Preservation of endothelial cell structure and function by intracoronary perfluorochemical in a canine preparation of reperfusion.

Abstract

To determine the effect of intracoronary perfluorochemical on endothelial cell structure and function, 16 dogs were randomized to receive either low-dose (15 ml/kg) intracoronary perfluorochemical (Fluosol-DA) or saline after 90 min of proximal occlusion of the left anterior descending coronary artery (LAD). The animals underwent reperfusion for 60 min with the introduction of perfluorochemical or saline 5 to 10 min after the onset of reperfusion. Endothelium-dependent coronary vasodilatory reserve was determined in vivo both at baseline and 1 hr after reperfusion by infusion of acetylcholine and then serotonin into the distal LAD bed in 12 animals (six in each group). Both agonists significantly increased regional flow measured by 133Xe washout in the two groups before occlusion, but at 1 hr after reperfusion only animals given perfluorochemical demonstrated a significant increase in flow. Vasodilatory reserve was assessed in vitro with cumulative dose-reponse curves to acetylcholine on LAD rings proximal and distal to the snare in all animals. These studies demonstrated a significant reduction in endothelial cell-mediated relaxation of epicardial arterial segments in the ischemic segment of control but not treated animals. Light microscopy revealed the presence of neutrophils within vessels in the ischemic zones in control animals only. Electron microscopy showed capillary obstruction by endothelial cell protrusions and neutrophil and red cell plugging in control animals in the ischemic region but an intact endothelium and predominantly unobstructed capillaries in treated animals. These findings suggest that the structural and functional endothelial damage after reperfusion may be prevented by the administration of intracoronary perfluorochemical after the onset of reperfusion. Circulation 76, No. 2, 469-479, 1987. EARLY CORONARY REPERFUSION reduces infarct size and improves ventricular function in man and animals.'-5 However, certain biochemical and anatomic changes occur with reperfusion that may result in the conversion of reversibly injured myocardial cells to irreversibly injured cells.6 The role of the endothelium is of particular interest in this phenomenon. Capillary damage has been suggested to be a major contributing factor to the development of microvascular damage We have previously demonstrated that intracoronary administration of the artificial blood substance, perfluorochemical (Fluosol-DA 20%; Alpha Therapeutic Corp., Los Angeles), soon after reperfusion significantly reduces infarct size and improves regional ventricular function in both the short-and long-term canine preparation.'0' 11 However, the mechanisms by which this drug salvages myocardium have not been investigated. We postulated that because of its small particle size and low viscosity, perfluorochemical may penetrate into the ischemic microvascular bed after reperfusion and potentially preserve the endothelium.

Effects of a prophylactic or therapeutic application of perflubron emulsion on myocardial ischaemia-reperfusion injury in rats

“…This result with perflubron emulsion conflicts with our results in the prophylactic group. It has been suggested that PFC may prevent reperfusion injury through anti-inflammatory, effective oxygen-carrying capacities and endothelium preservation [9,24]. The present data suggest that administration of perflubron emulsion improves areas of impaired perfusion when given prior to ischaemia.…”

Nitric oxide has no obligatory role in isoflurane late preconditioning against myocardial stunning

“…Lidocaine was used to prevent cardiac arrhythmias during ischemiareperfusion (Forman et al, 1987). Lidocaine blocks the sodium channels (which accounts for its anti-arrhythmic effect), as well as the ATPsensitive potassium (K ATP ) channels (Barthel et al, 2004).…”

“…Deflation of the coronary occluder was performed gradually to avoid ventricular fibrillation. A bolus injection of lidocaine (1 mg/kg) (Forman et al, 1987) was administered prior to the CAO to prevent cardiac arrhythmias during ischemia/ reperfusion. The recovery of WT was evaluated for 24 h following reperfusion.…”

Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period.

“…(Circulation 1991;83:237-247) E a xperimental studies have demonstrated that Reperfusion results in a significant impairment of myocardial salvage after reperfusion may be endothelial-dependent and -independent vasodilalimited by deleterious changes that occur in tory reserve in both large and small vessels after 90 the microvasculature in the perireperfusion period. [1][2][3][4][5][6][7] and 120 minutes of regional ischemia.67 There is extensive disruption of endothelial cells in capillaries of the reperfused bed associated with luminal obstruction by cellular elements, particularly neutrophils.3'5 These abnormalities result in a progressive decrease in blood flow to potentially viable myocytes after reperfusion with eventual lethal injury to these cells (reperfusion injury).113,7,8 Experimental studies support a role for the neutrophil in the pathogenesis of microvascular injury after reperfusion.9-13 Neutrophils may reduce microcirculatory flow by mechanically obstructing capillary lumens'2 or cause extensive endothelial cell disruption through the liberation of cytotoxic substances such as oxygen-derived free radicals and proteolytic enzymes.14-17 Activated neutrophils may further reduce blood flow by the release of vasoactive substances such as leukotrienes and platelet activating factor. '8 Additional limitation of infarct size with neutropenia, anti-inflammatory agents, and antineutrophil agents lend further support to the role of the neutrophil in mediating reperfusion injury.513, '9,20 Adenosine is an endogenous arteriolar vasodilator present in relatively high concentrations at the time of reperfusion.21 It is a metabolic by-product of ATP with numerous properties that may attenuate reperfusion injury, including inhibition of superoxide anion and proteolytic enzyme release by neutrophils,22,23 limitation of endothelial-neutrophil interactions,24 inhibition of platelet aggregation and thromboxane release,25 and augmentation of postreperfusion coronary blood flow.3'7 These cardioprotective efforts of adenosine support the hypothesis that it may be a potentially useful agent in limiting myocardial reperfusion injury.…”