J Thromb Thrombolysis. 1996;3(3):225-237. doi: 10.1007/BF00181665.
Monophosphoryl Lipid A: A Novel Agent for Inducing Pharmacologic Myocardial Preconditioning.
Journal of thrombosis and thrombolysis
Elliott
Affiliations
Affiliations
- Division of Pharmaceutical Development, Ribi ImmunoChem Research, Inc., 553 Old Corvallis Road, Hamilton, MT 59840.
PMID: 10613986
DOI: 10.1007/BF00181665
Abstract
Myocardial tissue appears to possess an endogenous protective mechanism whereby brief ischemic periods precondition cells to better withstand both reversible and irreversible injury associated with prolonged subsequent ischemic events. Protection develops within minutes of transient ischemia, dissipates within 1-2 hours, and then reappears 12-24 hours following the preconditioning ischemic event. This phenomena, known as ischemic preconditioning (IP), is associated with limitation of infarct size, contractile stunning, and ventricular arrhythmias in postischemic/reperfused hearts. Preconditioned myocardium displays reduced anerobic metabolism. ATPase function, and, hence, improved ATP preservation during ischemia, reduced cytosolic calcium concentrations during reperfusion, and preservation of ultrastructural and myofilament integrity. Efforts to dissect the intracellular signal transduction pathway operative in IP have met with some success. Ischemic preconditioning is associated w ith activation of myocyte Gi protein-coupled receptors such as adenosine and acetylcholine, activation of PKC, production of nitric oxide, and, eventually, opening of ATP-sensitive potassium (KATP) channels. Preconditioning can also be elicited by pharmacologic means using adenosine receptor agonists, activators of PKC, nitric oxide inducers, and KATP openers, among other strategies. Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin pharmacophore lipid A, has been evaluated for cardioprotective activity in numerous preclinical models of cardiac ischemia/reperfusion injury. MLA, when given as a single dose pretreatment in various canine and rabbit models 12-24 hours prior to ischemia, limits infarct size and reduces regional and global contractile dysfunction. Cardioprotection in various models is associated with preservation of ATP during ischemia, enhanced 5'-nucleotidase and adenosine kinase function during reperfusion, and in these aspects mimics ischemic pr econditioning. Priming of KATP channel for enhanced opening during ischemia may be a prerequisite for the cardioprotective activity of MLA and is another feature establishing a similarity between MLA and ischemia induced preconditioning. Efforts continue to further our understanding regarding how MLA may regulate KATP channel and thereby precondition myocardium. Ongoing studies include evaluation of a possible direct effect on the KATP channel, investigation of the ability of MLA to induce a secondary mediator of potassium channel modulation, and evaluation of MLA's ability to phosphorylate the KATP channel as a consequence of kinase activation. Pretreatment with MLA represents a novel method of pharmacologically preconditioning myocardium, displaying a time course for development similar to that of the second window of ischemic preconditioning. Prior clinical experience with MLA indicates that intravenous doses of up to at least 20 µg/kg may be given safely to humans. The drug is c urrently being evaluated in patients undergoing coronary artery bypass engraftment surgery and may prove to be a useful way to protect myocardium from anticipated ischemic events.
References
- Biochem Biophys Res Commun. 1995 Feb 6;207(1):25-32 - PubMed
- Crit Care Med. 1995 Jan;23(1):9-17 - PubMed
