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Abdulrahman, Aseel (2019) A study of α-Adrenoceptor agonists on porcine nasal and extra-nasal vasculature: insight into decongestant activity. PhD thesis, University of Nottingham.

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Abstract

Background and purposes: Sympathomimetics have long been used as medications to relieve the symptoms associated with nasal congestion, but in the last 15 years, the worldwide market has moved from largely topical formulation to oral consumption. Many of the existing drugs are thought to cause vasoconstriction by activating α-adrenoceptors present on nasal mucosa and reduce local blood flow and swelling. This thesis aims to re-evaluate the activity of various sympathomimetic drugs on the nasal and extra-nasal blood vessels and better characterise the pharmacological characteristics of α-adrenoceptors on these vessels. In addition to that, I have explored the potential for lithium ions to modify the action of directly-acting sympathomimetics on both nasal and extra-nasal blood vessels and vasculature.

Results: Isometric tension recordings of the porcine isolated splenic and nasal arteries showed that both noradrenaline and phenylephrine caused concentration-dependent contractions, but surprisingly were less potent (3-4-fold, respectively) in the latter vessel. Concentrations of phenylephrine known to occur in vivo following oral consumption (10-30nM) failed to either induce direct vasoconstriction or alter the magnitude and duration of electrically evoked contractions of the porcine vasculature. While pseudoephedrine failed to contract either nasal or extra-nasal vessels directly, it significantly enhanced electrically evoked noradrenergic contractions and increased the duration of responses. This effect was more marked in the nasal artery. Pharmacological characteristics of contractile responses to noradrenaline in porcine arteries, using a variety of selective and non-selective antagonists, revealed unsourmountable inhibition (Schild plot < 1) and evidence for the presence of two subtypes of α1-adrenoceptors. Attempts to reveal a constrictor role for α2-adrenoceptors in the splenic artery were only successfully provided by experimental conditions included both elevations of intracellular calcium ions and cyclic AMP.

Comparison of the vasoconstrictor effect of phenethylamine derivatives, e.g. phenylephrine or metaraminol, in splenic and nasal arteries revealed that responses to high concentrations were not sustained. However, the presence of 1mM lithium increased the magnitude and duration of constrictor responses. This effect was not observed when α1-adrenoceptors were stimulated by imidazoline derivatives. Using the perfused porcine nasal snout revealed that various sympathomimetics were also able to increase perfusion pressure and the inclusion of 1mM lithium in the perfusate significantly increased the maximum response and duration of pressor responses to phenylephrine.

Conclusion and implication: In summary, these data show that while the decongestant activity of topically applied phenylephrine could be accounted by a localised constrictor effect on nasal blood vessels, no mechanistic justification was uncovered for a naso-selective effect of orally consumed phenylephrine (10mg). In contrast, pseudoephedrine selectively enhanced noradrenergic contractions in the nasal vasculature. The major mediators of vasoconstriction in porcine blood vessels appear to involve two subtypes of α1-adrenoceptors (mainly α1A-adrenoceptors and probably α1B-adrenoceptors). For arterial vessels, α2-adrenoceptors could not be detected in vitro study without simultaneous elevation of cellular calcium ions and cyclic AMP. Finally, my findings raise the possibility that the nasal decongestant activity of topically applied phenylephrine may be enhanced by the presence of lithium ions, which may reduce the frequency of administration.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Wilson, Vincent Chan, Sue
Keywords:	Vasoconstriction; Nasal blood vessels; α-adrenoceptors; phenylephrine
Subjects:	Q Science > QP Physiology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	59470
Depositing User:	Abdulrahman, Aseel
Date Deposited:	15 May 2020 08:21
Last Modified:	11 Dec 2021 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/59470

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