Pharmacological Studies on Excitable Membrane and Vascular Smooth Muscle by Ropivacaine

• Main Authors: Pei-Lin Lin, 林佩玲
• Other Authors: 蔡明正
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/81806358419517980108

博士 === 國立臺灣大學 === 藥理學研究所 === 95 === Ropivacaine, a pure S-enantiomer, is a long-acting amide local anesthetic agent. It is similar to bupivacaine in chemical structure and anesthetic action. Ropivacaine produces sensory-motor differential blockade and results in less cardiac and neurotoxicity than bupivacaine. Since its clinical introduction in 1996, it is widely used for epidural anesthesia, nerve blockade, postoperative analgesia, and painless labor. Several reports have documented ropivacaine-induced convulsion and some have reported cardiotoxicity, such as cardiac arrest. The purposes of the study are as follows: (1) to investigate the possible mechanisms of ropivacaine-induced neurotoxicity using the central neuron of snail; (2) to identify the effects of ropivacaine in vasomotor tone on endothelium-dependent guinea pig aorta. The effects of ropivacaine on a central neuron (RP4) of giant African snail (Achatina fulica Ferussac) were recorded by pharmacological and electrophysiological technique. The RP4 neuron showed spontaneous firing of action potential. Extra-cellular application of ropivacaine (900μM) reversibly elicited bursts of potential on RP4 neuron. The bursts of potential elicited by ropivacaine were not blocked after administration of (1) prazosin (100 μM), propranolol (100 μM), atropine (1 mM), d-tubocurarine (100μM), (2) pretreatment with calcium-free solution, (3) pretreatment with H89 (10μM), and (4) pretreatment with chelerythrine (10 μM). The bursts of potential elicited by ropivacaine were blocked by pretreatment with U73122 (30 μM) or additions of neomycin (3.5 mM) or high magnesium solution (30 mM). Ropivacaine-elicited bursts of potential are closely associated with the phospholipase C activity, not directly related to (1) adrenergic or cholinergic receptors, (2) the extra-cellular calcium ion fluxes, (3) the PKA activity and (4) the PKC activity in the neuron. It suggests ropivacaine-induced neurotoxicity may be associated with phospholipase C activity. Isolated guinea pig aortic rings were suspended for isometric tension recordings. Ropivacaine (3 x 10-4 to 10-2 M) produced vasoconstriction in endothelium-denuded aortic rings, whereas no such response was observed in aortic rings with intact endothelium. In phenylephrine (10-5 M) precontracted intact aortic rings, ropivacaine induced a greater degree of vasorelaxation than acetylcholine. Yohimbine (10-6 M), propranolol (10-6 M) and atropine (10-6 M) all failed to affect the relaxation responses induced by ropivacaine. Pretreatment with indomethacin (10-5 M; cyclooxygenase inhibitor), L-NAME (10-3 M; nitric oxide synthase inhibitor), methylene blue (10-6 M; nitric oxide synthase and soluble guanylyl cyclase inhibitors) or ODQ (10-5 M; soluble guanylyl cyclase inhibitor), significantly decreased ropivacaine-induced relaxation of endothelium intact aortic rings (3 x 10-4 to 10-2 M). Ropivacaine elicits an endothelium-dependent vasorelaxation in the phenylephrine precontracted aortic rings via the nitric oxide (NO)-cyclic GMP pathway and the prostaglandin system. In conclusion, ropivacaine is a safer local anesthetic agent compared with bupivacaine. After accidental intravascular administration, ropivacaine-induced CNS and cardiovascular toxicity will be developed. Ropivacaine-induced neurotoxicity is highly associated with PLC activity and PLC inhibitor may offer a novel therapeutic approach for managing local anesthetic-induced convulsion or other transient neurological toxicity. Ropivacaine elicits an endothelium-dependent vasorelaxation in the phenylephrine precontracted aortic rings via the nitric oxide -cyclic GMP pathway and the prostaglandin system.