- Circ Res. 1984 Mar;54(3):277-85 - PubMed
- Mol Cell Biochem. 1996 Mar 9;156(1):1-8 - PubMed
- J Cardiovasc Pharmacol. 1995 Jan;25(1):163-7 - PubMed
- Circ Res. 1992 Feb;70(2):223-33 - PubMed
- Life Sci. 1994;55(14):1101-8 - PubMed
- Am J Physiol. 1988 May;254(5 Pt 2):H833-9 - PubMed
- J Mol Cell Cardiol. 1994 May;26(5):661-8 - PubMed
- Am J Physiol. 1991 Dec;261(6 Pt 2):H1675-86 - PubMed
- J Clin Invest. 1991 Jun;87(6):2056-66 - PubMed
- J Biol Chem. 1982 Oct 10;257(19):11808-15 - PubMed
- Circulation. 1990 Aug;82(2):609-19 - PubMed
- Am J Physiol. 1994 Mar;266(3 Pt 2):H1145-52 - PubMed
- Am J Physiol. 1993 Aug;265(2 Pt 2):H504-8 - PubMed
- Circulation. 1992 Oct;86(4):1310-6 - PubMed
- Am J Physiol. 1989 Dec;257(6 Pt 2):R1265-81 - PubMed
- Cardiovasc Res. 1993 May;27(5):832-8 - PubMed
- Proc Soc Exp Biol Med. 1990 Feb;193(2):167-70 - PubMed
- Circ Res. 1992 Jul;71(1):58-69 - PubMed
- Immunopharmacology. 1995 Feb;29(1):53-63 - PubMed
- Chest. 1995 Feb;107(2):307-10 - PubMed
- Am J Physiol. 1990 Sep;259(3 Pt 2):H820-6 - PubMed
- J Cardiovasc Pharmacol. 1993 Oct;22(4):653-63 - PubMed
- J Biol Response Mod. 1990 Oct;9(5):480-91 - PubMed
- Rev Infect Dis. 1984 Jul-Aug;6(4):439-43 - PubMed
- J Pharmacol Exp Ther. 1994 Aug;270(2):681-9 - PubMed
- J Mol Cell Cardiol. 1996 Jan;28(1):197-208 - PubMed
- J Mol Cell Cardiol. 1995 Jan;27(1):223-9 - PubMed
- Circulation. 1993 Sep;88(3):1264-72 - PubMed
- Am J Physiol. 1993 Apr;264(4 Pt 2):H1200-7 - PubMed
- Surgery. 1991 Aug;110(2):365-9 - PubMed
- Circ Res. 1994 Sep;75(3):586-90 - PubMed
- Cancer Res. 1981 Jul;41(7):2654-7 - PubMed
- Circulation. 1994 Apr;89(4):1769-75 - PubMed
- Circulation. 1993 Mar;87(3):893-9 - PubMed
- Free Radic Res Commun. 1991;12-13 Pt 2:725-35 - PubMed
- Circulation. 1995 Jun 1;91(11):2810-8 - PubMed
- Biochem Pharmacol. 1987 Jul 1;36(13):2101-7 - PubMed
- J Surg Res. 1992 Apr;52(4):395-400 - PubMed
- Infect Immun. 1990 Aug;58(8):2429-37 - PubMed
- Basic Res Cardiol. 1994 Nov-Dec;89(6):563-76 - PubMed
- J Clin Invest. 1994 May;93(5):2197-205 - PubMed
- Circ Res. 1990 Apr;66(4):913-31 - PubMed
- Biochem Biophys Res Commun. 1993 Apr 30;192(2):553-60 - PubMed
- Circulation. 1992 Feb;85(2):659-65 - PubMed
- J Pharmacol Exp Ther. 1994 Sep;270(3):1071-6 - PubMed
- Agents Actions Suppl. 1992;38 ( Pt 3):413-20 - PubMed
- Biochem Biophys Res Commun. 1990 Dec 14;173(2):541-7 - PubMed
- Am J Physiol. 1992 Dec;263(6 Pt 2):H1650-8 - PubMed
- Circ Res. 1993 Dec;73(6):1193-201 - PubMed
- Circulation. 1991 Jul;84(1):350-6 - PubMed
- Cardiovasc Res. 1994 Nov;28(11):1700-6 - PubMed
- Cardiovasc Drugs Ther. 1990 Apr;4(2):465-74 - PubMed
- Circulation. 1991 Jul;84(1):400-11 - PubMed
- Circulation. 1992 Feb;85(2):779-89 - PubMed
- Proc Natl Acad Sci U S A. 1989 Apr;86(7):2516-20 - PubMed
- Am J Cardiol. 1989 Jun 20;63(21):11J-17J - PubMed
- J Surg Res. 1990 Aug;49(2):126-31 - PubMed
- Annu Rev Pharmacol Toxicol. 1986;26:201-24 - PubMed
- Br J Pharmacol. 1996 Apr;117(8):1685-92 - PubMed
- Trends Pharmacol Sci. 1994 Jan;15(1):19-25 - PubMed
- Circulation. 1986 Nov;74(5):1124-36 - PubMed
- J Clin Invest. 1995 Apr;95(4):1446-56 - PubMed
- Virchows Arch B Cell Pathol Incl Mol Pathol. 1986;52(4):327-41 - PubMed
- Circ Res. 1987 May;60(5):700-7 - PubMed
- Circ Shock. 1994 Jul;43(3):107-14 - PubMed
- Pharmacology. 1995 Sep;51(3):152-9 - PubMed
- Eur J Pharmacol. 1991 Aug 6;200(2-3):375-6 - PubMed
- J Biol Response Mod. 1984;3(1):1-9 - PubMed
- Circ Res. 1995 Sep;77(3):611-21 - PubMed
- J Cardiovasc Pharmacol. 1994;24 Suppl 4:S28-34 - PubMed
- J Mol Cell Cardiol. 1984 Nov;16(11):1075-9 - PubMed
- Cardiovasc Res. 1995 Feb;29(2):269-74 - PubMed
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