I. Sharif et al., The effects of endothelin-1 on ischaemia-induced ventricular arrhythmias in rat isolated hearts, EUR J PHARM, 427(3), 2001, pp. 235-242
We have shown previously that a small bolus dose of endothelin-1, given int
ravenously before coronary occlusion, exerts a marked antiarrhythmic effect
in anaesthetised rats. The aim of the current study was to determine wheth
er or not this is due to a direct effect of endothelin-1 on the heart by as
sessing the antiarrhythmic effect of endothelin-1 against occlusion-induced
arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in L
angendorff mode (constant flow) and subjected to coronary artery occlusion
for 30 min. Coronary perfusion pressure and a surface electrocardiogram (EC
G) were monitored throughout the experiment. In the first series of studies
, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given p
rior to coronary occlusion, were assessed. A second series of hearts was gi
ven a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia.
A third series of experiments was performed using a modified (low K+) Kreb
s Henseleit solution to increase the incidence of ischaemia-induced ventric
ular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was a
dministered as a bolus injection 5 min before ischaemia. Infusion of endoth
elin-1 prior to ischaemia did not modify the incidence or severity of arrhy
thmias at any of the concentrations used. Bolus administration of endotheli
n-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing
normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pr
essure, with no preceding depressor response. Under these conditions, endot
helin-1 exerted only a very moderate reduction in arrhythmias, by reducing
the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, i
n hearts perfused with low K+ solution, bolus injection of endothelin-1, in
a dose that either had no effect on coronary perfusion pressure (0.1 pmol)
or produced a significant vasodilator effect with no significant pressor e
ffect (2 pmol), had no effect on ventricular fibrillation. Thus, in concent
rations that are sufficient to exert effects on the coronary vasculature, e
ndothelin-1 fails to modify arrhythmias in an isolated heart preparation. T
hese results suggest that the antiarrhythmic effects of endothelin-1 previo
usly observed in vivo are not due to a direct effect on either the myocardi
um or the coronary blood vessels. (C) 2001 Elsevier Science B.V. All rights
reserved.