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Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication.

Li FC, Yen JC, Chan SH, Chang AY - J. Biomed. Sci. (2012)

Bottom Line: Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart.The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied.We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, Republic of China.

ABSTRACT

Background: Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism.

Methods: The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time.

Results: Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism.

Conclusions: We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.

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METH dose-dependently reduces survival rate and survival time. Dose-dependent changes in survival rate and survival time in rats that received intravenous administration of METH or saline (Sal, vehicle control). Values are mean ± SEM, n = 5-16 animals per experimental group at the beginning of the experiment. *P < 0.05 versus saline group in the Fisher Exact Test.
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Figure 2: METH dose-dependently reduces survival rate and survival time. Dose-dependent changes in survival rate and survival time in rats that received intravenous administration of METH or saline (Sal, vehicle control). Values are mean ± SEM, n = 5-16 animals per experimental group at the beginning of the experiment. *P < 0.05 versus saline group in the Fisher Exact Test.

Mentions: Given at 12 mg/kg, i.v. administration of METH elicited a 25% reduction in survival rate at 240 min, which increased to 50% at a dose of 24 mg/kg (Figure 2). Similarly, METH (12 or 24 mg/kg, i.v.) induced a dose-dependent reduction in survival time (Figure 2).


Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication.

Li FC, Yen JC, Chan SH, Chang AY - J. Biomed. Sci. (2012)

METH dose-dependently reduces survival rate and survival time. Dose-dependent changes in survival rate and survival time in rats that received intravenous administration of METH or saline (Sal, vehicle control). Values are mean ± SEM, n = 5-16 animals per experimental group at the beginning of the experiment. *P < 0.05 versus saline group in the Fisher Exact Test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295663&req=5

Figure 2: METH dose-dependently reduces survival rate and survival time. Dose-dependent changes in survival rate and survival time in rats that received intravenous administration of METH or saline (Sal, vehicle control). Values are mean ± SEM, n = 5-16 animals per experimental group at the beginning of the experiment. *P < 0.05 versus saline group in the Fisher Exact Test.
Mentions: Given at 12 mg/kg, i.v. administration of METH elicited a 25% reduction in survival rate at 240 min, which increased to 50% at a dose of 24 mg/kg (Figure 2). Similarly, METH (12 or 24 mg/kg, i.v.) induced a dose-dependent reduction in survival time (Figure 2).

Bottom Line: Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart.The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied.We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, Republic of China.

ABSTRACT

Background: Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism.

Methods: The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time.

Results: Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism.

Conclusions: We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.

Show MeSH
Related in: MedlinePlus