In the last thirty years,it became over whelmingly apparent that the endothelium releases relaxing factors(EDRF),which diffuse to the underlying vascular smooth muscle cells and elicit endothelium-dependent vasodilata...In the last thirty years,it became over whelmingly apparent that the endothelium releases relaxing factors(EDRF),which diffuse to the underlying vascular smooth muscle cells and elicit endothelium-dependent vasodilatations.The best characterized EDRF is nitric oxide(NO)formed by endothelial NO synthase(e NOS).In the vascular smooth muscle cells,NO stimulates soluble guanylate cyclase which normally produces cyclic GMP.NO release by e NOS can be augmented by increases in shear stress or by activation of endothelial cell membrane receptors(e.g.in response toα2-adrenergic agonists,serotonin,vasopressin,adenosine diphosphate and bradykinin).The ability of the endothelial cell to release NO can be up-regulated by estrogens,repeated increases in blood flow,exercise,diet(ω3-unsaturated fatty acids,polyphenols),and down-regulated by oxidative stress and increased presence of oxidized low density lipoproteins(LDL).The bioavailability of NO is curtailed by aging,smoking,environmental pollution or obesity and in hypertension and diabetes.In addition to lesser direct relaxation of the underlying vascular smooth muscle,a decreased release of NO also permits the production of vasoconstrictor prostanoids and/or endothelin-1.Blunted endothelium-dependent relaxations can also be due to unresponsiveness of the vascular smooth muscle to NO.Finally,in coronary arteries,hypoxia and certain quinonescause acute augmentations of vasoconstrictor responses that depend on the presence of NO and the biased activation of soluble guanylate cyclase which produces cyclic IMP rather than cyclic GMP.Since hypoxia is implicated in exaggerated vasoconstrictions observed in coronary artery disease,the emerging role of this non-canonical cyclic nucleotide may help identifying novel therapeutic targets.展开更多
The natural compound thymoquinone, extracted from Nigella sativa(black cumin), is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endotheliumindependent vasodilator effects...The natural compound thymoquinone, extracted from Nigella sativa(black cumin), is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endotheliumindependent vasodilator effects in isolated rat aortae and pulmonary arteries, depending in part on activation of adenosine triphosphate-sensitive potassium channels and inhibition of voltage-dependent calcium channels. The compound also improves endothelial dysfunction in mesenteric arteries of ageing rodents and in aortae of rabbits treated with pyrogallol, by inhibiting oxidative stress. Serendipitously,thymoquinone was found to augment contractions in isolated arteries with endothelium of both rats and pigs. The endothelium-dependent augmentation it causes counterintuitively depends on biased activation of soluble guanylyl cyclase(sGC) producing inosine 3',5'-cyclic monophosphate(cyclic IMP) rather than guanosine 3',5'-cyclic monophosphate. This phenomenon shows a striking mechanistic similarity to the hypoxic augmentation previously observed in porcine coronary arteries. The cyclic IMP preferentially produced under thymoquinone exposure causes an increased contractility of arterial smooth muscle by interfering with calcium homeostasis. This brief review summarizes the vascular pharmacology of thymoquinone, focussing in particular on how the compound causes endothelium-dependent contractions by biasing the activity of sGC.展开更多
Hypoxia,or the lack of oxygen,has multiple impacts on the vascular system.The major molecular sensors for hypoxia at the cellular level are hypoxia inducible factor and heme oxygenase.Hypoxia also acts on the vasculat...Hypoxia,or the lack of oxygen,has multiple impacts on the vascular system.The major molecular sensors for hypoxia at the cellular level are hypoxia inducible factor and heme oxygenase.Hypoxia also acts on the vasculature directly conveying its damaging effects through disruption of the control of vascular tone,particularly in the coronary circulation,enhancement of inflammatory responses and activation of coagulation pathways.These effects could be particularly detrimental under pathological conditions such as obstructive sleep apnea and other breathing disorders.展开更多
