The Influence of Probenecid on the Proarrhythmic Effects of the Activation of α-1-adrenoceptor in the Atrioventricular Node of the Rat Heart

Abstract

The cardiac tissue contains not only beta-type adrenergic receptors (ARs) but also alpha-type ARs (α-ARs). Both types of ARs play a significant role in the regulation of the electrophysiology of cardiomyocytes in different parts of the heart, including the atrioventricular node (AVN). An augmentation of the α₁‑AR mediated component of adrenergic signaling causes an impaired conduction of excitation in the heart and the onset of different rhythm disturbances, including AVN-associated arrhythmias. The activation of α₁‑AR facilitates anionic transmembrane transport causing electrophysiological changes in myocytes. The purpose of this research is to study the effects of anion/chlorine blockade on the α₁-AR-mediated proarrhythmic alteration of AVN functioning. The functional characteristics of AVN, including AVN conduction time, AVN refractoriness, and AVN conduction alterations, were examined via recording of surface electrograms in the Langendorff-perfused isolated rat heart (Wistar, 250 ± 30 g). Phenylephrine (PE, 10 µM) was used as an α₁-AR agonist. Probenecid (100 µM) was used as the anion/chlorine transmembrane conductance blocker. The activation of α₁-AR by the PE agonist results in a statistically significant increase in atrioventricular delay (AVD, N = 10, p < 0.001) and the effective refractory period (ERP) in the AVN (by 9.8 ± 1.2%, n = 10, p < 0.001). Also, PE induces AV-blocks and oscillations in AVD (N = 10) at stimulation rates close to ERP. Probenecid significantly reduces the range of AVD oscillations during nonstationary conduction in the AVN. In addition, the probenecid attenuates the ERP prolongation caused by PE (107 ± 4 ms, N = 6 and 114.2 ± 5.35 ms, N = 10 in the presence of PE alone and PE with probenecid, respectively), thereby returning its values to the typical level for normal conditions. As a result, probenecid maintains the physiological mode of AVN conduction when α₁-ARs are stimulated. This also suggests that chloride channels and anion carriers may contribute to α₁-AR-mediated AVN arrhythmias.