Volume 44(6) December 2004 pp 631-638
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[gamma]-Hydroxybutyrate (GHB) is generally thought to be a central nervous system depressant; however, GHB also has sympathomimetic cardiovascular actions. Radio telemetry was used to record the cardiovascular responses elicited by GHB (180-1000 mg/kg IV) in conscious rats. GHB elicited increases in mean arterial pressure (MAP) (24 ± 3 to 60 ± 5 mm Hg) lasting from 28 ± 8 to 227 ± 37 minutes. GHB (560 and 1000 mg/kg IV) also elicited a prolonged tachycardic response (85 ± 23 and 95 ± 22 bpm). The hypertension and tachycardia elicited by GHB (560 mg/kg) were reversed by the intravenous and intracerebroventricular administration of the GABAb receptor antagonist CGP 35348. CGP 35348 also reversed GHB-mediated increases in renal sympathetic nerve activity (RSNA). Administration of the purported GHB receptor antagonist NCS-382 reversed the increase in heart rate but not the pressor response elicited by GHB in telemetered rats. These data indicate that the intravenous administration of GHB markedly increases MAP, heart rate, and RSNA in conscious rats via activation of central GABAb receptors. In addition, GHB receptors appear to selectively mediate the increase in heart rate elicited by large doses of GHB.
The recreational use of [gamma]-hydroxybutyrate (GHB), known on the street as “G” or “liquid X,” has increased greatly over the past several years because of its ability to elicit euphoric intoxication with a loss of social inhibition.1,2 As a club drug, GHB is often used at large dance parties and has also been used in chemical submission “date rape” crimes.3 GHB is popular among weightlifters and body builders, who use the drug for its purported anabolic effects.3 As the recreational use of GHB has increased, so too has the incidence of drug-related toxicity, some of which involves the cardiovascular system.4,5
As an endogenous compound metabolically linked to [gamma]-aminobutyric acid (GABA), GHB is commonly thought to be a central nervous system depressant; however, experimental evidence suggests that in addition to its depressant actions, GHB also has significant sympathomimetic cardiovascular actions.6-9 Unfortunately, the experimental and clinical literature does not consistently define the cardiovascular effects of GHB. Clinical reports of acute GHB intoxication in humans typically report bradycardia, hypotension, and respiratory depression.2,4,5 However, a scattering of reports in the literature indicate that this drug elicits sympathomimetic cardiovascular effects in humans and animals. The use of GHB as a preanesthetic agent in humans is associated with increases in mean arterial pressure (MAP) and heart rate.6 In animal models of hemorrhagic shock, the administration of GHB returns arterial pressure, heart rate, and cardiac output to prehemorrhage levels without volume replacement.8 The most compelling evidence of the sympathomimetic actions of GHB is the observation that intraperitoneal administration of GHB elicits pronounced and prolonged increases in MAP and heart rate in conscious rats.7,9 These cardiovascular responses are prevented by pretreatment with [alpha]- and [beta]-adrenergic receptor antagonists. These responses can also be prevented by spinal cord transection or prehypothalamic lesions.7,9 The intracerebroventricular (ICV) administration of GHB also increases MAP and heart rate.9 Taken together, these data suggest that the cardiovascular responses elicited by GHB involve the activation of central sympathetic pathways; however, the mechanisms underlying the sympathoexcitatory cardiovascular responses have not been determined.
As a central nervous system depressant, GHB produces anesthesia and sedation similar to that produced by other classic sedative-hypnotics.3 In fact, GHB has recently been approved by the Food and Drug Administration for the treatment of cataplexy associated with narcolepsy based on its ability to induce sedation without disturbing natural sleep patterns.10 As a neuromodulator, GHB is thought to alter dopaminergic, serotonergic, and opioid transmission;3,11-14 however, most available evidence suggests that central serotonergic, dopaminergic, or acetylcholinergic mechanisms do not play significant roles in mediating GHB’s cardiovascular responses.9 Although the mechanisms underlying the depressant actions of GHB have not been clearly defined, they are thought to involve, at least in part, the activation of specific GHB receptors and GABAb receptors.15,16 What role, if any, these receptor systems play in mediating the sympathomimetic cardiovascular responses elicited by GHB is unknown.
