Atrial fibrillation is the most common sustained arrhythmia in clinical medicine. Hypertension and heart failure are important risk factors for atrial fibrillation (Feinberg et al., 1995). Activation of the atrial angiotensin system has been suggested to play a role in the mechanisms of atrial fibrillation. In humans, chronic atrial fibrillation and paroxysmal atrial fibrillation are associated with significant changes in the atrial expression of angiotensin receptors (Goette et al., 2000a). In addition, patients with atrial fibrillation showed an increased expression of the extracellular signal-regulated kinases and angiotensin-converting enzyme in interstitial cells and marked atrial fibrosis (Goette et al., 2000b; Boldt et al., 2003). Angiotensin II, the major active component of the renin–angiotensin system, has various effects on ionic currents. Angiotensin II increases the intracellular free calcium, alters the potassium conductance, and induces the genesis of transient inward currents (Daleau & Turgeon, 1994; Enous & Opie, 1994; Boston et al., 1998; Yu et al., 2000). It has been shown to increase spontaneous firing activity and change the action potential (AP) duration of cardiomyocytes (Allen et al., 1988; Chen et al., 1991). These findings suggest that angiotensin II has a high arrhythmogenic activity and may play an important role in the pathophysiology of atrial fibrillation. However, our knowledge of the mechanisms of angiotensin II-induced atrial fibrillation is limited.
Angiotensin II receptor blockers (AIIRBs) are medications frequently used in the treatment of hypertension and congestive heart failure and have several cardiac electrophysiological effects. Nakashima et al. (2000) demonstrated that the shortening of the atrial refractory period during rapid atrial pacing was prevented by treatment with AIIRB. Another AIIRB, irbesartan, also was found to contribute to the maintenance of sinus rhythm after successful electrical cardioversion (Madrid et al., 2002). These findings suggest a role for AIIRBs in the treatment of atrial fibrillation. Nevertheless, it is not clear how AIIRBs prevent attacks of atrial fibrillation.
Pulmonary veins (PVs) are important sources of ectopic beats for the initiation of paroxysmal atrial fibrillation (Haissaguerre et al., 1998; Chen et al., 1999) and the maintenance of atrial fibrillation (Pappone et al., 2000). PVs are known to contain cardiomyocytes with electrical activity and are suggested to be subsidiary pacemakers (Blom et al., 1999; Perez-Lugones et al., 2003). Through several mechanisms, PVs have been found to have a high arrhythmogenic potential to induce atrial arrhythmias (Chen et al., 2000, 2001, 2002; Hocini et al., 2002; Zhou et al., 2002). Studies of single cells have shown that PVs have cardiomyocytes with and without pacemaker activity (Chen et al., 2001, 2002). Long-term (6–8 weeks) rapid atrial pacing (780 b.p.m.) and the administration of thyroid hormone or isoproterenol were demonstrated to increase PV arrhythmogenic activity (Chen et al., 2000, 2001, 2002). Angiotensin II is known to induce structural changes with increasing cellular uncoupling (Sun et al., 1997), which may further enhance the ectopic firing from PVs. Therefore, it is possible that angiotensin II may provoke atrial fibrillation by enhancing the ectopic electrical activity from the PVs, and AIIRB may prevent atrial fibrillation through suppression of the PV arrhythmogenic activity. The purpose of the present study was to investigate the effects of angiotensin II and AIIRB on the electrophysiological characteristics and electrical activity of the PVs.