Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed cerebral arterial spasm was induced by subarachnoid hemorrhage in 11 rhesus monkeys. Ten monkeys (62%) developed spasm. Of seven monkeys treated with salbutamol (a beta2-adrenergic stimulating drug), five had relief of vasospasm. Four monkeys, one of which had failed to respond to salbutamol alone, were treated with salbutamol and aminophylline (a phosphodiesterase-inhibiting drug), and all four were relieved of their vasospasm. When considered as one group, the monkeys had an 81% response rate. The authors suggest that a combination of beta2-adrenergic stimulation and phosphodiesterase-inhibition might be of value in preventing or treating delayed cerebral arterial pressure.
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PMID:Treatment of experiment delayed cerebral arterial spasm with a beta2-adrenergic stimulator and a phosphodiesterase inhibitor. 82 7

This paper describes the methods of prevention of delayed neurological deficit (DND) in patients with subarachnoid haemorrhage (SAH) due to ruptured intracranial aneurysm. To prevent the decrease in the cerebral flow, vasodilators, inhibitors of platelet aggregation and synthesis of endogenous prostaglandins, stimulators of prostacyclin synthesis of its analogue should be applied. It is also recommended to use the inhibitors of phosphodiesterase, blockers of serotonin and of calcium channel (particularly nimodipine). Therapy with the immunosuppressive drugs helps to prevent DND. With all those therapeutical methods DND is still a serious complication following SAH.
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PMID:[Management of intracranial vasospasm in rupture of cerebral aneurysm]. 181 Nov 86

We examined vascular reactivity to various vasoconstrictors and dilators, and the changes in calcium-calmodulin levels in canine basilar arteries after subarachnoid hemorrhage (SAH). Contractile responses to noradrenaline, serotonin, and potassium chloride were markedly attenuated at 48 hours (P less than 0.05), and further attenuated at 7 and 14 days after SAH (P less than 0.01). Dilation responses to calcium antagonist were maintained at 48 hours after SAH, but were markedly reduced at 7 and 14 days after SAH (P less than 0.05). Transmission electron micrographs of the basilar artery showed contraction of the media between 48 hours and 7 days and degeneration of smooth muscle cells over the 7 days after SAH. Electron microscopic cytochemical examination for calcium showed that intracellular deposits of calcium pyroantimonate increased in smooth muscle cells of basilar arteries at 1 hour after the first intracisternal injection of blood (early spasm), but decreased in smooth muscle cells at 48 hours after SAH (at the beginning of delayed vasospasm). They decreased further in the vessels 7 days after SAH. The calmodulin contents in the basilar arteries were decreased slightly at 6 hours, and significantly (P less than 0.05) at 48 hours after SAH, as determined by radioimmunoassay and phosphodiesterase assay. Therefore, it is considered that delayed vasospasm is not simply an active contraction of the vessels, but a functional or structural derangement of contractile elements of smooth muscle cells after 48 hours after SAH.
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PMID:Impairement of vascular reactivity and changes in intracellular calcium and calmodulin levels of smooth muscle cells in canine basilar arteries after subarachnoid hemorrhage. 258 28

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50S < 150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50S = 4.5 microM and > 10 microM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.
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PMID:Identification, characterization, and functional role of phosphodiesterase type IV in cerebral vessels: effects of selective phosphodiesterase inhibitors. 904 May 1

Subarachnoid hemorrhage (SAH) is associated with impaired nitric oxide (NO)-mediated cerebral vasodilatation. We tested the hypothesis that SAH causes alterations in the production of, hydrolysis of, or responsiveness to cGMP in the rat basilar artery in vivo. Rats were injected with saline or autologous blood into the cisterna magna. Two days later, effects of vasoactive drugs on basilar artery diameter were examined using a cranial window preparation. Vasodilator responses to ACh, sodium nitroprusside (SNP), and low concentrations (</=10(-5) M) of zaprinast, an inhibitor of phosphodiesterase V (PDE V), were impaired in SAH rats (P < 0.05). In contrast, vasodilator responses to adenosine and 8-BrcGMP were similar in control and SAH rats. Vasoconstrictor responses to 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, were unaffected by SAH. In the presence of zaprinast (10(-5)-10(-4) M), responses to ACh and SNP were equivalent in control and SAH rats. Thus an increased rate of cGMP hydrolysis by PDE V may be a major factor contributing to the impairment of NO-mediated cerebral vasodilatation after SAH.
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PMID:Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. 1056 24

