Abstract

Muscarinic antagonists relieve bronchoconstriction due to the progressive condition of chronic obstructive pulmonary disease (COPD). Recent meta-analyses have highlighted increased stroke and myocardial infarction with the long acting muscarinic receptor antagonist, Tiotropium bromide. Opening of the mitochondrial permeability transition pore (mPTP) triggers cardiomyocyte death, therefore modulation of the pore could promote cardiomyocyte survival.

Isolated perfused rat hearts were subjected to ischaemia/reperfusion (I/R) or normoxic protocols. Hearts were subjected to stabilisation, and perfusion ±Tiotropium (10 nM – 0.1 nM), Cyclosporin A (CsA) (200 nM) or Tiotropium (1 nM)±CsA. For I/R, regional ischaemia was induced following stabilisation. Hearts were stained using triphenyl-tetrazolium chloride (TTC) to determine infarct/risk ratios (%). Data was analysed using one-way ANOVA and LSD, presented as mean ±SEM.

All concentrations of Tiotropium significantly increased infarct/risk ratio compared with controls. CsA decreased infarct/risk with respect to controls (Normoxia: 5.1±1.0% vs 10.3±1.9%, p<0.05; I/R: 7.2±1.2% vs 50.9±3.9% and 10.3%±1.9%, p<0.0001), co-administration maintained this, with respect to Tiotropium (1 nM) in normoxia, and also with control in I/R (Normoxia: 8.4±2.1% vs 18.7±1.8%, p<0.0001; I/R: 16.3±0.8% vs 65.4±3.0% and 50.9%±3.9%, p<0.0001).

This is the first pre-clinical study to suggest that Tiotropium increases infarct/risk ratio in an isolated perfused heart model via mPTP opening, as CsA decreases Tiotropium- and ischaemia/reperfusion-mediated myocardial injury. These findings suggest for a role of the mitochondria in mediating the adverse cardiac side-effects seen clinically.