5 at D1). Basal adenylyl cyclase activity increased significantly from D1 to D7 in CTL (40.1 ± 7.8 pmoles cAMP/mg protein per minute), C20 (61.5 ± 6.2 pmoles cAMP/mg protein per minute), and C60 (55.6 ± 10.9 pmoles cAMP/mg protein per minute). A significant cocaine effect was observed on adenylyl cyclase activity in response to increasing concentrations of ISO in D7 hearts (P = 0.0018 by ANOVA) (Figure 1B) (CTL n = 8; C20 n = 5; C60 n = 5 for D7). Prenatal cocaine exposure attenuated the cAMP response to ISO in D7 hearts. To examine whether cocaine exposure affected postreceptor-mediated activation of adenylyl cyclase, adenylyl cyclase activity in response to stimulation by GTP at 200 µM was examined in a separate group of assays. GTP-stimulated myocardial adenylyl cyclase activity was significantly reduced in D1 C20 animals (n = 11) compared with CTL animals (n = 17), but it was comparable for CTL and C60 animals (n = 6). GTP significantly stimulated adenylyl cyclase activity in D7 hearts (CTL n = 17; C20 n = 13; C60 n = 12). Although there seemed to be less GTP-stimulated activity in the D7 C20 group, similar to the pattern observed for the D1 group, it failed to attain statistical significance (Table 2).



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  		Figure 1. Effect of isoproterenol on adenylyl cyclase activity in animals on Days 1 (D1) and 7 (D7). A, Significant ß-adrenoceptor (ßAR)-stimulated adenylyl cyclase activity was observed in control (CTL n = 8), cocaine 20 mg/kg (C20 n = 6), and cocaine 60 mg/kg (C60 n = 6) groups at D1 (P < 0.05 for all groups). The response to isoproterenol (ISO) stimulation was comparable in all groups. Basal activity were comparable among groups (in pmoles cAMP/mg protein per minute: 18.8 ± 3.1, 20 ± 2.7, and 17 ± 1.5 for CTL, C20, and C60, respectively). B, The ßAR agonist ISO significantly stimulated adenylyl cyclase activity in the CTL (n = 8; P = 0.0009) and C20 groups (n = 6; P = 0.0002), but not in the C60 group (n = 5; P = 0.15) at D7. Basal activity was comparable among the groups (40.1 ± 7.8, 61.5 ± 6.2, and 55.6 ± 10.9 pmoles cAMP/mg protein per minute for CTL, C20, and C60, respectively). * P < 0.05 versus basal activity.

 

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  		Table 2. GTP-Stimulated Adenylyl Cyclase Activity
 
ß-Adrenoceptor Density in Neonatal Rats
In D1 hearts, there was significant up-regulation in ßAR density in the C60 group (Figure 2A) (n = 6 for all groups at D1), but in D7 hearts, ßAR density was comparable in all three groups (Figure 2B) (n = 9 for all groups at D7). Kd values were comparable among all D1 (10 ± 2, 12 ± 3, and 13 ± 5 pM for CTL, C20, and C60, respectively) and D7 groups (13 ± 3, 12 ± 2, and 13 ± 3 pM for CTL, C20, and C60, respectively).



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  		Figure 2. ß-Adrenoceptor (ßAR) density in animals on Days 1 (D1) and 7 (D7). A, ßAR density (Bmax) in myocardial membranes was significantly greater in the cocaine 60 mg/kg group (C60 n = 6) than in the control group (CTL n = 6). There was no significant difference between the cocaine 20 mg/kg group (C20 n = 6) and CTL. B, On D7, CTL (n = 9), C20 (n = 9), and C60 (n = 9) Bmax values were similar. * P < 0.05 versus CTL.

 
G-Protein Immunoblotting
To further test whether the attenuated cyclase activity in response to GTP stimulation in D1 C20 hearts was the result of a cocaine effect at the stimulatory G (Gs) and/or inhibitory G proteins (Gi), the total amount of Gs and Gi proteins was quantified by immunoblotting using myocardial tissues from CTL, C20, and C60 animals at D1 and D7. In D1 hearts, up-regulation of Gi was consistently observed in C20 (n = 10) compared with CTL animals (n = 10), but Gi was comparable between CTL and C60 animals (n = 4) (Figure 3A). At D7, there was no significant difference in myocardial membrane Gi among the groups (Figure 3A) (CTL n = 9; C20 n = 9; C60 n = 4). In contrast, at D1, immunodetectable Gs was increased in C60 (n = 4) compared with CTL and C20 animals (n = 10 for both), two groups which had comparable Gs (Figure 3B). At D7, there was no significant difference in Gs (Figure 3B) (CTL n = 10; C20 n = 10; C60 n = 4) among the groups.



