Early and delayed preconditioning: differential mechanisms and additive protection

Abstract

The purposes of this study were to determine whether 1) 24-h endotoxin (ETX) pretreatment induces delayed ("second window") myocardial protection against ischemia-reperfusion (I/R), 2) acute adenosine (Ado) or phenylephrine (PE) pretreatment confers similar protection, 3) the mechanisms of Ado- and PE-induced early protection remain intact after endotoxemia, 4) Ado- and PE-induced protection may combine with ETX-induced delayed protection to optimize cardiac protection, and 5) these strategies of early and/or delayed myocardial protection require de novo protein synthesis. Rats (n = 6-8/group) were treated with ETX (0.5 mg/kg i.p.) or vehicle, with or without prior inhibition of protein synthesis. Twenty-four hours later, the hearts were isolated, perfused, and acutely pretreated with Ado or PE before I/R (20-min ischemia and 40-min reperfusion). Developed pressure, coronary flow, compliance (end-diastolic pressure), and reperfusion creatine kinase leak were measured. Results indicated that 1) Ado, PE, and ETX independently induced myocardial functional protection; 2) either Ado or PE acutely enhanced ETX induced protection; and 3) cycloheximide abolished delayed, but not acute, protection. We conclude that early and delayed forms of protection 1) may be combined to optimize protection and 2) differentially rely on de novo protein synthesis.

Functional Protection by Acute Phase Proteins α 1 -Acid Glycoprotein and α 1 -Antitrypsin Against Ischemia/Reperfusion Injury by Preventing Apoptosis and Inflammation

“…8 Such protection lasts for 30 minutes to 2 hours and is followed by a second window of protection appearing 12 to 24 hours later. This so-called ischemic preconditioning has been attributed to local protective mechanisms, including induction of heatshock proteins 29 and adenosine formation.…”

“…3 Protection against reperfusion injury can be induced by various means, including antecedent administration of endotoxin, 4 -6 heat shock, 7 and single or multiple periods of brief antecedent ischemia. 8 Besides such protection, the latter treatments are all expected to induce an APR. 3,9 During the APR, liver cells and various epithelial cells respond to increasing levels of, among others, TNF-␣ by producing acute phase proteins, including ␣ 1 -acid glycoprotein (AGP) and ␣ 1 -antitrypsin (AAT).…”

Clinical Importance of Ischemic Preconditioning

“…Geç tip önkoşullama ise, uyarıdan saatler sonra başlamasına karşın süreğendir ve yeni proteinlerin sentezine gereksinim duyar (10)(11)(12)(13) . Her iki tip önkoşul-lamada da erken dönem medyatörleri benzerdir; adenozin, norepinefrin, protein kinaz ve KATP kanalları ortak medyatörlerdir (13,19) .…”

“…Her iki tip önkoşul-lamada da erken dönem medyatörleri benzerdir; adenozin, norepinefrin, protein kinaz ve KATP kanalları ortak medyatörlerdir (13,19) . Geç tip önkoşullamada ise, yeni proteinlerin sentezlenmesi söz konusu olduğun-dan medyatörler farklıdır (12,13,20) . Geç tip önkoşulla-manın mekanizmasının detaylarının ortaya çıkması, önkoşullamanın kardiyak koruyucu etkisinde olumlu rol oynayacak yeni farmakolojik ajanların keşfedil-mesini sağlamıştır (22) .…”

“…Miyokardiyal İÖ oluşumu sırasında etkin olan moleküller; reseptör bağımlı tetikleyiciler (adenozin, bradikinin, opioidler, siklooksijenaz ve lipoksijenaz ürünleri, norepinefrin, anjiotensin, endotelin), reseptör bağımsız tetikleyiciler (serbest radikaller, nitrik oksit, kalsiyum), İÖ medyatörleri (G proteinleri jenle aktive edilen protein kinazlar, ısı şok proteinleri, endotoksin, Janus Kinaz, sinyal transdüktörü ve transkripsiyon aktivatörü yolağı, Rho-Kinaz yolağı) ve İÖ uç efektörleri (adenozin trifosfata duyarlı potasyum kanalları [KATP]) olarak sınıflandırılırlar (9)(10)(11)(12)(13)(14)(15)(16) .…”