br Results Compared to the respective untreated
Results Compared to the respective untreated groups, the VT duration was shorter in clonidine-treated ETB-deficient rats during phase I and in wild-type rats during phase II (Fig. 1A). Heart rate (HR) increased in both untreated groups, but this response was blunted after clonidine, mainly in ETB-deficient rats (Fig. 1B). Infarct size (as percent of the LV) was almost identical in the four groups (30.8±1.7% and 31.2±1.4% in untreated ETB-deficient and wild-type rats, and 30.3±1.9% and 29.7±1.1% in clonidine-treated groups, respectively). RV activation delay decreased marginally (p=0.080) from baseline in untreated wild-type rats at 5min post-ligation, but remained unchanged in clonidine-treated wild-type rats throughout the observation period. In contrast, it fiin increased in untreated ETB-deficient rats at 5min, and in clonidine-treated ETB-deficient rats at 5min, 30min, and 6h. The LV dV/dtmax decreased equally in both groups, with or without clonidine treatment, whereas the RV dV/dtmax remained stable (Fig. 2). The LV activation delay increased from baseline in clonidine-treated and untreated wild-type rats, although this effect was delayed in the latter group. Similar values were found in clonidine-treated and untreated ETB-deficient rats at 5min and 30min, but there was a trend (p=0.091) toward higher values in clonidine-treated ETB-deficient rats at 6h, reaching significance at 24h (Fig. 3).
Discussion Early-phase VTs decreased after clonidine in ETB-deficient rats, with a delayed effect observed in wild-type animals. The corresponding HR changes reiterate the proposed interaction between central inputs and ET-1 , affecting ischemia-induced arrhythmogenesis . Using activation mapping, we found subtle decreases of conduction delay in the RV myocardium of untreated wild-type rats during phase I, as opposed to stable values in their clonidine-treated counterparts. This finding indicates minor effects of central sympathetic inputs on conduction velocity, and compares favorably with an 8% increase after left stellate ganglion stimulation, previously reported in the non-ischemic canine myocardium . Although such action was also evident in ETB-deficient rats, Chromomeres was counteracted by conduction delays, indicating the modulating effects of ET-1. The absence of differences in dV/dtmax argues against noticeable effects of ET-1 on sodium current, implicating gap junctions, another major determinant of conduction. This view is consistent with the impaired conduction caused by gap junction remodeling observed in rat ventricular cardiomyocytes after incubation with ET-1 . In the LV myocardium, the activation delay was prolonged in wild-type rats post-MI, accompanied by a marked decrease in dV/dtmax. This time course, similar to that reported in dogs , is secondary to the well-described effect of ischemia on excitability, whereas small differences after clonidine suggest only a minimal influence by autonomic inputs. The mechanisms underlying arrhythmogenesis during evolving MI are more complex. We have presented evidence supporting a role of central sympathetic activation , but the similar conduction delay seen in our untreated and clonidine-treated wild-type rats refutes major effects on conduction; alternative mechanisms such as repolarization dispersion appear to be more likely . Distinct responses to clonidine were observed in the LV conduction delay in ETB-deficient rats, with higher values in treated animals during the delayed phase, further indicating modulation of sympathetic inputs by ET-1. Nonetheless, this pattern raises the possibility of additional mechanisms, with the transient outward potassium current appearing as a potential candidate; this current, implicated in conduction, is regulated by ET-1 and catecholamines and warrants further study. Future work should also assess intramural conduction and repolarization abnormalities, as well as activation patterns during eccentric depolarization, as in that arising from premature beats.