Pacing-induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase

Abstract

1. Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion-induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide. 2. Twenty-two dogs were paced (4 x 5 min periods at 220 beats min(-1)) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg(-1) i.v.), 0.5 h prior to coronary artery occlusion. Sham-operated non-paced dogs with and without aminoguanidine treatment served as controls. 3. Pacing markedly (P<0. 05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia-reperfusion insult 62%) compared to control, sham-operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia-reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min(-1). 4. These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.

Figure 1

The experimental protocol outlining the procedures observed for the four groups of anaesthetized dogs.

Figure 2

The distribution of ventricular arrhythmias; ventricular premature beats (VPBs), ventricular tachycardia (VT) and ventricular fibrillation (VF) during a 25 min occlusion of the left anterior descending coronary artery in anaesthetized dogs; this was followed by rapid reperfusion. Seven of the 12 sham-operated controls fibrillated during the occlusion and all but three had periods of ventricular tachycardia. Only two of these controls survived the combined ischaemia-reperfusion insult. These arrhythmias were markedly suppressed in the paced 24 h group; thus only two dogs fibrillated during the occlusion period and there was a 62% survival from the ischaemia-reperfusion insult. In the paced dogs given aminoguanidine (AG) only one of the nine dogs (i.e. 11%) survived ischaemia and reperfusion. There was no evidence that AG given prior to occlusion in unpaced dogs was pro-arrhythmic.

Figure 3

The total number of ventricular premature beats (VPBs) and the number of episodes of ventricular tachycardia (VT) during coronary artery occlusion in sham control dogs (SC), in dogs paced 24 h previously (SP24), in paced dogs given aminoguanidine (AG) prior to occlusion (SP24+AG) and in unpaced dogs also given AG (AG+occl.). ^*P<0.05 compared to sham controls.

Figure 4

The incidence of ventricular fibrillation during coronary artery occlusion and following reperfusion at the end of the 25 min occlusion in control dogs (SC), in dogs subjected to right ventricular pacing 24 h prior to the occlusion (SP24) and in paced (SP24+AG) and non-paced (AG+occl.) dogs given aminoguanidine (AG) 0.5 h prior to coronary artery occlusion. Also shown in the right hand panels is survival from the combined ischaemia-reperfusion insult. The marked protection against ventricular fibrillation during both occlusion and reperfusion which results from cardiac pacing is markedly attenuated by the prior administration of aminoguanidine. ^*P<0.05 compared to sham controls; †P<0.05 compared to paced dogs given aminoguanidine.

Figure 5

Changes in ST-segment elevation recorded from epicardial electrodes during a 25 min occlusion of the left anterior descending coronary artery in control dogs, dogs paced 24 h previously, and in dogs given aminoguanidine (50 mg kg⁻¹) prior to the coronary artery occlusion with or without pacing. Pacing decreased ST-segment elevation recorded over the ischaemic area; this was markedly attenuated by the prior administration of aminoguanidine.

Figure 6

Changes in the inhomogeneity of electrical activation within the ischaemic area in control dogs, dogs paced 24 h previously, and in dogs given aminoguanidine (50 mg kg⁻¹) prior to the coronary artery occlusion with or without pacing. Cardiac pacing reduced the severity of the changes in inhomogeneity; this was not seen in those paced dogs given aminoguanidine. ^*P<0.05 compared to sham controls.