Background-Endotoxin (lipopolysaccharide, LPS) is a trigger of the systemic
inflammatory response. We have previously found that vesnarinone and amrin
one, when given before LPS, prevented cytokine production and LPS-related c
ardiac dysfunction. We tested the hypothesis that vesnarinone would improve
intracellular Ca2+ handling and calcium-activated contractile force after
the onset of endotoxemia.
Methods and Results-Adult rabbits received a bolus injection of LPS or vehi
cle. Vesnarinone (3 mg/kg) was given intravenously 90 minutes later. Two ho
urs after LPS administration, hearts were perfused in the isolated Langendo
rff mode. Peak left ventricular developed pressure, +/-dp/dt, oxygen consum
ption (M(V)over dot o(2)), and rate X pressure product were evaluated in co
njunction with fluorescent spectroscopic determinations of intracellular ca
lcium concentrations (Ca-i) and the rate of Cai transient decline during di
astole (tau Ca). Peak left ventricular developed pressure and +/-dp/dt were
significantly lower in the LPS group. These were completely restored by ve
snarinone. There was significantly slower diastolic calcium removal (increa
sed tau Ca) in LPS hearts that was also corrected by vesnarinone; however,
the cytosolic calcium overload characteristic of LPS hearts was only partia
lly improved. Reduced mechanical inefficiency (the ratio of rate-pressure p
roduct to M(V)over dot o(2)) and myofilament sensitivity to Ca, were also s
ignificantly improved by vesnarinone.
Conclusions-Acute endotoxemia caused contractile protein calcium insensitiv
ity, oxygen wastage, and abnormal calcium cycling. Vesnarinone, given in th
e rescue mode, normalized LPS-induced myocardial dysfunction and partially
restored abnormal calcium cycling. Although the mechanisms responsible for
these effects require further clarification, it appears that agents such as
vesnarinone may be useful to treat inflammatory-induced myocardial dysfunc
tion.