Abstract
Whereas cadmium is a toxicant that has been shown to cause cardiovascular toxicity and mortality in mammals, few mechanistic studies address its acute circulatory actions. The present study assessed the hypothesis that cadmium effects dose-dependent acute circulatory fates via differential participation of the cardiovascular regulatory mechanisms in brain. In Sprague-Dawley rats maintained under propofol anesthesia, cadmium acetate (8 mg/kg, iv) induced significantly high mortality rate within 10 min, concomitant with progressive decline toward zero level of mean arterial pressure (MAP), heart rate (HR), baroreflex-mediated sympathetic vasomotor tone, and carotid blood flow (CBF). There were concurrent tissue anoxia, cessation of microvascular perfusion, reduction of mitochondrial membrane potential and ATP production, and necrotic cell death in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone. On the other hand, a lower-dose of cadmium (4 mg/kg, iv) resulted in only a transient decrease in MAP that was mirrored by an increase in CBF and baroreflex-mediated sympathetic vasomotor tone, minor changes in HR, along with transient hypoxia, and apoptotic cell death in RVLM. We conclude that cadmium elicits dose-dependent acute cardiovascular effects with differential underlying biochemical and neural mechanisms. At a higher-dose, cadmium induces high mortality by effecting acute cardiovascular collapse via anoxia, diminished tissue perfusion, mitochondrial dysfunction and bioenergetics failure that echo failure of cerebral autoregulation, leading to necrosis, and loss of functionality in RVLM. On the other hand, a lower-dose of cadmium elicits low mortality, transient decrease in arterial pressure, and hypoxia and apoptosis in RVLM that reflect sustained cerebral autoregulation.
Highlights
Cadmium is a heavy metal and an environmental toxicant
A majority of the reported mechanisms for cadmium-induced cardiovascular toxicity is based on either long-term exposure to cadmium in animals (Puri, 1999; Yoopan et al, 2008; FIGURE 8 | Estimation of mitochondrial membrane potential from freshly isolated mitochondria of rostral ventrolateral medulla (RVLM) tissue. (A) Mitochondria were gated based on light scattering properties in the forward-scattered light (FS) and SS modes by 20,000 events for each sample within the gate R1
Previous studies (Kuo et al, 1997b; Chan et al, 2005) demonstrated that disappearance of the baroreflex-medicated sympathetic vasomotor tone precedes brain stem death in comatose patients who succumbed to severe brain injury (Yien et al, 1997), systemic inflammatory response syndrome (Kuo et al, 1997b), or organophosphate poisoning (Yen et al, 2000)
Summary
Acute cadmium exposure induces cardiovascular toxicity that may lead to mortality (Dote et al, 2007; Miura et al, 2012). Much fewer studies address the acute circulatory fates of cadmium, in term of the cardiovascular regulatory mechanisms in brain. By passing the blood-brain barrier (BBB) and accumulating in the central nervous system (CNS), cadmium may induce neurotoxicity (Wang and Du, 2013) by acting directly on the central circulatory regulatory mechanisms. Clinical studies (Kuo et al, 1997b; Yien et al, 1997; Yen et al, 2000) demonstrated that the resultant defunct baroreflex-mediated sympathetic vasomotor tone is causally related to brain stem death in comatose patients
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