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

Cyclic GMP (cGMP) mediates smooth muscle relaxation in the central nervous system. In subarachnoid hemorrhage (SAH), decreases in intrinsic nitric oxide (NO) cause cerebral vasospasms due to the regulation of cGMP formation by NO-mediated pathways. As phosphodiesterase type V (PDE V) selectively hydrolyzes cGMP, we hypothesized that PDE V may function in the initiation of vasospasm. This study sought to identify the altered PDE V expression and activity in the vasospastic artery in a canine SAH model. We also used this system to examine possible therapeutic strategies to prevent vasospasm. Using a canine model of SAH, we induced cerebral vasospasm in the basilar artery (BA). Following angiographic confirmation of vasospasm on day 7, PDE V expression was immunohistochemically identified in smooth muscle cells of the vasospastic BA but not in cells of a control artery. The isolation of PDE enzymes using a sepharose column confirmed increased PDE V activity in the vasospastic artery only through both inhibition studies, using the highly selective PDE V inhibitor, sildenafil citrate, and Western blotting. Preliminary in vivo experiment using an oral PDE V inhibitor at 0.83 mg kg(-1) demonstrated partial relaxation of the spastic BA. PDE V activity was increased from control levels within the BA seven days after SAH. PDE V expression was most prominent in smooth muscle cells following SAH. These results suggest that clinical administration of a PDE V inhibitor may be a useful therapeutic tool in the prevention of vasospasm following SAH.
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PMID:Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model. 1223 30

Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 +/- 5.7% after cilostazol and 5.5 +/- 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 +/- 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 +/- 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.
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PMID:The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow. 1562 9

Nitric oxide (NO) is produced by the endothelial NOS (eNOS) in the intima and by the neuronal NOS (nNOS) in the adventitia of cerebral vessels. By activating soluble guanylyl cyclase, NO increases the production of 3'-5'cGMP, which relaxes smooth muscle cells and dilates the arteries in response to shear stress, metabolic demands and changes of pCO(2) (chemoregulation). 3'-5'cGMP is then metabolized by phosphodiesterases (PDEs). Aneurysmal subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow (CBF). Oxyhemoglobin, gradually released from the subarachnoid clot enveloping the conductive arteries, scavenges NO and destroys nNOS-containing neurons. This deprives the arteries of NO, leading to vasoconstriction which initiates delayed vasospasm. This arterial narrowing increases shear stress and stimulates eNOS, which under normal conditions would lead to increased production of NO and dilation of arteries. However, this does not occur because of transient eNOS dysfunction evoked by increased levels of an endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). Increased ADMA levels result from decreased elimination due to inhibition of the ADMA-hydrolyzing enzyme (DDAH 2) in arteries in spasm by hemoglobin metabolites, bilirubin-oxidized fragments (BOXes). This eNOS dysfunction sustains vasospasm until ADMA levels decrease and NO release from endothelial cells increases. This NO-based pathophysiological mechanism of vasospasm suggests that exogenous delivery of NO, modification of PDE activity, inhibition of the L-arginine-methylating enzyme (I PRMT 3) or stimulation of DDAH 2 may provide new therapies to prevent and treat vasospasm. This paper summarizes experimental and early clinical data that are consistent with the involvement of NO in delayed cerebral vasospasm after SAH and which suggests new therapeutic possibilities.
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PMID:Analysis of nitric oxide (NO) in cerebral vasospasm after aneursymal bleeding. 1847 89

Sildenafil, a phosphodiesterase-5 inhibitor commonly used for erectile dysfunction, may also have a beneficial therapeutic effect in the treatment of stroke, subarachnoid hemorrhage, dementia, learning, and neurodegenerative disorders by enhancing angiogenesis and neurogenesis. It also favorably influences the nitric oxide-cyclic guanosine monophosphate pathways, which are involved in the pathogenesis of a number of neurological diseases. Its potential therapeutic role in the treatment of the neurological disorders mentioned above is still under preclinical investigation. Sildenafil is currently being used to treat erectile dysfunction in patients with multiple sclerosis, Parkinson disease, multisystem atrophy, and spinal cord injury by improving their neurologically related erectile dysfunction. Conversely, it has been implicated in a number of neurological problems, such as intracerebral hemorrhage, migraine, seizure, transient global amnesia, nonarteritic anterior ischemic optic neuropathy, macular degeneration, branch retinal artery occlusion, and ocular muscle palsies. Thus, preclinical and very limited clinical data suggest that sildenafil may have therapeutic potential in selected neurological disorders. However, numerous reports are available regarding neurological adverse events ascribed to the drug. Although sildenafil shows some promise as a therapeutic agent in selected neurological disorders, well-designed clinical trials are needed before the agent can be recommended for use in any neurological disorder.
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PMID:Role of sildenafil in neurological disorders. 1905 Apr 13


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