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  		Figure 3. Effect of prenatal cocaine on G proteins in animals on Days 1 (D1) and 7 (D7). A, Immunodetectable inhibitory G protein (Gi). In D1 animals, the total amount of Gi proteins was significantly higher in cocaine 20 mg/kg (C20 n = 10) myocardial tissues compared with control (CTL n = 10), but it was comparable between cocaine 60 mg/kg (C60 n = 4) and CTL. In D7 animals, the total amount of Gi (n = 9 for both CTL and C20, n = 4 for C60) was comparable. Experiments were performed on individual hearts. B, Immunodetectable stimulatory G protein (Gs). No difference was found between D1 CTL (n = 10) and C20 (n = 10) in the amount of Gs proteins. C60 (n = 4) showed a significantly higher amount of Gs proteins compared with both CTL and C20. The total amount of Gs proteins (n = 10 for both CTL and C20, n = 4 for C60) was comparable in D7 myocardial membranes. * P < 0.05 versus CTL. P < 0.05 versus C20 of the same age.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major finding of this study was that perinatal cocaine exposure significantly modified the myocardial ßAR-cAMP signaling pathway in different ways. The effect of fetal cocaine exposure was a function of the cocaine dose during intrauterine drug exposure and the age of the animal at the time of assessment. In heart tissues from D1 animals, prenatal cocaine exposure was associated with an increase in ßAR number and an increase in the amount of Gi protein, but there was no change in ßAR-stimulated adenylyl cyclase activity. In contrast, in hearts from D7 animals, regardless of whether cocaine treatment had been continued during the postnatal period, ßAR-stimulated adenylyl cyclase activity was reduced without any change in ßAR number.

ßAR regulation differs between neonatal and adult hearts. Sustained ßAR stimulation induces uncoupling of ßAR-Gs and receptor down-regulation in the adult heart, whereas, in neonatal rats, repeated agonist exposure enhances ßAR signaling (18). The reason for this paradoxical response in the developing heart is unclear but seems to be temporally related to sympathetic innervation. The observed ßAR up-regulation in the newborn D1 heart in this model of intrauterine cocaine exposure may be a "sensitization" response. A possible explanation for the findings of myocardial ßAR up-regulation at D1 is the increased circulating catecholamine levels in the mother rat, and exposure of the neonatal heart to the large amount of maternally derived catecholamines induced an increase in ßAR number.

It is likely that the up-regulation of myocardial ßAR at D1 after prenatal cocaine exposure compensated for any alteration of the downstream signaling pathway. In D7 hearts, which no longer had evidence of ßAR upregulation we observed a decrease in ISO-stimulated adenylyl cyclase activity in the cocaine-exposed groups.

Therefore, the current data seem to support the idea that prenatal cocaine exposure impaired ßAR-Gs-cAMP signaling in both D1 and D7 hearts. This impairment may be less obvious in D1 hearts because there was also an increase in ßAR number, which may have masked the defect. However, in D7 hearts, the reduction in adenylyl cyclase activity in response to ßAR stimulation was much more evident in the absence of the compensatory effects of ßAR up-regulation.

These results further suggest that the defect in the ßAR-cAMP signaling pathway clearly involved effects of prenatal cocaine exposure on G proteins. Nonreceptor-mediated myocardial adenylyl cyclase activity in response to the maximal concentration of GTP was attenuated at D1 in the cocaine-exposed animals at the small-dose cocaine treatment (20 mg/kg)—the same group that also had an increase in the inhibitory G protein—which suggests that prenatal exposure to cocaine modified inhibitory G protein quantity and function. That GTP-stimulated adenylyl cyclase activity was unchanged after the large dose of intrauterine cocaine treatment in D1 hearts may be due to the combined effects of a more modest increase in Gi and a significant increase in Gs. These two effects might have offset each other. The effects of prenatal cocaine exposure on GTP-stimulated adenylyl cyclase activity in D7 hearts were smaller, and this also corresponded with smaller changes in the amount of immunodetectable G proteins.

