Sridhar Arun, Dech Spencer J, Lacombe Veronique A, Elton Terry S, McCune Sylvia A, Altschuld Ruth A, Carnes Cynthia A
Ohio State Univ., College of Pharmacy, 500 W. 12th Ave., Columbus, OH 43210, USA.
Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2192-8. doi: 10.1152/ajpheart.01146.2005. Epub 2006 Jun 9.
Hypertension is a common cause of heart failure, and ventricular arrhythmias are a major cause of death in heart failure. The spontaneous hypertension heart failure (SHHF) rat model was used to study altered ventricular electrophysiology in hypertension and heart failure. We hypothesized that a reduction in the inward rectifier K(+) current (I(K1)) and expression of pacemaker current (I(f)) would favor abnormal automaticity in the SHHF ventricle. SHHF ventricular myocytes were isolated at 2 and 8 mo of age and during end-stage heart failure (>/=17 mo); myocytes from age-matched rats served as controls. Inward I(K1) was significantly reduced at both 8 and >/=17 mo in SHHF rats compared with controls. There was a reduction in inward I(K1) due to aging in the controls only at >/=17 mo. We found a significant increase in I(f) at all ages in the SHHF rats, compared with young controls. In controls, there was an age-dependent increase in I(f). Action potential recordings in the SHHF rats demonstrated abnormal automaticity, which was abolished by the addition of an I(f) blocker (10 muM zatebradine). Increased I(f) during hypertension alone or combined increases in I(f) with reduced I(K1) during the progression to hypertensive heart failure contribute to a substrate for arrhythmogenesis.
高血压是心力衰竭的常见病因，而室性心律失常是心力衰竭患者死亡的主要原因。自发性高血压心力衰竭（SHHF）大鼠模型被用于研究高血压和心力衰竭时心室电生理的改变。我们假设内向整流钾电流（I(K1)）的降低和起搏电流（I(f)）的表达会促使SHHF心室出现异常自律性。在2月龄、8月龄以及终末期心力衰竭（≥17月龄）时分离SHHF心室肌细胞；来自年龄匹配大鼠的心肌细胞作为对照。与对照组相比，SHHF大鼠在8月龄和≥17月龄时内向I(K1)均显著降低。仅在≥17月龄时，对照组中由于衰老导致内向I(K1)降低。与年轻对照组相比，我们发现SHHF大鼠在所有年龄段I(f)均显著增加。在对照组中，I(f)随年龄增长而增加。SHHF大鼠的动作电位记录显示出异常自律性，加入I(f)阻滞剂（10 μM 扎替雷定）后这种异常自律性被消除。单纯高血压期间I(f)增加，或在进展为高血压性心力衰竭过程中I(f)增加并伴有I(K1)降低，共同构成了心律失常发生的基础。