In spite of the potential for GHB to elicit clinically significant cardiovascular responses, the mechanisms mediating the sympathomimetic actions of this central nervous system depressant have not been systematically studied. Therefore, the goals of this study were (1) to characterize the cardiovascular responses elicited by the acute intravenous administration of GHB; (2) to identify the role of the sympathetic nervous system in mediating the sympathomimetic cardiovascular responses elicited by GHB; and (3) to determine whether GABAb and/or GHB receptors are involved in mediating these responses.
Experiments were performed using male Sprague-Dawley rats (249-346 g; Harlan,
MAP and heart rate were recorded in conscious, unrestrained rats in their home cages using a radio telemetry system (Dataquest A.R.T. 2.2; Data Sciences International,
Renal sympathetic nerve activity (RSNA) was recorded in conscious rats (n = 5) using a modification of the method of Kapusta and Obih.19 Briefly, anesthesia was induced with methohexital sodium and supplemented with propofol injectable emulsion. Anesthetized animals were instrumented with femoral venous cannulas. A polyurethane cannula was also inserted into the femoral artery to allow for recording of arterial pressure. The left kidney was exposed through an incision in the left flank. A branch of a renal nerve bundle was dissected free and placed on a bipolar platinum wire electrode. RSNA was amplified (Ã—10,000-50,000) and filtered (low 30; high 10,000 Hz) using a Grass P511 amplifier. The recording electrode and nerve were then embedded in dental impression material. The electrode cable was secured to the abdominal muscles, and the flank incision was closed in layers. The amplified and filtered signal was collected and stored on a polygraph and a personal computer using BIOPAC acquisition and analysis software (BIOPAC Systems,
For experiments requiring the ICV administration of drugs, a stainless steel cannula was stereotaxically implanted into the right lateral cerebral ventricle of ketamine/xylazine-anesthetized rats at least 3-5 days before experimentation. The coordinates used to position the cannula were 0.3 mm posterior to the bregma, 1.3 mm lateral to midline, and 4.5 mm below skull surface.20 Verification of cannula position in the lateral ventricle was made by observation of cerebrospinal fluid flow from the implanted steel cannula after removal of the obturator and by observing injected dye in the lateral ventricle following completion of the study and subsequent postmortem brain section.21-23
Seven rats were instrumented with telemetry probes and femoral venous cannulas for intravenous administration of drugs. One week after surgery, the rats’ home cages were placed over telemetry receivers, where they remained for the duration of the experiment. On the first morning of the study, the rats received a single intravenous dose of saline or GHB (180, 320, 560, or 1000 mg/kg), and the cardiovascular responses were recorded continuously for at least 3 hours. GHB was injected (50 µL to 1 mL) over 1-2 minutes followed by a 0.5 to 0.7 mL saline flush. On subsequent days, doses of GHB or saline were administered in random order so that the order of doses was different for each animal and only 1 dose was administered per day. Each animal received all doses of GHB. The volumes of saline injected as controls corresponded with the volumes of the 180- (small volume control) and 1000-mg/kg (large volume control) doses of GHB.
To determine whether GHB and/or GABAb receptors were involved in mediating the MAP and heart rate responses elicited by GHB, a separate group of 9 rats was instrumented with telemetry probes and femoral venous cannulas. One week after surgery, baseline MAP and heart rate were recorded. The rats were then given a single intravenous dose of GHB (560 mg/kg), and the MAP response was continuously monitored. At or near the peak of the pressor response (35-45 minutes after GHB injection), either the GHB receptor antagonist NCS-382 (50 mg/kg, IV, n = 4) or the GABAb receptor antagonist CGP 35348 (50 mg/kg, IV, n = 5) was administered, and the cardiovascular parameters recorded. NCS-382 has been shown to block the discriminative stimulus effects of GHB.24,25 CGP 35348 has been shown to block the discriminative stimulus effects of GHB and baclofen (GABAb agonist) in rats.25 To determine the effects of both antagonists on baseline MAP and heart rate, a separate group of 5 rats were instrumented with telemetry probes and femoral venous cannulas. One week later, the animals received a single intravenous injection of CGP 35348 (50 mg/kg) or NCS-382 (50 mg/kg), and the cardiovascular responses were recorded. Seven days later the rats received the other antagonist. To evaluate the role of GABAb receptors in non-GHB-mediated hypertension, 5 rats were instrumented with telemetry probes and 2 femoral venous cannulas. On the day of the experiment, each rat received an intravenous infusion of the [alpha]1-adrenergic receptor agonist phenylephrine (1 µg/25 µL/min to 3.7 µg/90 µL/min) to achieve an average increase in MAP of 66 ± 5 mm Hg. Once the phenylephrine-induced hypertension was stable, CGP 35348 (50 mg/kg, IV) was administered, and the MAP response was recorded for 10 minutes. Afterward, the phenylephrine infusion was stopped, and the MAP was allowed to return to baseline.
