2.5 MEASUREMENT OF BLOOD PRESSURE IN EXPERIMENTAL HYPERTENSION
2.6.2 Intervention through drug treatment
2.7.1.2 Mechanically induced arrhythmias
The interventions that induce arrhythmia mechanically alter fundamental properties of the myocardium within a circumscribed area giving rise to local blocks and spontaneously firing ectopic foci. Two models that utilise this approach are the coronary artery ligation model and the coronary artery ligation-reperfusion model. Regional myocardial ischaemia and
reperfusion are both powerful arrhythmogenic stimuli. These arrhythmias are attributed to re-entry and are inhibited by sodium conductance inhibitors and potassium inhibitors (Curtis and Hearse, 1989). Theoretically, both classes of drugs may encourage ventricular fibrillation and ventricular tachycardia to terminate since they effectively increase the re- entry wavelength.
The rat heart is used frequently to investigate arrhythmias resulting from ischaemia and reperfusion because of its lack of collaterals (Maxwell et ai., 1987), and because the rat atria exclusively receive its blood supply from extracoronary vessels (Halpern, 1957). This leads to reproducible zones of severe ischaemia upon ligation of the coronary artery. Furthermore, the use of the rats makes much economical sense since large numbers of animals are used in these experiments to generate quantitative information. It is worth noting that the differences observed in rats from other larger hearts compels an investigator to confirm the findings in other species.
The mechanism of initiation of ischaemia-induced arrhythmias is different from the mechanism responsible for initiating the reperfusion-induced arrhythmias. This was shown by Curtis and Hearse (1989), who by using perfused rat heart showed that perfusion of the non-ischaemic tissue with high potassium concentration prevented the induction of ischaemia-induced ventricular fibrillation but not reperfusion-induced ventricular fibrillation. On the other hand, the authors showed that both types of arrhythmias are maintained by a common electrophysiological mechanism since a high intracellular potassium concentration increased spontaneous termination of ventricular fibrillation regardless of whether the fibrillation was induced by ischaemia or reperfusion.
2.7.1.2a Coronary artery ligation (CAL) Model
There are a number of cardiac diseases that involve acute ischaemia and as a result a number of experimental models have been designed to mimic part of the complex events occurring in the human disease. Experimentally, ischaemia is often induced by the occlusion of the coronary artery. In exposed hearts coronary occlusion can be accomplished by typing a ligature around the coronary artery or by clamping. In anaesthetised animals with the chest closed, a coronary artery can be occluded either by inflating a balloon occluder positioned around the artery or by suddenly tightening a snare previously placed around the vessel (Wit and lanse, 1992). Large animals like dogs, pigs and cats are used to study ventricular arrhythmias whilst rats are mostly used to study changes in the metabolic pathways resulting from ischaemic and reperfusion (lanse et ai., 1998). The arrhythmias produced by coronary artery ligation are etiologically similar to the arrhythmias occurring in man in association with local ischaemia brought about by heart infarction.
It is thought that there is species difference when it comes to these arrhythmias. These differences are due to differences in the electrophysiological properties of the heart and differences in cardiac and coronary artery anatomy (Wit and lanse, 1992). The variability in the presence or absence of collaterals in different species is one contributing factor to the observed species difference. For instance, pigs and rats are devoid of coronary collaterals, which is not the case with dogs (Maxwell et ai., 1987). Thus following coronary occlusion, there is a higher chance of residual blood flow through collaterals in dogs and neither in rats nor pigs. In the larger animals on the one hand, the arrhythmias induced by ischaemia occur in two distinct phases that are commonly called phase 1A and phase 1B (lanse et ai.,
1998). These phases correspond to the two phases that have been observed in humans.
According to Wit and lanse (1992), available data from humans suggest that there is an early phase of acute arrhythmia and a delayed phase of subacute arrhythmia that are separated by a period of decreased arrhythmias. On the other hand, in smaller species like rats there seem to be no clear separation of type 1A from type lB.
The factors that will determine whether or not this arrhythmia occurs are; the size of the ischaemic area, the degree of collateral flow, heart rate, the mode of coronary artery occlusion, presence of a previous infarction, activity of the autonomous nervous system and hypertrophy in the non-ischaemic myocardium (Wit and lanse, 1992; lanse et ai., 1998). These arrhythmias respond best to strong class I agents (Brooks et ai, 1989). The authors contend that other workers have also shown that class IV agents like Verapamil and nifedipine do suppress extrasystoles that occur in this model.
2.7.1.2h Coronary Artery Ligation! Reper/usion (CALR) Model
In experimental animals, restoration of blood flow to the myocardium after a brief period of ischaemia is associated with the occurrence of severe ventricular arrhythmias. This reperfusion-induced arrhythmia is related to the ventricular fibrillation and sudden cardiac death that are seen in humans upon release of coronary spasm or platelet disaggregation causing restoration of blood flow to a previously ischaemic region of the myocardium.
Thus, reperfusion arrhythmias are distinct from ischaemia-induced arrhythmias and they are encountered in man (Manning and Hearse, 1984). Unlike the arrhythmias that occur upon coronary artery occlusion, the reperfusion-induced ones have a rapid onset (within 20 seconds after release of ligature) and are of short duration, 1-2 minutes. Their severity is
dependent upon the duration of the preceding occlusion. Kane et al., (1984) showed that the most severe reperfusion-induced arrhythmias occur after an occlusion period of 5 or 15 minutes when 56 and 50 % of the animals developed ventricular fibrillation respectively.
The authors showed that when duration of occlusion was reduced to 2 minutes or extended to 20 minutes, the number of the arrhythmias was markedly reduced and no ventricular fibrillation occurred. Thus, the severity of these arrhythmias is highly dependent on the duration of the ischaemia.
The actual mechanisms of initiation and maintenance of reperfusion-induced arrhythmias are less well established and it is unclear whether re-entry or automaticity predominates. The suggestion that abnormal automaticity might be the cause of the arrhythmias is supported by the fact that reperfusion elicits delayed after-depolarisation capable of triggering automaticity (Opie et al., 1986; Pogwizd and Corr, 1986). There is also evidence that suggest that generation of oxygen radicals may playa major role in causing the tissue injury that is associated with reperfusion (Jeroudi, et al., 1994: Roth, et al., 1997).
These arrhythmias, in contrast to those that occur when the occlusion is present, do not appear to be influenced by alterations in autonomic nervous activity. This fact is backed by evidence that has shown that reperfusion-induced arrhythmias are not affected by bilateral vagotomy and ~l-adrenoceptor blockade with atenolol (Kane et al., 1984). Drugs that block the fast inward sodium channel (class I antiarrhythmic drugs according to the Vaughan Williams classification) are effective, particularly in reducing the incidence of reperfusion- induced ventricular fibrillation in rats. Although class I drugs are generally effective in the rat, they are not clearly antiarrhythmic in dog and pig reperfusion arrhythmia models (Brooks et al., 1989). This might be due to species difference as has been discussed before.
It is also postulated that antioxidants and calcium antagonists may offer a protection against reperfusion injury that results from the increased generation of reactive oxygen radicals (Bernier and Hearse, 1988; Jeroudi, et ai., 1994; Roth, et ai., 1997). Roth et aI., (1997) showed that, during reperfusion, diminished superoxide radical production of circulating neutrophils has beneficial effects on tissue injury that is caused by reactive free radicals.
Thus, antioxidants offer a cardioprotection effect during heart ischaemia-reperfusion.