AJP - Cell Physiology, Vol 261, Issue 5 C780-C786, Copyright © 1991 by American Physiological Society
HMG CoA reductase inhibitors affect Na(+)-H+ antiport activity in human lymphoblasts
L. L. Ng and J. E. Davies
Department of Pharmacology, Leicester Royal Infirmary, University of Leicester, United Kingdom.
The Na(+)-H+ antiport is a membrane-bound glycoprotein that extrudes
intracellular acid loads and regulates cellular volume. Cellular synthesis
of the oligosaccharide side chains of glycoproteins is dependent on a
supply of mevalonate, itself a product of the rate-limiting enzyme of
cholesterol synthesis 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
reductase. The effect of two HMG CoA reductase inhibitors (simvastatin and
25-hydroxycholesterol) on intracellular pH and Na(+)-H+ exchange was
therefore studied. Inhibition of the Na(+)-H+ antiport by these agents led
to a fall in intracellular pH but did not impair the regulatory volume
increase response to a hypertonic stimulus. The inhibitory effect of
simvastatin was prevented by mevalonate but not dolichol or squalene. The
effect of 25-hydroxycholesterol was more complex and not easily reversed.
Thus HMG CoA reductase inhibitors reduced the ability of human lymphoblasts
to expel an intracellular acid load via the Na(+)-H+ antiport, although the
response of the antiport to an osmotic stimulus was preserved.