Six rats were instrumented with telemetry probes, femoral venous cannulas, and ICV cannulas and allowed to recover. On the first day of the experiment, the animals received a single intravenous injection of GHB (560 mg/kg), and the MAP response was continuously monitored. At or near the peak of the MAP response, the GABAb antagonist CGP 35348 (50 µg/rat) was administered ICV, and the cardiovascular parameters were recorded.26 To determine the effect of CGP 35348 on baseline MAP and heart rate, the rats received a single ICV injection of CGP 35348 (50 µg/rat) in the absence of GHB, and their cardiovascular responses were recorded. All ICV injections were administered in a total volume of 5 µL. ICV cannulas were not removed for a minimum of 15 minutes after drug administration.
Five rats were instrumented for renal sympathetic nerve recording and were allowed to awaken from anesthesia. MAP and heart rate were monitored until stable baselines were achieved. The minimum time from the end of surgery until stable baselines were achieved was 4 hours. Baseline arterial pressure, MAP, heart rate, and integrated RSNA were recorded for at least 10 minutes. GHB (560 mg/kg, IV) was administered, and the cardiovascular and neural responses monitored until the MAP and RSNA responses appeared to plateau. At this point, CGP 35348 (50 mg/kg, IV) was administered, and the cardiovascular and neural responses continuously recorded.
The output from the telemetry probes was recorded (250 Hz) using receivers placed under the home cages. The data were sent to a consolidation matrix before being stored on a personal computer. Data acquisition was controlled using Data Sciences Dataquest acquisition software. The data were averaged into 2-second bins and displayed. The magnitude of the peak changes in MAP and heart rate elicited by the drugs were calculated off-line as the difference between the baselines and peak drug response using the Dataquest analysis program. Response durations were also calculated off-line using the Dataquest analysis program. The duration of the MAP response was calculated as the interval between drug administration and the point at which the MAP returned within 7 mm Hg of baseline. The duration of the heart rate response was calculated as the interval between the second increase in heart rate and the point at which the heart rate returned to within 7 bpm of baseline. In nerve recording studies, heart rate, MAP, and integrated RSNA were collected and analyzed using the computer-based BIOPAC system. The renal nerve activity was recorded (30 Hz to 10 kHz; Grass P511) and sampled at 2 KHz. RSNA measurements were performed using Labtech Notebook (version 6.1.1; Laboratory Technology,
The drugs used in this study were [gamma]-hydroxybutyrate, NCS-382 ([5,7,8,9-tetrahydro-5-hydroxy-6H-benzocyclohepten-6-ylidene]-monosodium salt acetic acid), pentobarbital, phenylephrine (all from Sigma-Aldrich, St Louis, MO), methohexital sodium (Brevital sodium; Jones Pharma, St Lous, MO), propofol (Gensia Sicor Pharmaceuticals, Irvine, CA), ketamine (Phoenix Scientific, Inc, St Joseph, MO), and xylazine (Vedco, Inc, St Joseph, MO). CGP 35348 (3-aminopropyl diethoxymethyl phosphinic acid) was graciously supplied by Drs Charles France and Andy Coop,
Figure 1 shows a typical experimental recording of the MAP and heart rate responses elicited by the administration GHB (1000 mg/kg, IV) in a conscious telemetered rat. This dose of GHB elicited a large and prolonged increase in MAP. GHB also elicited an immediate but transient increase in heart rate followed by a prolonged tachycardia. The 560 mg/kg dose of GHB produced a similar pattern of MAP and heart rate responses. The magnitudes of the initial increases in heart rate ranged from 52 ± 16 to 74 ± 6 bpm and were not significantly different from the increase in heart rate elicited by corresponding control doses of saline (Fig. 2). Therefore, the initial increases in heart rate elicited by GHB were not considered a drug effect. Lower doses of GHB (180 and 320 mg/kg, IV) also increased arterial pressure but not heart rate. Figure 2 summarizes the peak MAP and heart rate responses elicited by GHB and saline in 7 rats. The increases in MAP elicited by GHB peaked within 7 ± 2 to 36 ± 7 minutes, and the durations of these pressor responses ranged from 28 ± 8 to 227 ± 37 minutes. The administration of 560 and 1000 mg/kg doses of GHB also elicited tachycardic responses that peaked 41 ± 6 and 53 ± 7 minutes after drug administration and lasted 77 ± 21 and 95 ± 13 minutes, respectively. The small volume control injections of saline significantly increased heart rate (P = 0.01) but did not significantly increase MAP (Fig. 2). The administration of large-volume control injections of saline significantly increased MAP (P < 0.001) and heart rate (P < 0.001); however, the durations (6 ± 2 and 6 ± minutes, respectively) of these responses were significantly shorter (P = 0.001 and P < 0.001, respectively) than those elicited by the 1000 mg/kg dose of GHB.
