THE EFFECT OF THE NEUROLYTIC AGENT ETHANOL ON CYTOPLASMIC CALCIUM IN ARTERIAL SMOOTH-MUSCLE AND ENDOTHELIUM

Background and Objectives. Celiac plexus neurolysis, although effectiv e in relieving pain associated with upper abdominal malignancy, occasi onally results in paraplegia. Diffusion of the neurolytic agent to art eries supplying the spinal cord has been postulated as a cause, and pr evious studies with isolated lumbar segmental arteries have demonstrat ed contraction in response to ethanol and phenol. The mechanism of thi s contractile effect is unknown, but a role for insular free calcium ( Cart,) is suggested by the known involvement of Ca-i(2+) in both smoot h muscle vasoconstriction and toxic cell injury. The authors sought to determine whether nontoxic concentrations of ethanol cause a direct e levation of Ca-i(2+) in arterial smooth muscle and endothelium. Method s. Primary cultures of human aortic smooth muscle and endothelial cell s were studied to determine the direct effect of ethanol independent o f interactions with agonists or contractile proteins. Ca-i(2+) levels were determined in single cells with digitized video fluorescence micr oscopy, using ratio imaging of the Ca-i(2+)-sensitive fluorophore fura -2. Results. In aortic smooth muscle cells, initial Care, was 98 +/- 4 1 nM (n = 59 cells). Histamine (10 mu M) as a positive control caused an increase in Ca-i(2+), as expected. Ethanol alone, at doses of 2-5% (v/v) also caused a sustained elevation in Carl, of physiologically si gnificant magnitude. Ethanol at doses of 5% or lower did not cause any visibly apparent injury within 30 minutes. In contrast, 10% or higher ethanol doses quickly caused membrane blebbing, a sign of toxic injur y, followed by cell death within 20 minutes. Aortic endothelial cells were more resistant to ethanol than smooth muscle cells, in terms of b oth Ca-i(2+) elevation and cell death. Conclusions. Ethanol, even at n ontoxic concentrations, has a direct effect on aortic smooth muscle Ca -i(2+), large enough to be associated with significant vasoconstrictio n. The findings suggest a possible role for pharmacologic agents that presence Ca-i(2+) homeostasis in protecting against neurolysis-induced paraplegia, although additional study is required before clinical app lication is appropriate.