From the Institut für Pharmakologie und Toxikologie (F.B.),
Karl-Franzens-Universität Graz, A-8010 Graz, Austria, and University of
Cape Town Medical School (L.H.O.), Ischaemic Heart Disease Research Unit, Cape
Town, South Africa.
Correspondence to Dr Friedrich Brunner, Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria. E-mail friedrich.brunner{at}kfunigraz.ac.at
Background—Circulating endothelin
(ET)-1 is elevated in ischemia/reperfusion and may exert
proischemic effects. The aim of the present study was to
characterize the effects of ET-1 in rat isolated hearts using
subtype-selective ET receptor antagonists, agents
modulating the cytosolic Ca2+ concentration, or the
activity of cGMP-dependent protein kinase.
Methods and Results—Rat hearts perfused at constant pressure were
made ischemic by reducing flow to 0.2 mL ·
min-1 · g-1, followed by reperfusion at
normal pressure (each phase, 25 minutes). Drugs were infused during the
ischemic phase only. Parameters monitored were
extent and time-to-onset of contracture in ischemia, left
ventricular developed pressure (LVDevP), coronary
flow (CF), and diastolic relaxation during reperfusion. The
ETA receptor-selective antagonist PD 155080 (50
nmol/L) reduced peak ischemic contracture (-49%) and delayed
its time to onset (+56%) and improved recovery of reperfusion LVDevP
(+12%), CF (+16%), and diastolic relaxation (+50%).
Infusion of an ETA/ETB-nonselective
antagonist, PD 142893 (200 nmol/L), had similar effects on
all parameters, whereas infusion of BQ-788 (20 nmol/L), an
ETB receptor-selective antagonist, was without
effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased
its extent (+23%) and reduced recovery of both LVDevP (-31%) and CF
(-18%), effects that were counteracted by HOE 642 (10 µmol/L), a
Na+/H+ exchange inhibitor, but not
by nicardipine (30 µmol/L), a Ca2+ entry
blocker; activation of cGMP-dependent protein kinase by the
cell-permeable cGMP analog
Sp-8-p-chlorophenylthioguanosine-3',5'-cyclic monophosphorothioate
(10 µmol/L) improved function without preventing the effects of
ET-1.
Conclusions—The data indicate that ET-1 exacerbates
ischemic contracture and worsens ventricular and
coronary reperfusion dysfunction by activating ETA
receptors via a mechanism likely involving activation of
Na+/H+ exchange in this model.
© 1998 American Heart Association, Inc.
Basic Science Reports
Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury
Key Words: endothelin • nitric oxide • ischemia • reperfusion • hemodynamics
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