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Hopps, Jamie (2013) Vascular actions of oleamide in health and disease. PhD thesis, University of Nottingham.

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Abstract

Oleamide, an endocannabinoid-like mediator, is a fatty acid that shares structural similarities with anandamide. Oleamide induces cannabimimetic responses and is a potent vasodilator of rat small mesenteric arteries. The cardiovascular actions of oleamide have received relatively little attention in comparison to those of anandamide, the prototypical endocannabinoid. The aim of this study was to examine the vascular effects of oleamide in both health and disease, making a comparison with those of anandamide.

This study demonstrated that oleamide caused vasorelaxation of the rat isolated aorta. The vasorelaxant actions of oleamide were found to be tissue dependent as oleamide did not evoke vascular responses in the porcine mesenteric and coronary arteries. Anandamide did not produce similar responses to oleamide in any of these vessels, displaying marked differences between the two compounds. Oleamide-induced vasorelaxation of the rat aorta was abolished by capsaicin pre-treatment but this was independent of sensory-nerve activity. This demonstrates a potential additional site of action for oleamide and prompted further investigations into the vascular actions of capsaicin. Oleamide also caused relaxation of the rat perfused whole mesenteric arterial bed. This response was diminished by a depolarising concentration of extracellular K+, implicating the involvement of K+ channels.

Capsaicin evoked relaxation of both rat aortae and porcine coronary arteries. The vasorelaxant effect of capsaicin was insensitive to capsaicin pre-treatment and the presence of capsazepine, a TRPV1 antagonist. It was also found that the presence of capsaicin inhibited the uptake of Ca2+ in depolarised porcine coronary arteries and rat aortae on reintroduction of calcium. In porcine coronaries, capsaicin abolished the contractile response to Bay-K 8644, a L-type calcium channel activator. Therefore, it is proposed that capsaicin inhibits L-type calcium channels to drive vasorelaxation, demonstrating a TRPV1-independent mechanism of action for capsaicin.

Having described the vasorelaxation of Wistar aortae, the effects of hypertension on the vascular actions of oleamide were determined. Oleamide-induced vasorelaxation was significantly enhanced in aortae from spontaneously hypertensive rats (SHR) compared to those from normotensive Wistar Kyoto (WKY) controls. Oleamide caused approximately 40% relaxation of the SHR aorta compared to 15% in the WKY isolated aorta. Similarly, responses to anandamide were also increased in aortae from hypertension causing 30% relaxation compared to 10% in arteries from normotensive controls. Augmented vasorelaxation to oleamide and anandamide was opposed by pre-treatment of vessels with capsaicin, an effect independent of TRPV1 receptors. Inhibition of cyclooxygenase with indomethacin potentiated responses to oleamide in WKY aortae to a level comparable to responses in SHR aortae. Thus, this thesis suggests that changes in the cyclooxygenase pathway are important in regulating responses to oleamide in hypertension and may represent an adaptive change in the early stages of established hypertension in SHR rats.

In summary, this study provides further evidence of the vasorelaxant nature of oleamide, which can be enhanced in arteries from hypertension. Augmented responses in hypertension may relate to alterations in the cyclooxygenase pathway during the early stages of established hypertension in the SHR. This investigation also documents the capsaicin-sensitive nature of oleamide responses in aortic rings, which exists independently of sensory-nerve mediated activity. The observation of a non-TRPV1 capsaicin-sensitive mechanism may ultimately lead to the uncovering of an alternative mechanism of action for capsaicin in conduit arteries and a novel site of action for oleamide.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Randall, M.D. Dunn, W.R.
Subjects:	QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Biomedical Sciences UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	13132
Depositing User:	EP, Services
Date Deposited:	05 Nov 2013 12:00
Last Modified:	20 Dec 2017 20:51
URI:	https://eprints.nottingham.ac.uk/id/eprint/13132

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