Direct Effect of Ropivacaine Involves Lipoxygenase Pathway Activation in Rat Aortic Smooth Muscle

Purpose: Ropivacaine is a long-acting amino-amide local anesthetic that induces vasoconstriction in vitro and in vivo. The aim of this study was to investigate the pathways involved in arachidonic acid metabolism associated with S-ropivacaine-induced contraction of rat aortic smooth muscle in vitro.

Methods: Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dose-response curves were generated with concentrations of 10(-5) to 10(-3) M ropivacaine enantiomer in the presence or absence of quinacrine dihydrochloride, nordihydroguaiaretic acid, quinacrine dihydrochloride plus nordihydroguaiaretic acid, indomethacin, fluconazole, AA-861, and verapamil. The maximal S-ropivacaine-induced contractile response achieved at 3x10(-4) M was also assessed in aortic rings pretreated with normal or calcium-free Krebs solution.

Results: Ropivacaine enantiomers induced dose-dependent biphasic contractions in aortic rings. S-ropivacaine (10(-4), 3x10(-4) M) induced a stronger contraction than R-ropivacaine. Quinacrine dihydrochloride (2x10(-5), 4x10(-5) M) attenuated the S-ropivacaine-induced biphasic contraction in a dose-dependent manner. Indomethacin (3x10(-5), 6x10(-5) M), nordihydroguaiaretic acid (10(-5) M), and AA-861 (10(-5) M) also attenuated the S-ropivacaine-induced dose-dependent biphasic contraction, whereas fluconazole (3x10(-5)) had no effect. Combined pretreatment with quinacrine dihydrochloride and nordihydroguaiaretic acid almost completely abolished the S-ropivacaine-induced contraction. S-ropivacaine-induced contractile responses were attenuated by verapamil (10(-5) M) and calcium-free Krebs solution.

Conclusion: S-ropivacaine induces dose-dependent biphasic contractions in rat aortic smooth muscle through a mechanism requiring extracellular calcium that is mediated by activation of the lipoxygenase pathway and, to a lesser extent, the cyclooxygenase pathway.