FIGURE 1. Typical experimental record showing the heart rate (HR, top panel) and mean arterial pressure (MAP, bottom panel) responses elicited by the injection of GHB (1000 mg/kg, IV) in a conscious telemetered rat. Arrow, GHB injection.
FIGURE 2. Summary of the peak mean arterial pressure (MAP) and heart rate (HR) responses elicited by the intravenous injection of GHB and saline in conscious rats (n = 7). Small (open squares) and large (open diamond) volumes of saline corresponded to the volumes of the 180- and 1000-mg/kg doses of GHB, respectively. (Top) Averages of the peak increases in HR elicited by GHB and large volumes of saline. (Bottom) Averages of the peak increases in MAP elicited by each dose of GHB and the small and large volumes of saline. Values are means ± SEM.
The experimental record in Figure 3 demonstrates the ability of CGP 35348 to reverse the hypertension elicited by GHB (560 mg/kg, IV) in a telemetered rat when administered at the peak of the GHB-mediated increase in MAP. CGP 35348 also reversed the secondary tachycardia, lowering heart rate below baseline (Fig. 3). The decrease in MAP and/or heart rate elicited by the intravenous administration of NCS-382 or CGP 35348 was measured at the lowest point within 10 minutes. The effects of CGP 35348 on the GHB-mediated increases in MAP and the secondary tachycardic response in 5 rats are summarized in Figure 4A. In a separate group of 5 rats, the intravenous administration of CGP 35348 (50 mg/kg) alone significantly increased MAP (18 ± 3 mm Hg) and heart rate (56 ± 9 bpm), and these increases were significantly greater than those elicited by saline.
FIGURE 3. Typical experimental record showing reversal of the GHB-mediated increases in heart rate (HR, top panel) and mean arterial pressure (MAP, bottom panel) elicited by administration of the GABAb receptor antagonist CGP 35348 in a conscious telemetered rat. Single arrow, injection of GHB (560 mg/kg, IV). Double arrow, injection of CGP 35348 (50 mg/kg, IV).
FIGURE 4. Effect of CGP 35348 (A) and the GHB receptor antagonist NCS-382 (B) on the mean arterial pressure (MAP) and heart rate (HR) responses elicited by GHB (560 mg/kg, IV). Values are means ± SEM. *Significantly different from baseline. #Significantly different from peak GHB-mediated response.
In 5 rats, the intravenous infusion of phenylephrine increased MAP 66 ± 5 mm Hg. Five and 10 minutes after the subsequent intravenous administration of CGP 35348, MAP was unchanged at 66 ± 4 and 66 ± 3 mm Hg, respectively.