Changes in G protein-coupled receptors, G proteins, and cAMP signaling after chronic cocaine exposure have been documented in the CNS (10–13). In most chronic cocaine exposure models in adults, the effects of cocaine have only been examined in distinct brain regions and seemed to be species-dependent (19–21). In rhesus monkeys that received repeated injections of cocaine, DA-1 receptor and ßAR density were both reduced in the caudate nucleus (20). In the rat, chronic cocaine use reportedly increases central ßAR binding capacity, as well as norepinephrine-stimulated cAMP accumulation (22). Studies have documented an alteration in G proteins in the CNS associated with cocaine (10–13). Rats that received chronic cocaine treatment for two weeks showed a decrease in ADP-ribosylation, as well as immunoreactivity of Gi{alpha} in the nucleus accumbens (10). Other studies have reported that chronic cocaine administration causes a down-regulation in Gi mRNA in the rat hippocampus (20) and an increase in adenylyl cyclase activity in rat whole brain preparations (22). Consequently, chronic cocaine exposure in the adult animal modified the inhibitory G-protein gene expression, protein content, and the adenylyl cyclase activity modulated by the Gi.

Although prenatal chronic cocaine exposure may be considered a form of chronic cocaine exposure, the effects may be quite different due to the immaturity of the target organism and the likely contribution of indirect actions of cocaine on the maternal-fetal unit. In contrast to the down-regulation of DA-1 receptors reported after chronic exposure in adult rhesus monkeys (21), prenatal cocaine exposure causes and up-regulation of central DA-1 receptor mRNA (23). Therefore, chronic cocaine exposure in adult and fetal monkeys seemed to induce opposite changes in DA-1 receptors in the brain. The discordant effects in adult and developing animals have not been documented in the rat, nor has it been examined with regard to the ßAR system. The present data suggest that myocardial ßAR became up-regulated after cocaine exposure in the fetal rat, similar to the changes in central ßAR after chronic cocaine exposure in the adult rat.

In addition to changes in receptor number and the amount of G protein, cocaine exposure also leads to an uncoupling of receptor-effector coupling (24,25). For example, prenatal cocaine exposure in the rabbit diminishes the DA-1 receptor-mediated activation of striatal Gs proteins (26) without changes in the actual amount of Gs or Gi proteins, which indicates that DA-1 receptors were uncoupled from Gs and the cAMP signaling pathway. Moreover, the uncoupling of the central DA-1 receptor from Gs was evident from Postnatal Day 10 until Postnatal Day 100. Although whether ßAR-Gs uncoupling occurred in the neonatal myocardium was specifically examined, the changes observed could also involve additional defects at the level of receptor-G protein coupling. This will be a subject of future investigation.

In conclusion, prenatal cocaine exposure in the rat modified the myocardial ßAR-cAMP signaling pathway during the first week of postnatal life. This signaling pathway plays a very important role in the regulation of cardiac function. Abnormalities in cardiac contractile function have been reported in cocaine-exposed human neonates. The changes in the ßAR-cAMP signaling pathway documented in the neonatal rat heart after perinatal cocaine exposure may underlie the mechanism(s) for abnormal cardiac function reported in the clinical setting. The present results are the first part of a continuing investigation examining the effect of prenatal cocaine exposure in the postnatal heart. Future studies will determine whether these changes continue beyond the immediate postnatal period and the functional significance of these changes in the developing cardiovascular system.


   Acknowledgments
 
Supported by NIH Grant R29 DA 09624.

I gratefully acknowledge the technical assistance of Ms. Erlinda Samaniego, Dr. Yan Guo, and Ms. Du Fang. I also thank Dr. Yvonne Vulliemoz and Dr. Carol Hirshman for their insightful critiques of the manuscript.


   Footnotes
 
The work was presented in part at the 1997 annual meeting of the American Society of Anesthesiology.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 3, 1999.




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L. S. Sun, S. Takuma, R. Lui, and S. Homma
The Effect of Maternal Cocaine Exposure on Neonatal Rat Cardiac Function
Anesth. Analg., September 1, 2003; 97(3): 878 - 882.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press