Anesthetic cutoff in cycloalkanemethanols. A test of current theories
Raines, D.E.; Korten, S.E.; Hill, A.G.; Miller, K.W.
Anesthesiology 78(5): 918-927
1993
ISSN/ISBN: 0003-3022 PMID: 8489064 Document Number: 419616
Background: N-alkanols containing up to 12 carbons are anesthetic; however, those with more than 12 carbons are not. This phenomenon has been termed cutoff. Lipid disordering theories of anesthesia suggest that cutoff occurs because the alkyl chains of long-chain alcohols approach the length and shape of the lipids of neuronal membranes and, therefore, intercalate into membranes without perturbing them. Protein theories suggest that cutoff occurs because the size of long-chain alcohols exceeds that of a protein binding site having finite dimensions. These theories were tested with a new series of alcohols, the cycloalkanemethanols, c(C-nH-2n-1) cntdot CH-2 cntdot OH. Methods: Anesthetic potency was measured in Rana pipiens tadpoles using the reversible loss of righting reflexes as the endpoint. The change in order parameter induced by cycloalkanemethanols and n-alkanols in lipid bilayers made of egg phosphatidylcholine and cholesterol was measured with electron paramagnetic resonance spectroscopy. Results: On ascending the series from cyclopropanemethanol (EC-50 = 54 +- 3.2 mM) to cycloundecanemethanol (EC-50 = 7.0 +- 0.12 mu-M) anesthetic potencies first increased exponentially but then decreased sharply at cyclododecanemethanol (EC-50 = 13 +- 0.2 mu-M). Cyclotetradecanemethanol was found not to cause anesthesia in tadpoles, even after 48 h of exposure, although saturated solutions shifted the dose-response curve of octanol from 66 +- 2.6 to 47 +- 2.8 mu-M. A linear loss in the ability to disorder lipid bilayers was observed on ascending both alcohol series such that cyclotetradecanemethanol and n-tridecanol actually increased bilayer order.