Inhibitory effect of SM-20550, an Na + /H + exchange inhibitor, on accumulation of leukocytes in ischemia and reperfusion

Abstract

The effect of an Na+/H+ exchange inhibitor, SM-20550, on the adhesion, emigration and accumulation of leukocytes was studied in ischemia and reperfusion injury models using rat mesenteric venules or rabbit heart. Anesthetized rats underwent occlusion of the superior mesenteric artery (20 min) followed by reperfusion (60 min). After ischemia and reperfusion, the numbers of adherent and emigrated leukocytes increased significantly. Bolus intravenous administration of SM-20550 reduced the numbers of adherent and emigrated leukocytes in a dose-dependent manner, with statistical significance at dosages >0.1 mg/kg. Anesthetized rabbits underwent occlusion of the coronary artery (30 min) followed by reperfusion (5 h). Intravenous administration of SM-20550 before ischemia significantly reduced the neutrophil accumulation in the area-at-risk by 46% and reduced the infarct size by 38%. These results suggest that the inhibitory effect of SM-20550 on the neutrophil accumulation could be one of the mechanisms by which this drug limits the severity of infarctions.

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…immediately after initiation of ischemia) reduced total infarction area by ~50%, and partially prevented formation of brain edema [96]. These effects may be relevant to preservation of blood-brain barrier function and improved reperfusion rates [97], as well as to reduced accumulation of leukocytes in damaged brain tissue [98]. In the same model, another selective NHE blocker, sabiporide (3 mg/kg, i.v.…”

MRI/MRS evaluation of cariporide in a canine long‐term model of reperfused ischemic insults

“…The most important factor influencing patient mortality and morbidity is the extent of myocardial necrosis. Many laboratories have documented reduced infarct sizes with a variety of NHE inhibitors in short‐term animal models (4–9). Rupprecht et al reported significantly reduced enzyme release during the first 72 hours postreperfusion in their small patient group; however, results from Théroux et al's GUARDIAN clinical trial indicate that there were no benefits, in the trial as a whole, at 36 days, in the endpoints of death or myocardial infarction (16, 25).…”

“…This study investigated the effects of cariporide in the canine heart following a reperfused ischemic insult. NHE inhibitors have been well documented as cardioprotective agents in short‐term ischemia/reperfusion models (4–11, 23, 24). However, to our knowledge, this is the first study of the long‐term effects of a high dose of cariporide in an animal infarct model.…”

“…Mathey et al have demonstrated in a rabbit model with varying lengths of ischemia that shorter periods of ischemia, less than approximately 45 minutes, do not induce this complement activation (29). However, the majority of laboratories studying the effects of cariporide have used shorter periods of ischemia, less than 45 minutes (4, 5, 8–11, 24). A study from the laboratory of Klein et al assessed 45‐, 70‐, and 90‐minute occlusions following pretreatment with 1 mg/kg cariporide in pigs.…”

“…These two factors are thought to play key roles in reducing the degree of reperfusion injury (3). Numerous studies assessing NHE inhibitors in isolated heart and in vivo animal models for up to 24 hours after reperfusion have reported significant improvements in the attenuation of arrhythmias (4, 5), reduced tissue necrosis (4–9), and enhanced contractility (10, 11).…”