Synergistic interaction of lithium ions with L-erythromethoxamine and phenylephrine contractions in porcine blood vessels: no role for inhibition of inositol monophosphatase

S. Yahya1, R. Mahajan2, V. Wilson1. 1Life Sciences, University of Nottingham, Nottingham, UNITED KINGDOM, 2Anaesthesia and Intensive Care, University of Nottingham, Nottingham, UNITED KINGDOM.

Introduction: Contractions to maximally-effective concentrations of phenylephrine (PE) and L-erythromethoxamine (LEM) in the porcine isolated splenic artery (PSA) are increased and better maintained in the presence of lithium ions (Yahya et al., 2016). We have examined whether this effect of lithium ions and whether inositol monophosphatase, a target in the treatment of manic depression (Atack et al., 1995), is implicated in this synergistic action.

Methods: The PSA, splenic vein (PSV) and renal artery (PRA) were dissected from spleens and kidneys obtained from a local abattoir. Vessels were stored overnight at 4oC and 5mm ring segments prepared the following day for isometric tension recording in Krebs Henseleit solution gassed at with 95%O2/5%CO2 and maintained at 37oC. Differences were considered significant by either a paired Student’s t-test or ANOVA and a post-hoc Dunnett’s test.

Results: Lithium (1mM) caused a significant increase in the maximal response of the PSV to PE (89.3±10.2% to 120.3±8.2%*, n=4), but not in the PRA (150.1±11.4% to 165.1±9.5%, n=4). After 60 min exposure to PE, however, the contractions in both preparations waned significantly to 58.3±1.6% and 48.1±3.8% of the response to 60mM KCl for the PSV and PRA, respectively. In the presence of the lithium, however, PE contractions of the PSV (107.7±7.5%*, n=4) and PRA (144.2±8.7%*, n=4) were better maintained (p <0.01). Table 1 shows that 0.3 and 1mM lithium ions, but not 0.1mM, increased the maximal contraction to 30µM LEM in the PSA. In contrast, 300µM L690,330 neither increased nor prevented the response to LEM waning over 60 min. After exposure to LEM alone for 60 min the subsequent addition of 1mM lithium ions failed to alter the residual constrictor tone (n=6). Table 1: The effect of lithium ions and 300µM L690,330 on the mean (±sem) maximal response to LEM in the PSA * - Denotes a statistically significant difference (p < 0.01) from LEM alone.

Discussion: We have demonstrated that lithium ions, at concentrations at or below the plasma levels used to treat bipolar disorders, enhances and maintains constrictor responses to the phenylephrine and LEM in porcine arteries and veins in vitro - but only if used prior to the agonists. This action is not mimicked by L690,330, a potent, competitive inhibitor of inositol monophosphatase (Atack et al., 1995).

Reference: Atack JR et al., (1995). Trends Neurosci. 18, 343-349. Yahya et al., BPS Meeting abstract #581 (2016).