Abstract
TRADITIONAL local anesthetics (LAs) block voltage-gated sodium channels (NaChs) and inhibit the propagation of action potentials in excitable membranes. Voltage-gated NaChs are the main target of LAs. LAs are known to block nerve, skeletal, muscle, and cardiac muscle NaChs, which are primarily responsible for excitability of their respective tissue. LA potency, as Na+channel blockers, is governed by channel state, with open and inactivated states being favored over resting states. Voltage-dependent conformational changes of the LA binding site can explain the changes of LA affinity between resting, open, and inactivated states. There are structural similarities between voltage-gated sodium and calcium channel proteins, even though these two channels differ strongly in their ion selectivity. The homologous domains of the α-subunit of NaChs can be aligned with 32–37% sequence identity with that of the L-type calcium channels. Both α-subunits form a fourfold pseudosymmetry with four repeated domains, each with six transmembrane segments. There are drugs that can block both calcium channels and NaChs. It has been reported that there is a correlation between the potencies of calcium channel blockers in preventing neurotoxicity induced by veratridine in brain neuronal cultures and their binding affinity for [H3]batrachotoxinin-B binding sites. 6 This raises a possibility that some calcium channel blockers may block Na+channels with a high affinity. Few LAs for pain management produce analgesia of long duration. The development and availability of such LAs that can cause reversible blockade of neural functions is desirable and advantageous for certain pain management in the clinic. Prenylamine, a coronary vasodilator, is a calcium channel blocker formerly used in the treatment of angina pectoris but now superseded by safer antianginal drugs. 7–10 The general pharmacologic activities, including surface anesthesia, of prenylamine and some of its cycloalipahtic derivatives have been previously studied. 11 The LA properties of prenylamine on voltage-gated NaChs have not been characterized thus far. We selected prenylamine because it contains large hydrophobic moieties (fig. 1). Previous results indicate that LAs with two large hydrophobic moieties are more potent in vivo . 12,13 This study examines the LA properties of prenylamine in vitro by electrophysiologic studies of the NaCh on neuronal GH3cells and assesses its usefulness as a long-acting LA in vivo by neurobehavioral examination of sciatic nerve block in the rat in comparison with the known LA anesthetic bupivacaine.