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Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril.
- Source :
-
Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2001 Nov; Vol. 33 (11), pp. 2023-35. - Publication Year :
- 2001
-
Abstract
- Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.<br /> (Copyright 2001 Academic Press.)
- Subjects :
- Angiotensin-Converting Enzyme Inhibitors pharmacology
Animals
Antihypertensive Agents pharmacology
Binding, Competitive
Body Weight
Dose-Response Relationship, Drug
Endothelium, Vascular cytology
Endothelium, Vascular metabolism
Heart Failure metabolism
Hemodynamics
Kinetics
Male
Muscles metabolism
Myocardium cytology
Myocardium metabolism
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type III
Oligopeptides pharmacology
Organ Culture Techniques
Organ Size
Papillary Muscles metabolism
Peptides, Cyclic pharmacology
Piperidines pharmacology
Protein Binding
Quinapril
RNA, Messenger metabolism
Rats
Rats, Wistar
Receptor, Endothelin A
Receptor, Endothelin B
Receptors, Endothelin metabolism
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Vasoconstrictor Agents pharmacology
Viper Venoms pharmacology
Endothelin-1 metabolism
Isoquinolines pharmacology
Myocardial Contraction
Myocardial Infarction metabolism
Tetrahydroisoquinolines
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2828
- Volume :
- 33
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of molecular and cellular cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 11708846
- Full Text :
- https://doi.org/10.1006/jmcc.2001.1467