Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril.
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.
Qi
X L
XL
Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada.
Sia
Y T
YT
Stewart
D J
DJ
Wei
G
G
Nguyen
Q T
QT
Cernacek
P
P
Picard
P
P
Sirois
M
M
Rouleau
J L
JL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism; D006439:Hemodynamics; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009132:Muscles / Q000378:metabolism; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009842:Oligopeptides / Q000494:pharmacology; D009924:Organ Culture Techniques; D009929:Organ Size; D010210:Papillary Muscles / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D000077583:Quinapril; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D019332:Endothelin-1; D007546:Isoquinolines; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D044005:Tetrahydroisoquinolines; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000077583:Quinapril; C072247:cyclo(Trp-Asp-Pro-Val-Leu)