Role of Rostral Ventrolateral Medulla in Methamphetamine-Induced Cardiovascular Dysfunction in Rats

• Main Authors: Faith Chia-Hsin Li, 李佳欣
• Other Authors: Jiin-Cherng Yen
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/89082676582970326938

博士 === 國立陽明大學 === 藥理學研究所 === 100 === Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on RVLM. Moreover, this study further tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by acute intoxication of METH. 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. 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 RVLM cardiovascular regulation was positively and significantly correlated with the concentration of METH in the key neural substrate involved in this homeostatic mechanism. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of AP or HR and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a superoxide dismutase mimetics, 4-hydroxy-2,2, 6,6-tetramethylpiperidine-1-oxyl; or a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO. In animals that survived, toxic doses of METH induced apoptotic cell death in RVLM. The physiological changes and ATP loss in RVLM were restored by an apoptosome inhibitor, 4-chloro-2-[3-(3-trifluoromethyl -phenyl)-ureido] benzoic acid (NS3694). On the other hand, necrotic cell death in RVLM was found in animals that deceased following METH administration. Comparably, the physiological changes and ATP loss in RVLM of these animals were effectively reversed by an oxidative stress-induced necrotic cell death inhibitor, (2-[1H-indol-3-yl]-3-pentylamino-maleimide (IM-54, 3 pmol), but not by NS3694. In conclusion, on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. 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. Furthermore, METH-induced apoptotic or necrotic mechanisms in RVLM may differentially play determinant roles in the survival of animals. This study found that sustained anoxia and cessation of local blood flow that leads to bioenergetics failure and oxidative stress because of mitochondrial dysfunction, leading to acute necrotic cell death in RVLM underpins cardiovascular collapse elicited by lethal doses of METH.