文摘In the last thirty years,it became over whelmingly apparent that the endothelium releases relaxing factors(EDRF),which diffuse to the underlying vascular smooth muscle cells and elicit endothelium-dependent vasodilatations.The best characterized EDRF is nitric oxide(NO)formed by endothelial NO synthase(e NOS).In the vascular smooth muscle cells,NO stimulates soluble guanylate cyclase which normally produces cyclic GMP.NO release by e NOS can be augmented by increases in shear stress or by activation of endothelial cell membrane receptors(e.g.in response toα2-adrenergic agonists,serotonin,vasopressin,adenosine diphosphate and bradykinin).The ability of the endothelial cell to release NO can be up-regulated by estrogens,repeated increases in blood flow,exercise,diet(ω3-unsaturated fatty acids,polyphenols),and down-regulated by oxidative stress and increased presence of oxidized low density lipoproteins(LDL).The bioavailability of NO is curtailed by aging,smoking,environmental pollution or obesity and in hypertension and diabetes.In addition to lesser direct relaxation of the underlying vascular smooth muscle,a decreased release of NO also permits the production of vasoconstrictor prostanoids and/or endothelin-1.Blunted endothelium-dependent relaxations can also be due to unresponsiveness of the vascular smooth muscle to NO.Finally,in coronary arteries,hypoxia and certain quinonescause acute augmentations of vasoconstrictor responses that depend on the presence of NO and the biased activation of soluble guanylate cyclase which produces cyclic IMP rather than cyclic GMP.Since hypoxia is implicated in exaggerated vasoconstrictions observed in coronary artery disease,the emerging role of this non-canonical cyclic nucleotide may help identifying novel therapeutic targets.
基金support from the General Research Fund(17112914)of the Hong Kong Research Grant Councilthe Seed Funding Programme for Basic Research by University Research Committee of the University of Hong Kong(201511159163)
文摘The natural compound thymoquinone, extracted from Nigella sativa(black cumin), is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endotheliumindependent vasodilator effects in isolated rat aortae and pulmonary arteries, depending in part on activation of adenosine triphosphate-sensitive potassium channels and inhibition of voltage-dependent calcium channels. The compound also improves endothelial dysfunction in mesenteric arteries of ageing rodents and in aortae of rabbits treated with pyrogallol, by inhibiting oxidative stress. Serendipitously,thymoquinone was found to augment contractions in isolated arteries with endothelium of both rats and pigs. The endothelium-dependent augmentation it causes counterintuitively depends on biased activation of soluble guanylyl cyclase(sGC) producing inosine 3',5'-cyclic monophosphate(cyclic IMP) rather than guanosine 3',5'-cyclic monophosphate. This phenomenon shows a striking mechanistic similarity to the hypoxic augmentation previously observed in porcine coronary arteries. The cyclic IMP preferentially produced under thymoquinone exposure causes an increased contractility of arterial smooth muscle by interfering with calcium homeostasis. This brief review summarizes the vascular pharmacology of thymoquinone, focussing in particular on how the compound causes endothelium-dependent contractions by biasing the activity of sGC.
基金The current research is supported by the Hong Kong Research Grant Council(University of Hong Kong,No.780410M)by the Research Centre of Heart,Brain,Hormone and Healthy Aging of the University of Hong Kongby the World Class University program(R31-20029)funded by the Ministry of Education,Science and Technology,South Korea.
文摘Hypoxia,or the lack of oxygen,has multiple impacts on the vascular system.The major molecular sensors for hypoxia at the cellular level are hypoxia inducible factor and heme oxygenase.Hypoxia also acts on the vasculature directly conveying its damaging effects through disruption of the control of vascular tone,particularly in the coronary circulation,enhancement of inflammatory responses and activation of coagulation pathways.These effects could be particularly detrimental under pathological conditions such as obstructive sleep apnea and other breathing disorders.
