Decreased inward rectifier and voltage-gated K⁺ currents of the right septal coronary artery smooth muscle cells in pulmonary arterial hypertensive rats

In vascular smooth muscle, K⁺ channels, such as voltage-gated K⁺ channels (Kv), inward-rectifier K⁺ channels (Kir), and big-conductance Ca²⁺-activated K⁺ channels (BK(Ca)), establish a hyperpolarized membrane potential and counterbalance the depolarizing vasoactive stimuli. Additionally, Kir mediates endothelium-dependent hyperpolarization and the active hyperemia response in various vessels, including the coronary artery. Pulmonary arterial hypertension (PAH) induces right ventricular hypertrophy (RVH), thereby elevating the risk of ischemia and right heart failure. Here, using the whole-cell patch-clamp technique, we compared Kv and Kir current densities (I(Kv) and I(Kir)) in the left (LCSMCs), right (RCSMCs), and septal branches of coronary smooth muscle cells (SCSMCs) from control and monocrotaline (MCT)-induced PAH rats exhibiting RVH. In control rats, (1) I(Kv) was larger in RCSMCs than that in SCSMCs and LCSMCs, (2) I(Kv) inactivation occurred at more negative voltages in SCSMCs than those in RCSMCs and LCSMCs, (3) I(Kir) was smaller in SCSMCs than that in RCSMCs and LCSMCs, and (4) I(BKCa) did not differ between branches. Moreover, in PAH rats, I(Kir) and I(Kv) decreased in SCSMCs, but not in RCSMCs or LCSMCs, and I(BKCa) did not change in any of the branches. These results demonstrated that SCSMC-specific decreases in I(Kv) and I(Kir) occur in an MCT-induced PAH model, thereby offering insights into the potential pathophysiological implications of coronary blood flow regulation in right heart disease. Furthermore, the relatively smaller I(Kir) in SCSMCs suggested a less effective vasodilatory response in the septal region to the moderate increase in extracellular K⁺ concentration under increased activity of the myocardium.

Effect of four 5-hydroxytryptamine type 4 receptor agonists on rat cardiac Iκ1 channels and proarrhythmic risk stratification / 中国药理学与毒理学杂志

OBJECTIVE To compare the effect of four 5-hydroxytryptamine type 4 (5-HT4) receptor agonists:cisapride,zacopride,macopride and 2-[1-(4-piperonyl) piperazinyl]-benzothiazole (BZTZ),on rat cardiac inward rectifier potassium channel (IK1)and heart rhythm.METHODS The whole-cell configuration of patch-clamp technique was used to record effects of 5-HT4 receptor agonists onIk1 in enzymatic dissociated rat ventricular myocytes or Kir2.1 transfected HEK 293 cells.Western blotting was used to observe the expression of Kir2.1 channel exposed 24 h to agents in ventricular myocytes.Langendorff-perfused hearts were perfused with four agents respectively for 30 min.The electrocardiogram was recorded simultaneously.RESULTS BZTZ,cisapride and mosapride 0.1-10 μmol· L-1 decreasedIk1 in a concentrationdependent manner.At the same concentration (1 μmol· L-1),BZTZ showed the most potent inhibition onIκ1 (P＜0.01),followed by cisapride.Mosapride showed slight inhibition efficiency.However,zacopride enhanced Iκ1 (P＜0.01).In Kir2.1 heterologous expression systems,zacopride activated Kir2.1 current (P＜0.01) while mosapride had no effect.In ex vivo Langendorff-perfused hearts,BZTZ and cisapride 1μmol· L-1 elicited singnificant rhythm disturbances,and the total of premature ventricular beats (PVB) were 159±28 and 61±13.50％ (4/8) (P＜0.05) and 25％ (1/8) of the hearts exhibited ventricular tachycardia (VT),while 37.5％ (3/8) and 12.5％ (1/8) of the hearts exhibited ventricular fibrillation (VF),respectively.Mosapride and zacopride had no side effects on heart rhythm.Zacopride also suppressed BZTZ-or cisapride-induced arrhythmias.BZFZ had the strongest proarryhthmic potency among the 5-HT4 agonists,followed by cisapride,mosapride and zacopride.CONCLUSION Iκ1 might be an independent risk factor for arrhythmogenesis and a new target for screening safe 5-HT4 receptor agonists and gastrointestinal prokinetic agents.