Circulating endocannabinoids during hematopoietic stem cell transplantation: A pilot study

AbstractObjectiveHematopoietic stem cell transplantation (HCT) is a stressful and rigorous medical procedure involving significant emotional and immune challenges. The endocannabinoid (eCB) signaling system is involved in regulation of both the immune system and emotional reactivity, yet little is known about its function during HCT. We investigated the role of the eCB signaling system in a group of HCT recipients.MethodsA total of 19 HCT recipients were enrolled and provided psychosocial data and blood samples at three peri-transplant time points: prior to transplant, hospital discharge, and approximately 100 days post-transplant. Psychosocial factors, inflammatory molecules, and the eCBs were determined and assessed for changes over this period and association with each other.ResultsHCT recipients demonstrated significant changes over the peri-transplant period in inflammatory molecules and psychosocial functioning, but not in circulating concentrations of the eCBs. Associations among these variables were most likely to be present pre-transplant and least likely to be present immediately post-transplant, with depressive symptoms and inflammation most significantly associated. The eCB 2-arachidonoylglycerol (2-AG) was significantly, positively associated with both interleukin (IL)-6 and C-reactive protein (CRP) and negatively associated with depressive symptoms.ConclusionsThe eCB signaling system may have alternative sources and regulatory mechanisms in addition to the immune system. Given the significant associations with inflammatory molecules and depressive symptoms in the peri-transplant period, it is important to better understand this system and its potential implications in the setting of complex and stressful medical procedures such as HCT

Cannabinoidergic regulation of functional state of heart (part I)

Установлено, что у наркотизированных животных каннабиноиды вызывают продолжительную гипотензию и брадикардию, которые являются следствием стимуляции СВ1-рецепторов. Эндогенные каннабиноиды не участвуют в регуляции частоты сердечных сокращений и артериального давления у интактных животных. Исследования, выполненные на больных ишемической болезнью сердца, показали, что марихуана может провоцировать приступ стенокардии. Установлено, что каннабиноиды вызывают продолжительную гипотензию и брадикардию, которым могут предшествовать транзиторная тахикардия и гипертензия, связанные с активацией ваниллоидных TRPV1 рецепторов. Продолжительная гипотензия - результат прямого действия каннабиноидов на артерии

Untersuchungen zur entzündungshemmenden Wirkung von Cannabis sativa L.- Extrakten im Modell der Gewebekulturen

In this study, which is a part of a project of the European Union, the anti-inflammatory effects of extracts of Cannabis sativa L. with a very low content of THC, were examined. Three varying extracts of cannabis were studied by the use of different cell models (microglia, chondrocytes, SK-N-H cells and monocytes) and their effects were analysed by enzymes immuno assay, enzyme linked immunosorbent assay and western blot. The proteins of interest were prostaglandin E2, cyclooxygenase- 2 and the cytokines interleukin-1β, interleukin-6 and tumornecrosisfactor-α. For the first time standardized plant extracts with very low THC content (below 0.3%) were tested on their anti-inflammatory effects

Vascular actions of oleamide in health and disease

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

Vascular actions of oleamide in health and disease

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