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Acute cardiometabolic side effects of clozapine in rodents

University of British Columbia

Clozapine (CLZ) is considered the treatment of choice for treatment resistant schizophrenia. Although highly efficacious, the widespread use of CLZ is limited by metabolic side effects, fatal agranulocytosis and cardiovascular complications such as myocarditis via unknown mechanisms. As the autonomic nervous system (ANS) is known to regulate metabolic and cardiovascular function, we sought to assess the involvement of the ANS in the cardiometabolic effects of CLZ in rodent models. Glucose dysregulation from acute CLZ treatment was evaluated using the hyperinsulinemic euglycemic clamp (HIEC) and the intraperitoneal glucose tolerance test (IGTT). Plasma catecholamine (CAT) levels were measured using high performance liquid chromatography (HPLC) to determine autonomic activity. We also assessed the metabolic liability of the principal metabolite of CLZ, norclozapine (NOR), and compared the results to its parent compound. In a separate series of experiments, we measured cardiovascular parameters in response to CLZ in a novel rodent model of CLZ-induced tachycardia. We attempted to reverse CLZ-induced tachycardia with mecamylamine (MEC), a ganglionic blocker, and propranolol (PRO), a β-adrenoceptor blocker. Lastly, we performed a study to evaluate the use of adrenoceptor ligands in treating CLZ-induced glucose dysregulation. Our results indicate NOR does not induce metabolic dysregulation at the same severity as CLZ, despite substantial retention of NOR in plasma. NOR induced insulin resistance but not glucose intolerance at the highest dose compared to vehicle. CLZ induced tachycardia and depressor effects immediately following injection. MEC and PRO reversed the tachycardia, where MEC caused significant depressor effects. The effects were not noted with PRO. There was a significant elevation in plasma NE levels from CLZ treatment which was reversible with MEC. Our pilot study showed β-adrenoceptor blockers reversed insulin resistance associated with CLZ, whereas α-adrenoceptor antagonists had no effect. The results suggest both β1- and β2-adrenoceptor blockade contribute to insulin sensitivity. In conclusion, the present series of experiments indicate the ANS mediates CLZ’s cardiometabolic side effects and warrants further studies focusing on autonomic dysregulation as a potential target for treating these adverse effects.

Text

2022-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74443

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/