Protection against myocardial dysfunction induced by global ischemia-reperfusion by antisense-oligodeoxynucleotides directed at beta(1)-adrenoceptor mRNA.

Abstract

Plasma catecholamine levels rise, and myocardial beta(1)-adrenoceptor (beta(1)-AR) sensitivity increases during ischemia. These factors enhance myocardial injury and cardiac dysfunction. beta(1)-AR blockers are clinically used to protect heart against ischemia and to improve cardiac dysfunction in patients with ischemic heart disease, but these agents often cause intolerable side effects. To examine the potential cardioprotective effect of therapy with antisense-oligodeoxynucleotides directed at beta(1)-AR mRNA (beta(1)-AS-ODNs) during myocardial ischemia-reperfusion, Sprague-Dawley rats were treated with beta(1)-AS-ODNs or inverted-oligodeoxynucleotides (IN-ODNs), each 200 microg/rat. Hearts were excised, perfused, and subjected to global ischemia (30 min) followed by reperfusion (30 min). Other rats were given selective beta(1)-AR blocker atenolol (2 mg/kg) or saline before excising the hearts. Ischemia-reperfusion resulted in cardiac dysfunction, indicated by an increase in coronary perfusion pressure and left ventricular end-diastolic pressure and a decrease in developed left ventricular pressure, as well as evidence of lipid peroxidation in saline-treated rats (all P <.05 versus control values). Administration of AS-ODNs or atenolol, but not IN-ODNs, protected hearts against functional deterioration and lipid peroxidation (P <.05 versus saline or IN-ODNs treatment). AS-ODNs therapy appeared to be equivalent to atenolol in these effects. Expression of beta(1)-AR protein as well as mRNA in the myocardium were markedly up-regulated after ischemia-reperfusion, and treatment with beta(1)-AS-ODNs, but not atenolol, decreased the rise in enhanced expression of beta(1)-AR. These observations imply that beta(1)-AS-ODNs can ameliorate cardiac dysfunction after ischemia-reperfusion by reducing the expression of beta(1)-AR in the ischemic-reperfused myocardium.

• Authors: H Chen, Y C Zhang, D Li, M I Phillips, P Mehta, M Shi, J L Mehta
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 294 Issue 2 Pg. 722-7 (Aug 2000) ISSN: 0022-3565 [Print] United States
• PMID: 10900253 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Oligonucleotides, Antisense
• RNA, Messenger
• Receptors, Adrenergic, beta-1
• Malondialdehyde

Topics

• Animals
• Coronary Circulation (drug effects)
• Coronary Disease (etiology, metabolism, prevention & control)
• In Vitro Techniques
• Lipid Peroxidation (drug effects)
• Male
• Malondialdehyde (metabolism)
• Myocardial Ischemia (complications)
• Myocardial Reperfusion Injury (metabolism, physiopathology, prevention & control)
• Myocardium (metabolism)
• Oligonucleotides, Antisense (genetics, therapeutic use)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, Adrenergic, beta-1 (biosynthesis, genetics)
• Stroke Volume (drug effects)
• Ventricular Dysfunction, Left (etiology, metabolism, prevention & control)