Endothelin does not contribute to the attenuation in myocardial function and blood flow after repetitive ischemia in the rat heart.
An increased release of the potent vasoconstrictor endothelin (ET) may play a role in the development of myocardial stunning. We, therefore, hypothesized that blockade of ET with either monoclonal antibodies against ET-1 and ET-3 (a-ET1/3-ab) or with the ET(A) receptor antagonist BQ123 would improve the reduction in myocardial blood flow (MBF; H2 clearance) and fractional wall thickening (FT; pulsed Doppler) after repetitive ischemia/reperfusion in an in situ perfused rat model. Under baseline conditions, ET-1 dose dependently decreased MBF and increased mean arterial blood pressure. FT and heart rate were unaltered. Pretreatment with both a-ET1/3-ab or BQ123 effectively blocked the effects of ET. Following repetitive ischemia, MBF was significantly reduced from 3.5 +/- 0.4 to 2.1 +/- 0.3 ml x min-1 x g-1 (p < 0.05) and FT from 16.2 +/- 1.7 to 9.4 +/- 1.1% in the control group (p < 0.05). Pretreatment with either antibodies did not significantly improve the attenuation in MBF and FT at the end of the ischemic protocol. These results indicate that inhibition of ET-1 by monoclonal antibodies or by ET(A) receptor blockade does not influence the decrease in MBF and FT in repetitive ischemia/reperfusion. We, therefore, propose that ET is not a major determinant in the development of myocardial stunning.
Tiefenbacher
C P
CP
Department of Cardiology, University of Heidelberg, Germany. ctiefenbacher@krzmail.krz.uni-heidelberg.de
Tweddell
A
A
Batkai
S
S
Zimmermann
R
R
Tillmanns
H
H
Kübler
W
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D011920:Rats, Inbred WF; D044022:Receptor, Endothelin A; D012008:Recurrence
D000911:Antibodies, Monoclonal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)