Vasoconstriction potency induced by aminoamide local anesthetics correlates with lipid solubility

Abstract

Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED(50)) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED(50)) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED(50) in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r(2) = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

Figures

Figure 1

Concentration-response curves induced by levobupivacaine, ropivacaine, lidocaine, and mepivacaine in isolated endothelium-denuded (a) and -intact (b) aorta. All values are shown as mean ± SD and expressed as the percentage of the maximal contraction induced by 60 mM KCl. N indicates the number of rats from which descending thoracic aortic rings were derived. (a) Isotonic 60 mM KCl-induced contraction in endothelium-denuded aorta: 100% = 2.94 ± 0.66 g (n = 6) with levobupivacaine, 100% = 3.24 ± 0.51 g (n = 6) with ropivacaine, 100% = 2.88 ± 0.49 g (n = 6) with lidocaine, and 100% = 2.91 ± 0.36 g (n = 6) with mepivacaine. *P < 0.01  versus 10−6 M levobupivacaine; †P < 0.01  versus 10−6 M ropivacaine; ‡P < 0.01  versus 10−6 M lidocaine; #P < 0.01  versus 10−5 M mepivacaine. (b) Isotonic 60 mM KCl-induced contraction in endothelium-intact aorta: 100% = 2.42 ± 0.50 g (n = 6) with levobupivacaine, 100% = 2.44 ± 0.43 g (n = 6) with ropivacaine, 100% = 2.11 ± 0.56 g (n = 6) with lidocaine, and 100% = 2.43 ± 0.28 g (n = 6) with mepivacaine. *P < 0.001 versus 10−6 M levobupivacaine; †P < 0.01  versus 10−6 M ropivacaine; ‡P < 0.05  versus 10−6 M lidocaine; #P < 0.001  versus 10−5 M mepivacaine.

Figure 2

Relationship between logarithm of local anesthetic concentration producing 50% of the local anesthetic-induced maximal contraction (ED50) in isolated endothelium-denuded aorta and logarithm of octanol/buffer partition coefficient (log P) of local anesthetics. All values are shown as mean ± SD. Each anesthetic was tested in aortic rings from six rats.