Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. When a cerebral aneurysm ruptures, bleeding and clot formation occur around the surface of the brain, including several major blood vessels. The resulting condition, known as subarachnoid haemorrhage (SAH), often results in death or severe disability and is a significant cause of stroke. Delayed cerebral vasospasm and impaired vasodilatation are critical clinical complications that occur after SAH. Mechanisms contributing to the development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. The present short review briefly decribes recent advances in our knowledge of two relatively novel aspects of the mechanism(s) underlying the vascular abnormalities following SAH. 2. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of nitric oxide (NO). Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be particularly effective for dilating cerebral arteries after experimental SAH. 3. Subarachnoid haemorrhage often involves decreased responsiveness of cerebral arteries to NO. This could be due to impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels. However, an alternative explanation is that there may be an increased rate of cGMP hydrolysis by phosphodiesterase (PDE)-V in the cerebral vascular wall and that this abnormality contributes substantially to the impairment of NO-mediated cerebral vasodilatation after SAH. In support of this proposal, vasodilator responses to NO are reported to be normalized when coadministered with a PDE-V inhibitor following experimental SAH. 4. Thus, in cerebral vascular muscle after SAH, abnormalities of vasodilator mechanisms involving potassium channel function and also NO/cGMP activity may contribute to cerebral vascular dysfunction. These mechanisms may also represent useful and novel therapeutic targets for the treatment of vasospasm.
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PMID:Cerebrovascular dysfunction after subarachnoid haemorrhage: novel mechanisms and directions for therapy. 1170 98

Maintenance of vascular tone by the endothelium involves the production of endothelium-derived nitric oxide (NO). NO, produced from endothelial nitric oxide synthase diffuses to the underlying smooth muscle to stimulate soluble guanylate cyclase, resulting in increased cyclic GMP levels, and subsequent smooth muscle relaxation and blood vessel dilatation. Endothelial dysfunction, manifested as diminished NO bioavailability, is a common feature of a number of vascular-related diseases.. Oxidative stress can be defined as an imbalance between reactive oxygen species (ROS) production and/or impaired ROS metabolism that favours them being present in excess of physiological levels. Oxidative stress can negatively impact many cell types, including in the vasculature. There is now a wealth of evidence suggesting that oxidative stress is a major cause of endothelial dysfunction in the cerebral circulation. This review will summarize disease models in which both oxidative stress and endothelial dysfunction occur in the cerebral circulation, namely hypertension involving angiotensin II (Ang II), diabetes, subarachnoid hemorrhage, stroke and Alzheimer's disease. Molecular mechanisms by which oxidative stress occurs, (eg increased NADPH-oxidase activity) will also be discussed.
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PMID:Oxidative stress and endothelial dysfunction in cerebrovascular disease. 2119 59


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