Am. Shah et al., INHIBITION OF MYOCARDIAL CROSSBRIDGE CYCLING BY HYPOXIC ENDOTHELIAL-CELLS - A POTENTIAL MECHANISM FOR MATCHING OXYGEN-SUPPLY AND DEMAND, Circulation research, 80(5), 1997, pp. 688-698
Previous studies have shown that cardiac endothelial cells release sub
stances that influence myocardial contraction. Since PO2 is an importa
nt stimulus that modulates endothelial function, we investigated the e
ffects of acute moderate hypoxia and reoxygenation on the release of c
ardioactive factors by endothelial cells. Endothelial cells cultured f
rom several vascular beds were superfused with normoxic (equilibrated
with room air; PO2, approximate to 160 mm Hg) or hypoxic (PO2, 40 to 5
0 mm Hg) physiological buffer solution, and the superfusates were reeq
uilibrated to a PO2 of approximate to 160 mm Hg and then tested for th
eir effects on various myocardial assays. Endothelial cell viability a
nd buffer ionic composition were unaltered after the superfusion proce
dures. The superfusates of hypoxic endothelial cells induced rapid, po
tent, reversible inhibition of isolated cardiac myocyte contraction wi
thout reducing cytosolic Ca2+ transients. This activity was not lost a
fter heating (95 degrees C) and was present in low molecular weight (M
-r, <500) superfusate fractions. Hypoxic endothelial superfusate reduc
ed unloaded shortening velocity of human skinned soleus muscle fibers.
It markedly depressed in vitro actin motility over cardiac myosin and
reduced the rate of actin-activated cardiac myosin ATPase activity bu
t had no effect on corresponding smooth muscle myosin assays. Reoxygen
ation of hypoxic endothelial cells resulted in loss of this inhibitory
activity. These data indicate that cultured endothelial cells respond
to acute moderate hypoxia by releasing an unidentified substance(s) t
hat inhibits myocardial crossbridge cycling, independent of Ca2+ or ot
her second messenger signaling pathways. Such a mechanism could have i
mportant implications for the regulation of oxygen supply-demand balan
ce in the heart and be relevant to conditions such as myocardial hiber
nation.