Bradykinin modulates endothelin-1-enhanced and monocrotaline-induced pulmonary arterial hypertension-associated arrhythmogenesis in rabbit right ventricular outflow tract via a nitric oxide-dependent pathway.

Bradykinin, a vasoactive substance, lowers ventricular tachycardia inducibility in ischemic animal models. The right ventricular outflow tract (RVOT) has distinctive electrophysiological characteristics and calcium homeostasis, leading to its high arrhythmogenesis. Endothelin-1 (ET-1), a vasoconstrictor, plays a key role in the pathophysiology of pulmonary arterial hypertension (PAH) and increases the risk of ventricular arrhythmia. This study investigated whether bradykinin modulates the impact of ET-1 or PAH-induced RVOT arrhythmogenesis in a rabbit model. Using conventional microelectrodes and whole-cell patch clamp techniques, action potentials and ionic currents were recorded in control, ET-1-treated or monocrotaline-induced PAH isolated rabbit RVOT tissues and isolated cardiomyocytes before and after bradykinin treatment. Fluorescence imaging was performed in RVOT myocytes with and without bradykinin to evaluate calcium transient and sarcoplasmic reticulum (SR) calcium content, and nitric oxide (NO) production. In rabbit RVOTs, bradykinin decreased contractility, shortened action potential duration, reduced ICa-L, NCX, and IKr-tail currents, increased Ito, and lowered calcium transients and SR calcium content, with prolonged time to peak and delay τ, as well as increased NO production. Bradykinin also ameliorated the pro-arrhythmia effects of ET-1 in the RVOTs under rapid ventricular pacing. The anti-arrhythmic effect of bradykinin on ET-1-induced RVOT arrhythmogenesis was blocked by treatment with L-NAME (a non-selective NOS inhibitor) or L-NIO (an eNOS inhibitor). In addition, bradykinin mitigated rapid pacing-induced arrhythmias in PAH RVOTs. In conclusion, bradykinin modulates RVOT electrophysiology and ET-1-induced arrhythmogenesis via NO synthesis, suggesting a novel therapeutic target for RVOT arrhythmias in patients with PAH.