Vesnarinone restores contractility and calcium handling in early endotoxemia

Citation
K. Takeuchi et al., Vesnarinone restores contractility and calcium handling in early endotoxemia, CIRCULATION, 102(19), 2000, pp. 365-369
Citations number
25
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Journal title
CIRCULATION
ISSN journal
00097322 → ACNP
Volume
102
Issue
19
Year of publication
2000
Supplement
S
Pages
365 - 369
Database
ISI
SICI code
0009-7322(20001107)102:19<365:VRCACH>2.0.ZU;2-9
Abstract
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.