In a separate group of rats, the ICV administration of CGP 35348 (50 µg/rat) at the peak of the GHB-mediated pressor response returned MAP and the secondary increase in heart rate to baseline within 18 ± 4 (n = 6) and 13 ± 6 minutes (n = 4), respectively (Fig. 5). In control animals, the average time interval from the peak of the GHB-mediated pressor response to the return to baseline was significantly greater (91 ± 15 minutes, n = 7). Similarly, the time from the peak of the secondary tachycardia to the return to baseline in control animals was also significantly longer (87 ± 41 minutes, n = 7) than in treated rats. The central administration of CGP 35348 alone did not significantly alter baseline MAP (102 ± 4 versus 102 ± 7 mm Hg) or heart rate (333 ± 8 versus 332 ± 20 bpm) when measured approximately 18 minutes after drug administration.
FIGURE 5. Summary of the effect of CGP 35348 (50 µg/rat, ICV) on the increases in mean arterial pressure (MAP, n = 6) and heart rate (HR, n = 4) elicited by GHB (560 mg/kg, IV) in conscious, telemetered rats. Values are means ± SEM. *Significantly different from baseline. #Significantly different from the peak GHB-mediated response.
In a separate group of 4 rats, the intravenous administration of NCS-382 completely reversed the GHB-mediated increase in heart rate but not the pressor response (Fig. 4B). The administration of NCS-382 (50 mg/kg, IV, n = 4) alone increased MAP (22 ± 2 mm Hg) and heart rate (56 ± 13 bpm). Although the increase in MAP elicited by NCS-382 alone was significantly greater than that elicited by saline, the increases in heart rate elicited by the antagonist alone and saline were not significantly different.
Figure 6 shows a typical experimental record of the cardiovascular and renal sympathetic nerve responses elicited by GHB (560 mg/kg, IV) alone and after the subsequent administration of CGP 35348 in a conscious rat. In this rat, the injection of GHB (560 mg/kg, IV) increased RSNA and MAP (Fig. 6). At the plateau of the renal sympathetic nerve response, the administration of CGP 35348 reversed the increase in RSNA, reduced the hypertension, and lowered heart rate (Fig. 6). The decreases in MAP and heart rate after injection of CGP 35348 were preceded by a brief (<1 min) increase in MAP (14 ± 1 mm Hg, n = 5), which coincided with the injection. Figure 7 summarizes the RSNA, MAP, and heart rate responses elicited by GHB (560 mg/kg, IV) alone and after the subsequent administration of CGP 35348 in 5 rats. In these experiments, GHB elicited significant increases in RSNA (P < 0.01) and MAP (P < 0.001), both of which were reversed by administration of CGP 35348 (Fig. 7). Unlike the tachycardia observed in the telemetered rats, GHB tended to decrease heart rate in rats used for nerve recording studies (Fig. 7). The administration of CGP 35348 significantly reduced heart rate (Fig. 7).
FIGURE 6. Typical experimental record showing the heart rate (HR), arterial pressure (AP), mean arterial pressure (MAP), and integrated renal sympathetic nerve activity (RSNA) responses elicited by GHB in a conscious rat. Also shown is the effect of CGP 35348 on the GHB-mediated cardiovascular and sympathetic nerve responses. Single arrow, 16 minutes after injection of GHB (560 mg/kg, IV). Double arrow, injection of CGP 35348 (50 mg/kg, IV). Horizontal calibration is 1 minute.
FIGURE 7. Effects of CGP 35348 on the peak cardiovascular and sympathetic nerve responses elicited by GHB in conscious rats (n = 5). Values are means ± SEM. *Significantly different from GHB-mediated response.
Previous studies have shown that the intraperitoneal injection of GHB elicits marked and prolonged increases in MAP and heart rate in conscious rats.7,9 The present study showed for the first time that the intravenous administration of GHB consistently increases MAP in conscious rats. The 560- and 1000-mg/kg doses of GHB elicited a large increase in heart rate that coincided with the sustained hypertension. There is great variability in the dose of GHB used by humans. Therapeutic doses of GHB used to treat narcolepsy are approximately 64 mg/kg, which is below the lowest cardiovascular effective dose used in the current study (180 mg/kg). However, the doses used by individuals who misuse GHB are more difficult to document. There are reports in the literature of individuals using as much as 570 mg/kg of GHB per day.27 When GHB was used as an anesthetic in humans, IV doses ranged from 69 to 210 mg/kg.6 The dose-response relationships for GHB’s cardiovascular effects in rats are in good agreement with those used for the drug’s behavioral effects in rats.16,25
In the present study, GHB also significantly increased RSNA in conscious rats, providing the first direct demonstration that GHB increases sympathetic nerve activity. The fact that central and peripheral administration of CGP 35348 attenuated or reversed the cardiovascular and neural effects of GHB indicates that central GABAb receptors mediate the sympathoexcitatory cardiovascular responses elicited by GHB. The inability of CGP 35348 to reverse a non-GHB-mediated hypertension reflects its ability to block GABAb receptors rather than a nonspecific vasodilatory action.
