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Title: Could subtype selective α-adrenoceptor agonists make better nasal decongestants : a study on porcine nasal and systemic blood vessels
Author: Denfria, Hamza
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2016
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Abstract:
Introduction: Nasal decongestants are medications used to relieve nasal congestion to ease breathing. Nasal decongestants work by targeting alpha (a) adrenoceptors in the nasal blood vessels. Since most of nasal decongestants work on OT-adrenoceptors, more work is being conducted to develop and improve nasal decongestants to target a2-adrenoceptors which induce more vasoconstriction in nasal circulation rather than the systemic circulation. A im s: a comparison is needed to study a-adrenoceptors in nasal and extra-nasal blood vessels and to assess the potential benefits of targeting a2-adrenoceptors or other compounds to improve pharmacotherapy of nasal decongestion. Results: Immunohistochemistry of porcine nasal artery and porcine splenic artery revealed that both arteries seem to have a similar population of a1A-adrenoceptors but a2A-adrenoceptors seem to be more expressed in the tunica media of the splenic artery. Contraction studies suggest that nasal artery was less sensitive to a-adrenoceptor agonists than the systemic artery (splenic artery) and interestingly, phenylephrine showed higher potency and efficacy in the splenic artery. On the other hand, a2- adrenoceptors seemed to be more active and functional in the nasal artery (but not the splenic) and they responded well to a2-adrenoceptor agonists. Also, their blockade affected the response to a2-adrenoceptor agonists. However, Schild plot analysis revealed a dominant role of cp-adrenoceptors in mediating the contraction of porcine splenic artery. Moreover, manipulation of signal transduction pathways in the porcine splenic artery uncovered a hidden role of a2-adrenoceptors mediating contractile response to noradrenaline and even phenylephrine. In addition, this manipulation improved the functionality of a2-adrenoceptors in nasal artery and in perfused porcine nasal mucosa as well. When it came to the sympathetic supply to the nasal artery, electrical field stimulation and the effect of cocaine on the responses to tyramine revealed the nasal artery to have good sympathetic supply, more than the splenic artery. But, despite this, the nasal artery failed to show responses to other indirectly acting sympathomimetics. On the other hand, manipulation of nitric oxide (NO) levels did not change the responses of nasal artery to different agonists and the responses of the splenic artery were small too. This happened while the endothelium of both porcine nasal artery and porcine splenic artery was intact. To improve and develop available methods of studying nasal mucosa in vivo, a new method was developed to perfuse isolated porcine nasal mucosa. The new method was able to record pressure changes in response to various compounds which most probably reflect changes in the arterial side of the nasal circulation. Finally, the splenic vein was used to represent the venous side of circulation and it showed a good response to a2-adrenoceptror agonists. Even the pharmacological manipulation of the splenic vein did not affect its already prominent response to a2-adrenoceptror agonists. However, c^-adrenoceptors remain the main mediators of vasoconstriction in the splenic vein. The response of splenic vein to tyramine did not suggest the presence of a rich sympathetic supply to the vessel. Conclusion: These results suggest that a,-adrenoceptors are the major mediator of vasoconstriction to sympathomimetics in all preparations while a2-adrenoceptors are involved to varying extents in the control of porcine blood vessels. However, a2-adrenoceptors are more important in the nasal circulation and the venous side of the circulation than they are in the splenic artery. These finding in addition to the complexity of the vascular structures inside the nose and the involvement of different mechanisms in the control of nasal circulation, may not support targeting one subtype of a-adrenoceptors to treat nasal congestion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.718460  DOI: Not available
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