Abstract
Plasma catecholamine levels rise, and myocardial β1-adrenoceptor (β1-AR) sensitivity increases during ischemia. These factors enhance myocardial injury and cardiac dysfunction. β1-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 β1-AR mRNA (β1-AS-ODNs) during myocardial ischemia-reperfusion, Sprague-Dawley rats were treated with β1-AS-ODNs or inverted-oligodeoxynucleotides (IN-ODNs), each 200 μg/rat. Hearts were excised, perfused, and subjected to global ischemia (30 min) followed by reperfusion (30 min). Other rats were given selective β1-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 β1-AR protein as well as mRNA in the myocardium were markedly up-regulated after ischemia-reperfusion, and treatment with β1-AS-ODNs, but not atenolol, decreased the rise in enhanced expression of β1-AR. These observations imply that β1-AS-ODNs can ameliorate cardiac dysfunction after ischemia-reperfusion by reducing the expression of β1-AR in the ischemic-reperfused myocardium.
Footnotes
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Send reprint requests to: J. L. Mehta, M.D., Ph.D., Professor of Medicine and Physiology, University of Florida, Department of Medicine, Box 100277, JHMHC, Gainesville, FL 32610. E-mail:mehta{at}medmac.ufl.edu
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↵1 This study was supported in part by a Merit Review Award from the Department of Veterans Affairs and a National Institutes of Health MERIT Award.
- Abbreviations:
- β-AR
- β-adrenoreceptor
- AS-ODN
- antisense-oligodeoxynucleotide
- β1-AS-ODN
- antisense-oligodeoxynucleotide directed at β1-AR mRNA
- SHR
- spontaneously hypertensive rats
- IN-ODN
- inverted-oligodeoxynucleotide
- DOTAP
- 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane
- DOPE
- l-α-dioeoyl phosphatidylethanolamine
- CPP
- coronary perfusion pressure
- LVEDP
- left ventricular end diastolic pressure
- LVSP
- left ventricular systolic pressure
- dLVP
- developed left ventricular pressure
- RT-PCR
- reverse transcription-polymerase chain reaction
- MDA
- malondialdehyde
- Received February 8, 2000.
- Accepted April 4, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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