Further supporting the involvement of GABAb receptor mechanisms are reports that the systemic or central administration of the selective GABAb agonist baclofen increases arterial pressure and heart rate in rats, presumably by increasing central sympathetic outflow.28-30 More specifically, evidence suggests that GABAb receptors in the nucleus of the tractus solitarius (NTS) play important roles in regulating cardiovascular function and may be an important site of action for GABAb agonists.31-33 Altered GABAb receptor function in the NTS has been implicated in the pathogenesis of several forms of experimental hypertension.34,35 The activation of GABAb receptors in the NTS also attenuates baroreceptor reflex function, leading some investigators to suggest that the decrease in reflex function is responsible for the increase in arterial pressure and heart rate elicited by GABA agonists.32,33,36 Whether GHB, like baclofen, alters baroreceptor reflex function to increase sympathetic outflow via activation of GABAb receptors is unknown. The conclusion that the increases in arterial pressure, heart rate, and RSNA elicited by GHB involve the activation of central GABAb receptors raises the possibility that the NTS may be an important locus for the cardiovascular actions of this drug. However, previous studies have shown that increases in arterial pressure and heart rate elicited by intraperitoneal GHB could be prevented by prehypothalamic lesions, lesions that spared the NTS.7,9 Conversely, similar lesions did not prevent the cardiovascular response elicited by systemically administered baclofen.30
Surprisingly, activation of GHB receptors appears to mediate the increase in heart rate elicited by GHB. The mechanism by which GHB receptor activation increases heart rate is unknown. The ability of NCS-382 to completely reverse the tachycardia without reducing the hypertension raises the possibility that GHB receptors may contribute to baroreceptor heart rate reflex function. Whether the GHB receptors in question are located in the NTS, on vagal preganglionic neurons in the nucleus ambiguus, or some other pathway is unknown.
Although the cardiovascular and neural responses elicited by GHB appear to be mediated by the activation of GABAb receptors, it is not clear whether this reflects a direct or indirect action of GHB. GHB has been shown to have agonist activity at recombinant GABAb receptor complexes in oocytes 37 and to have low affinity for GABAb receptors in vitro.3,15 However, GHB may also indirectly activate GABAb receptors following its metabolism to GABA in vivo.38
The heart rate responses elicited by GHB in the telemetry and sympathetic nerve recording studies were not consistent in that GHB elicited tachycardia in the telemetry studies but decreased heart rate in the sympathetic nerve-recording studies. It is possible that these differences reflect a residual cardiac effect of the barbiturate anesthesia used during instrumentation of the rats.
In conclusion, the acute intravenous administration of GHB elicits large and prolonged increases in MAP and heart rate in conscious rats. These increases appear to be mediated by an increase in central sympathetic outflow via activation of central GABAb receptors. Whether the GABAb receptors in question are located in forebrain sympathetic pathways, the NTS, or some other brain region is unknown. GHB receptors appear to selectively mediate the increase in heart rate elicited by GHB. The magnitude and duration of the sympathomimetic cardiovascular responses elicited by GHB are cause for concern because they are, in many ways, similar to those elicited by sympathomimetic stimulants (eg, cocaine and methamphetamine), which are known to produce cardiac and cardiovascular toxicity.17,18,39 Whether the administration of GHB also produces cardiac and cardiovascular toxicity is unknown; however, given the widespread recreational use of GHB and its use as a therapeutic agent, further investigation of the cardiovascular actions of this drug is warranted.
The authors would like to thank Ms Lisa Badon and Mr Brian Ogden for their expert technical assistance and Ms Velga Kenigs for her assistance in the nerve-recording studies. The authors would also like to thank Drs Charles France and Andy Coop for providing CPG 35348 (DA14986 awarded to C. P. France). We also thank Drs Lisa Gerak and Peter Winsauer for their discussions and editorial comments.
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