Synergistic interaction of lithium ions and α1-adrenoceptor agonists in vascular and non-vascular porcine smooth muscle

Yahya, Saif (2019) Synergistic interaction of lithium ions and α1-adrenoceptor agonists in vascular and non-vascular porcine smooth muscle. PhD thesis, University of Nottingham.

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Phenylephrine, L-erythromethoxamine and metaraminol are selective α1-adrenoceptor agonists having phenethylamine chemical structure and used to treat a variety of clinical conditions, including sepsis, anaesthesia associated hypotension, nasal congestion, haemorrhoids, and the evaluation of eye function. Their action involves activation of α1-adrenoceptor on the smooth muscle of major organs to induce a contraction and the resultant therapeutic benefit is dependent on the maintenance of stable response. The signalling mechanism most closely linked to α1-adrenoceptors in smooth muscle is stimulation of phosphatidylinositol metabolism, which induces subsequent elevation of intracellular calcium ions. Lithium ions are also used clinically in the treatment of bipolar disorders and are known to prevent degradation of a key mediator of phosphoinositide metabolism and there are a few reports suggest that this cation can enhance or maintain contractions mediated by α1-adrenoceptors. In the present study, I have investigated the interaction between lithium ions and constrictor responses to a variety of agonists, including selective α1-adrenoceptor agonists, with a particular focus on both the potency of the constrictor agent and the time course of responses. I have also used pharmacological approaches to better understand the basis of a novel interaction between lithium ions and selective α1-adrenoceptor agonists.

Two methods have been employed. Isometric tension recording of isolated vascular and urethral smooth muscle determined using a standard approach of maintaining the tissue in Krebs-Henseliet solution gassed with 95%O2/5%CO2. Agonists were added either cumulatively or as a single concentration and the magnitude and time course of the contraction assessed with lithium and in the presence of selective inhibitors. In addition, the time of course of changes in human skin blood flow, using laser Doppler flowmetry, to the iontophoretic application of phenylephrine has also been evaluated.

Our in vitro results show that the contractions of the isolated vascular smooth muscle to KCl and the thromboxane mimetic (U46619), were sustained for up to three hours. In contrast contraction to high concentrations to noradrenaline, 5HT, histamine, vasopressin, angiotensin II, carbachol and the selective α1-adrenoceptor agonist were not. Furthermore, in porcine isolated splenic artery segments, the use of therapeutic concentration of lithium (1mM) increased the maximum response to the selective α1-adrenoceptor agonists (and carbachol) almost 2 fold it did not increase the sensitivity of the tissue to these drugs. In contrast, the time course of responses to noradrenaline, cirazoline, 5HT, histamine, vasopressin and angiotensin II was not affected by lithium. Interestingly, similar interaction was also reported in isolated porcine renal and mesenteric arteries, splenic vein and urethral smooth muscle.

Moreover, our results showed that this interaction is sensitive to Ca2+ and abolished in the absence of this cation. This interaction prevents the desensitisation of the receptors which develop following the repetitive exposure to a high concentration of α1-adrenoceptor agonists. Furthermore, we confirm that this synergistic interaction is not related to internalisation, or inhibition of inositol monophosphatase, glycogen synthase kinase, Rho kinase or nitric oxide pathways. Although we reported similar enhancement in the time course of phenylephrine using nM of Na+-K+ ATPase inhibitor (ouabain), the magnitude of the response was much smaller than that reported with lithium.

Our in vivo results demonstrate that the time course of contraction induced by iontophoresis of phenylephrine was relatively stable for more than 30 minutes which suggest that the concentrations reaching the superficial blood vessels were low and therefore there was no point of investigating the effect of lithium on the contraction induced by phenylephrine in this system.

In conclusion, I have demonstrated that the use of high concentration of phenethylamine derived α1-adrenoceptor agonists synergistically interact with therapeutics concentration of LiCl in various smooth muscle preparations and that phosphoinositide metabolism is not involved. This synergistic effect appeared as sustain in the time course of the contraction induced by these agonists and could be accompanied by an enhancement in the magnitudes of the response. Further clinical studies using different approaches are needed to detect any potential clinical uses of this interaction.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Mahajan, Ravi
Wilson, Vince
Keywords: Phenylephrine, L-erythromethoxamine, Metaraminol, Phosphatidylinositol metabolism, Lithium ions, Constrictor responses
Subjects: Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 57276
Depositing User: Yahya, Saif
Date Deposited: 03 Apr 2020 13:21
Last Modified: 15 Oct 2021 04:30

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