Abstract
Cigarette smoke includes nicotine that increases ventricular tachycardia (VT) risk. Chronic obstructive pulmonary disease (COPD) and right ventricular outflow tract (RVOT) constitute the primary risk factor and origin of VT, respectively. To investigate the arrhythmogenesis of nicotine in COPD, we employed tachypacing with or without H89, KN93 and KB-R7943 treatment, along with patch clamp experiments and Masson's trichrome staining in control rabbits and rabbits with human leukocyte elastase (0.3 unit/kg)-induced COPD. Following 20-Hz tachypacing and isoproterenol treatment, COPD RVOTs had a higher VT incidence than control RVOTs. Nicotine-treated COPD RVOTs had higher ventricular arrhythmogenesis than non-treated COPD RVOTs. VTs induced in COPD and nicotine-treated COPD RVOTs were suppressed by H89, KN93, or KB-R7943. COPD RVOT myocytes exhibited shorter action potentials than control RVOT myocytes; nicotine-treated COPD RVOT myocytes exhibited longer action potentials than COPD RVOT myocytes. Both COPD and nicotine-treated COPD myocytes had smaller L-type Ca(2+) currents and larger NCX currents than control RVOT myocytes. Nicotine-treated COPD RVOT myocytes had larger late Na(+) currents than control and COPD RVOT myocytes. COPD and nicotine-treated COPD RVOTs exhibited more fibrosis. Nicotine-treated COPD RVOTs had the highest level of fibrosis. COPD intensifies RVOT VT through electrical and structural remodelling and Ca(2+) dysregulation through the activation of PKA, CaMKII and NCX signalling pathways. Nicotine further exacerbates VTs in the rabbit RVOT triggered by COPD.