An adenosine agonist and preconditioning shift the distribution of myocardial blood flow in conscious pigs
American Journal of Physiology. Heart and Circulatory Physiology
An adenosine agonist and preconditioning shift the distribution of myocardial blood flow in conscious pigs. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H368-H375, 1999.-The goal of this study was to determine whether the cardioprotective effects of an A 1 -receptor agonist and ischemic preconditioning (IPC) involve a shift in the pre-coronary artery occlusion (CAO) spatial distribution of myocardial blood flow, which might shed light on the mechanism of IPC and explain its heterogeneous
... heterogeneous effects. Accordingly, 60 min of CAO followed by 72 h of coronary artery reperfusion (CAR) was examined in three groups of conscious pigs 10-14 days after instrumentation with aortic and left atrial catheters and coronary artery occluders. Myocardial infarct size, expressed as a fraction of the area at risk (AAR), was reduced significantly (P Ͻ 0.05) by infusion of the A 1 agonist (27.1 Ϯ 6.6%) and to a greater extent (P Ͻ 0.05) by IPC (11.6 Ϯ 5.1%) compared with infarct size in vehicletreated animals (55.1 Ϯ 2.9%). Transmural myocardial blood flow (radioactive microspheres) in the AAR shifted toward lower levels after infusion of the A 1 agonist (1.27 Ϯ 0.19 vs. 0.74 Ϯ 0.10 ml · min Ϫ1 ·g Ϫ1 ) or IPC (1.27 Ϯ 0.11 vs. 0.96 Ϯ 0.09 ml · min Ϫ1 ·g Ϫ1 ) but not after infusion of the vehicle (1.20 Ϯ 0.10 vs. 1.23 Ϯ 0.09 ml · min Ϫ1 ·g Ϫ1 ). This study demonstrated that both pretreatment with an adenosine A 1 agonist and also IPC altered the spatial distribution of pre-CAO myocardial blood flow, which might reflect a downregulation of metabolic state and thus play a role in the cardioprotective effects of IPC. myocardial ischemia; infarction; coronary blood flow; myocardial stunning INTERVENTIONS THAT REDUCE myocardial necrosis consequent to coronary artery occlusion (CAO), e.g., coronary artery reperfusion (CAR) and ischemic preconditioning (IPC), result in patchy (heterogeneous) rather than confluent (homogeneous) necrosis. It is also well recognized that myocardial blood flow in the absence of ischemia is heterogeneous. The spatial heterogeneity of myocardial blood flow has been observed in various species, including dogs (2, 35), rabbits (3), and baboons (6, 13). Recently we reported (6) that the spatial heterogeneity of myocardial blood flow could predict salvage or necrosis before CAO and reperfusion in conscious baboons. We found that infarcted tissues had higher pre-CAO myocardial blood flow, whereas the salvaged tissues were characterized by lower pre-CAO myocardial blood flow. We reasoned that interventions that induce cardioprotection may also induce a similar pattern of spatial redistribution of blood flow, particularly if the shift to lower blood flow might reflect reduced metabolic demands and consequently elicit cardioprotection. To test this hypothesis, we examined the effects of two interventions known to induce cardioprotection; the first was an adenosine agonist, and the second was IPC. The phenomenon of IPC, first described by Murry et al. (18) in 1986, is perhaps the most powerful intervention for cardioprotection. Adenosine, potentially through the A 1 receptor, has been implicated in the mechanism of preconditioning in various animal species (1, 8, 17, 27, 28, 31) . To test the above hypothesis, we first needed to determine whether an A 1 agonist and IPC would induce cardioprotection in conscious pigs. The second goal was to examine myocardial blood flow before and after infusion of a selective A 1 -receptor agonist and before and after IPC to determine whether these interventions would alter the pre-CAO spatial distribution of myocardial blood flow. It was also necessary to demonstrate in the control group that small samples of myocardium with higher pre-CAO blood flow would indeed result in a higher incidence of infarct. Pigs were used in this study because they have few native collaterals (34) and no detectable xanthine oxidase (19, 22) in their myocardium, two important aspects similar to the human heart. In addition, experiments in conscious, chronically instrumented animals are not complicated by the acute effects of surgery and anesthesia (4, 32). Furthermore, the infarct size was measured by using pathological techniques after reperfusion for 3 days, eliminating the possibility that the infarct size might have been underestimated due to potential errors in the triphenyltetrazolium chloride technique (26). METHODS Animal preparation. Twenty-four Yorkshire farm pigs (22 Ϯ 1 kg body wt) were pretreated with Telazol (2-3 mg/kg im) and atropine (0.05 mg/kg im). General anesthesia was induced with thiamylal sodium (10-20 mg/kg iv), the animals were intubated, and anesthesia was maintained with halothane (0.5-1.5 vol%). With the use of a sterile surgical technique, thoracotomy was performed at the left fifth intercostal space. Tygon catheters (Norton Plastics, Akron, OH) were implanted in the descending aorta and in the left atrium for pressure measurements and radioactive microsphere injection and withdrawal. A solid-state miniature pressure gauge was implanted in the left ventricular (LV) cavity to obtain measurements of LV pressure and the first derivative of The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.