Cholinergic modulation of cardiac function: Selective disruption by organophosphorus anticholinesterases
Abstract
Scope and Method of Study: Organophosphorus insecticides (OPs) elicit toxicity by inhibiting acetylcholinesterase (AChE). Most OPs also inhibit a related enzyme, butyrylcholinesterase (BChE), which is highly expressed in cardiac tissues. However, little is known regarding the function of BChE or its possible role in OP toxicity. While aging is associated with higher sensitivity to neurotoxicity of some OPs, little is known about age-related sensitivity of the cardiac system. In the present study, we evaluated the in vitro sensitivity of adult and aged rat tissues to the active metabolites of two common OPs, chlorpyrifos (CPF) and parathion (PS), namely chlorpyrifos oxon (CPO) and paraoxon (PO). We noted that CPO had greater selectivity towards BChE, while PO preferentially inhibited AChE. Moreover, BChE in heart from aged rats was found to be more sensitive in vitro to CPO than BChE in adult heart. We evaluated the effects of OP-induced BChE and/or AChE inhibition on heart rate, body temperature and physical activity in adult and aged rats. In all cases, we evaluated the effects of OP-induced BChE and/or AChE inhibition on heart rate, body temperature and physical activity using radiotelemetry. Findings and Conclusions: BChE was significantly more sensitive than AChE to inhibition by CPF both in vitro and in vivo, while the reverse was true for PS. Furthermore, BChE in the heart from aged rats was significantly more sensitive to CPO than BChE in heart of adult rats in vitro. Selective BChE inhibition in the heart by isoOMPA, in the absence of AChE inhibition, significantly reduced heart rate, suggesting BChE does play a role in the regulation of cholinergic neurotransmission in the heart. Both CPF and PS elicited dose-dependent AChE and BChE inhibition in atria, ventricles and other tissues in both age-groups. Effective dosages initially decreased heart rate, temperature and motor activity in both adult and aged rats. Heart rate remained depressed for four days, while temperature recovered to baseline and activity increased above baseline in both age groups, with both OPs. Atrial cholinesterases in aged rats appeared more sensitive to both CPF and PS, but this difference was not correlated with higher sensitivity to cardiac dysregulation. Equitoxic doses of CPF and PS produce very different degrees of functional toxicity, with PS eliciting more extensive cholinergic signs than CPF in both adult and aged rats. In contrast, relatively similar changes in heart rate, body temperature, and motor activity were observed following exposure to CPF or PS.
Collections
- OSU Dissertations [11222]