Download Effects of Fumonisins on Cardiovascular Function in Swine

Effects of Fumonisins on Cardiovascular Function in Swine
Geoffrey W. Smith, Peter D. Constable, and Wanda M. Haschek
Introduction
Fumonisins (FB), are a group of naturally occurring mycotoxins produced by the fungus
Fusarium moniliforme. These toxic metabolites of corn have been implicated in field cases of
porcine pulmonary edema (PPE). The mechanism of fumonisin-induced pulmonary edema in
swine is currently unknown; however, it may be related to altered sphingolipid biosynthesis. It
was recently discovered that fumonisins are naturally occurring inhibitors of sphingosine
(sphinganine) N-acyltransferase. This enzyme is a key component in the pathway for
sphingolipid biosynthesis. We previously reported that this fumonisin-induced enzyme
inhibition results in increased concentrations of free sphinganine and sphingosine in the serum
and tissues of swine, as well as a depletion of complex sphingolipids. Sphingosine is an
important intracellular second messenger that participates in receptor interaction and signal
transduction through modulation of various calcium channels, protein kinases, and calmodulindependent enzymes.
More recent studies have shown that low concentrations of sphingosine inhibit the L-type
calcium channels in the heart, thereby potentially reducing cardiac contractility. In vitro studies
using frog atrial muscle tissue have demonstrated that fumonisin blocked L-type calcium
channels and decreased atrial mechanical activity. It is therefore likely that a fumonisin-induced
increase in sphingosine concentrations could produce various cardiovascular effects in pigs,
thereby inducing the pulmonary edema seen in field cases of fumonisin toxicity.
Objectives
1. To examine the effects of fumonisins on the cardiovascular system of swine.
2. To determine if fumonisins decrease cardiac contractility in swine.
Results
In 2 separate studies, groups of pigs were fed fumonisins at a dose of either 0 or 20 mg
hydrolyzed fumonisin B1/kg/day for 7 days. On day 8, pigs were anesthetized and surgically
fitted with arterial and/or pulmonary catheters. Cardiovascular measurements were obtained
during anesthesia and 18 hours after recovery from anesthesia. Pigs fed fumonisins had
significant decreases in maximal rate of change of left ventricular pressure (dP/dtmax), heart rate,
cardiac output, and mean aortic pressure,
1
Departments of Veterinary Pathobiology and Clinical Medicine, University of Illinois at
Urbana-Champaign
a significant increase in mean pulmonary artery pressure and pulmonary vascular resistance, and
no change in left ventricular end-diastolic pressure, pulmonary wedge pressure, ventricular
relaxation rates, and central venous pressure. Additionally, there were no significant differences
found in electrocardiograms from fumonisin-treated pigs.
Discussion
The major findings of these studies were that fumonisin decreases the cardiac contractility of
pigs (reduced dP/dtmax) without effecting the rate of ventricular relaxation. Additionally we have
demonstrated a reduction in heart rate, cardiac output, and mean aortic pressure, with a
significant increase in pulmonary artery pressure. We also found that sphingosine and
sphinganine concentrations are increased in the cardiac muscle of fumonisin-treated pigs as
compared to controls.
These results indicate that field cases of fumonisin-induced pulmonary edema in swine are due to
left-sided heart failure. We propose that the fumonisin-induced increase in tissue sphingosine
concentrations inhibits the L-type calcium channels of cardiac cells, thereby decreasing calcium
release and cardiac contractility. The increase in sphingosine also inhibits the calcium channels
of cardiac pacemaker cells thereby decreasing heart rate. Pulmonary edema is likely to form as
the contractile rate of the heart decreases mean arterial pressure below the level needed for the
regulation of the cardiac circulation.
Acknowledgements
This study was partially funded by the Illinois Pork Producers Association.
References
Hannun, Y.A., and R.M. Bell. 1989. Functions of sphingolipids and sphingolipid
breakdown products in cellular regulation. Science 243:500.
Haschek, W.M., G. Motelin, D.K. Ness, et al. 1992. Characterization of fumonisin
toxicity in orally and intravenously dosed swine. Mycopathologia 117:83.
McDonough, P.M., K. Yasui, R. Betto, et al. 1994. Control of cardiac Ca2+ levels:
Inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel
conductance. Circ. Res. 75:981.
Riley, R.T., N.H. An, J.L. Showker et al. 1993. Alteration of tissue and serum sphinganine
to sphingosine ratio: An early biomarker of exposure to fumonisin-containing feeds in
pigs. Toxicol. Appl. Pharmacol. 118:105.
Smith, G.W., P.D. Constable, C.W. Bacon et al. 1996. Cardiovascular effects of
fumonisins in swine. Fundam. Appl. Toxicol. 31:169.
Smith, G.W., P.D. Constable, and W.M. Haschek. 1996. Cardiovascular responses to short-
term fumonisin exposure in swine. Fundam. Appl. Toxicol. 33:140.
Wang, E., W.P. Norred, C.W. Bacon et al. 1991. Inhibition of sphingosine biosynthesis by
fumonisins. J. Biol. Chem. 266:14486.