Cardiovascular responses elicited by intragastric administration of BDL and GHB.

Gamma-hydroxybutyrate (GHB) and its metabolic precursor, 1,4-butanediol (BDL), are widely used recreational drugs. Although most commonly described as CNS depressants, GHB and BDL elicit significant sympathomimetic cardiovascular responses [increases in mean arterial pressure (MAP) and heart rate] when administered parenterally. Given that humans most commonly ingest both drugs orally, we examined the dose-response relationships for intragastrically administered GHB and BDL on MAP and heart rate in conscious rats using radiotelemetry. The intragastric administration of GHB increased MAP. BDL increased both MAP and heart rate and was approximately 10-fold more potent as a cardiovascular stimulant than GHB when administered intragastrically. Pretreatment with ethanol prevented the lethality of BDL. These data indicate that 1) both GHB and BDL produce cardiovascular responses when administered intragastrically and 2) BDL is more potent and potentially more dangerous than GHB when administered via this route.

Pressor responses to ephedrine are mediated by a direct mechanism in the rat.

The mechanism of the pressor response to ephedrine is controversial. In the present study. i.v. injections of ephedrine increased systemic and pulmonary arterial pressure, and i.a. injections decreased hindlimb blood flow in a dose-related manner. Responses to ephedrine were inhibited by alpha-receptor blocking agents and were not attenuated by blockade of the norepinephrine reuptake transporter (NET) or by catecholamine depletion using reserpine or a combination of reserpine and alpha-methyl-p-tyrosine, whereas responses to tyramine and amphetamine were inhibited by these treatments. The magnitude of the pressor response to ephedrine was similar in anesthetized and conscious rats. Tachyphylaxis developed to pressor responses to ephedrine and amphetamine with sequential injections; however, ephedrine tachyphylaxis differed in that subsequent responses to alpha-receptor agonists were attenuated. These results suggest that the systemic and pulmonary pressor and hindlimb vasoconstrictor responses to ephedrine are mediated by direct action on alpha-adrenergic receptors and that the release of norepinephrine from adrenergic terminals plays no significant role. These results provide support for the hypothesis that responses to ephedrine are directly mediated in the intact rat, whereas responses to amphetamine are mediated in a large part by the release of norepinephrine from adrenergic terminals.

Interaction between 1,4-butanediol and ethanol on operant responding and the cardiovascular system.

The current studies characterized the rate-decreasing and cardiovascular responses produced by 1,4-butanediol administered alone and in combination with ethanol to test the hypothesis that these effects resulted from the degradation of 1,4-butanediol to gamma-hydroxybutyrate. One group of rats responded under a fixed-ratio 20 schedule of food presentation; ethanol and 1,4-butanediol dose-dependently decreased response rates. Ethanol administered in combination with 1,4-butanediol attenuated the rate-decreasing effects of 1,4-butanediol without altering the potency of ethanol. In separate groups of conscious rats, radio telemetry was used to record mean arterial pressure and heart rate. In contrast to its depressant effects on schedule-controlled responding, 1,4-butanediol increased mean arterial pressure and heart rate; these increases were attenuated by ethanol. Thus, the behavioral and cardiovascular actions of 1,4-butanediol are similar to those elicited by gamma-hydroxybutyrate. The ability of ethanol to attenuate the behavioral and cardiovascular effects of 1,4-butanediol indicates that these effects require the conversion of 1,4-butanediol to gamma-hydroxybutyrate.

Mechanisms underlying the sympathomimetic cardiovascular responses elicited by gamma-hydroxybutyrate.

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.

Cardiovascular responses elicited during binge administration of cocaine.

Cocaine use is often characterized by a repeated pattern of frequent administrations (binge) followed by periods of abstinence. The repeated binge administration of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) alters cardiovascular function and the arterial pressure and heart rate responses elicited by these drugs. Whether repeated binges of cocaine similarly affect cardiovascular function and cardiovascular responsiveness is unknown. Radiotelemetry was used to record the cardiovascular responses elicited during three successive cocaine binges (5 mg/kg, t.i.d., for 4 days) in conscious, unrestrained rats. Each binge was separated by a 10-day cocaine-free period. The effects of cocaine administration on vascular reactivity and vasovagal, Bezold-Jarisch reflex function were also evaluated. The intravenous administration of cocaine increased both mean arterial pressure (MAP) and heart rate. The arterial pressure and heart rate responses elicited by cocaine, both within and between the binges, were remarkably similar. The arterial pressure and heart rate responses elicited by the intravenous administration of sodium nitroprusside, acetylcholine and phenylephrine before each binge and 10 days after the last binge were not altered after the binge administration of cocaine. Likewise, Bezold-Jarisch reflex function elicited by intravenous serotonin was unchanged after the binge administration of cocaine. These results indicate that the administration of cocaine using this repeated binge model does not alter the arterial pressure and heart rate responses elicited by the drug, nor does it alter the cardiovascular responses elicited by a variety of vasoactive substances.

Changes in cardiovascular responsiveness and cardiotoxicity elicited during binge administration of Ecstasy.

The recreational use of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) is often characterized by a repeated pattern of frequent drug administrations (binge) followed by a period of abstinence. Radiotelemetry was used to characterize the cardiovascular responses elicited during three MDMA binges (3 or 9 mg/kg b.i.d. for 4 days), each of which was separated by a 10-day MDMA-free period. The heart rate and mean arterial pressure (MAP) responses elicited by 3-mg/kg doses of MDMA were consistent within and between the three binges. In the first binge the 9-mg/kg doses of MDMA increased MAP and produced a biphasic (decrease/increase) heart rate response. The bradycardia elicited by MDMA in the first binge (-75 bpm) was enhanced in the second and third binges (-186 and -287 bpm, respectively). Significant hypotension accompanied the increased bradycardic responses. Atropine abolished the hypotension and significantly attenuated the bradycardic responses. The MAP and heart rate responses elicited by sodium nitroprusside, acetylcholine, phenylephrine, and serotonin (5-HT) were evaluated before each binge and 10 days after the last binge. The hypotension, but not the tachycardia elicited by sodium nitroprusside was attenuated by the repeated administration of MDMA. The responses to phenylephrine, acetylcholine, and 5-HT were unaltered after MDMA. The hearts of treated rats contained foci of inflammatory infiltrates (lymphocytes and macrophages), some of which contained necrotic cells and/or disrupted cytoarchitecture. MDMA produced cardiac arrhythmias in some rats. These results indicate that the binge administration of MDMA can significantly alter cardiovascular and cardiovascular reflex function and produce cardiac toxicity.