Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glaucoma, the third leading cause of blindness in the western world, is characterized by painless, gradual loss of visual fields which may lead to severe visual impairment or even blindness. In 4 years of operation of a mobile glaucoma unit for screening and early diagnosis of glaucoma, 10,037 subjects aged 18-95 years were screened (4504 women, 45%); 55% were under 50 years (Graph 1). Ocular hypertension was diagnosed in 8.0%; primary open angle glaucoma (POAG) in 0.8%, with 2/3 already under treatment, the rest newly diagnosed. Pseudo-exfoliative glaucoma was diagnosed in 0.2%; only 2 cases had closed angle glaucoma; 91% of those screened were normal (Fig. 4; age stratification, Graph 3). POAG increased with age, from 0.2% in those under 40 years to 10% in those over 80; POAG was more common in men, but OHT was similar in both sexes (6.0% vs. 5.3%). There was no correlation between incidence of POAG and place of work except in the Sorek Nuclear Center (1.9% vs. 0.8%, p = 0.11). Other conditions significantly more frequent in POAG than normals were diabetes mellitus (x 2.5), systemic hypertension (x 4), myopia (x 2) and history of intraocular surgery (x 6).
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PMID:[Early detection of glaucoma by a mobile unit--results from 10,000 examinees]. 1088 8

Vasopressin (AVP) is a cyclic nonapeptide hormone that exhibits many physiological effects including free water reabsorption, vasoconstriction, cellular proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a healthy organism, AVP plays an important role in the homeostasis of fluid osmolality and volume status. However, in several diseases or conditions such as the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhoea and ocular hypertension, AVP may play an important role in their pathophysiology. Recently, orally-active non-peptide AVP receptor antagonists were developed by random screening of chemical entities and optimisation of lead compounds. These include agents specific for the V(1)-vascular and V(2)-renal AVP receptor subtypes. Dual V(1)/V(2) AVP receptor antagonists are also being studied. Some of these non-peptide receptor antagonists have been studied extensively, while others are currently under investigation. Potential therapeutic indications for AVP receptor antagonists comprise: 1) The blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure, Raynaud's syndrome, peripheral vascular disease and dysmenorrhea. 2) The blockade of V(2)-renal AVP receptors in the syndrome of inappropriate secretion of vasopressin, congestive hart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatraemia. 3) The blockade of V(3)-pituitary AVP receptors in ACTH-secreting tumours. This review examines the pharmacology of orally-active non-peptide AVP receptor antagonists and their clinical applications.
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PMID:Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists. 1132 60

AVP receptors represent a logical target for drug development. As a new class of therapeutic agents, orally active AVP analogs could be used to treat several human pathophysiological conditions including neurogenic diabetes insipidus, the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhea, and ocular hypertension. By immunoprecipitation and immunoblotting, we elucidated the phosphorylation pattern of green fluorescent protein-tagged AVP receptors and showed interactions with the specific kinases PKC and GRK5 that are agonist-, time- and receptor subtype-dependent. The tyrosine residue of the NPWIY motif present in the 7th helix of AVP receptors is rapidly and transiently phosphorylated after agonist stimulation. This phosphorylation is instrumental in the genesis of the mitogenic cascade linked to the activation of this receptor, presumably by establishing key intramolecular contacts and by participating in the creation of a scaffold of proteins that produce the activation of downstream kinases. The random screening of chemical entities and optimization of lead compounds recently resulted in the development of orally active non-peptide AVP receptor agonists and antagonists. Furthermore, the identification of the molecular determinants of receptor-ligand interactions should facilitate the development of more potent and very selective orally active compounds via the approach of structure-based drug design. We developed three-dimensional molecular docking models of peptide and non-peptide ligands to the human V1 vascular, V2 renal and V3 pituitary AVP receptors. Docking of the peptide hormone AVP to the receptor ligand binding pockets reflects its dual polar and non-polar structure, but is receptor subtype-specific. The characteristics of non-peptide AVP analogs docking to the receptors are clearly distinct from those of peptide analogs docking. Molecular modeling of the results of site-directed mutagenesis experiments performed in CHO cells stably transfected with the human AVP receptor subtypes revealed that non-peptide antagonists establish key contacts with a few amino acid residues of the receptor subtypes that are different from those involved in agonist binding. Moreover, these interactions are species-specific. These findings provide further understanding of the signal transduction pathways of AVP receptors and new leads for elucidation of drug-receptor interactions and optimization of drug design. NOTE TO THE READER: The recent cloning and molecular characterization of AVP/OT receptor subtypes call for the revision of their nomenclature. For the sake of clarity and reference to their main site of expression, we call the V1a receptor the V1 vascular receptor, the V2 receptor the V2 renal receptor and the V1b or V3 receptor the V3 pituitary receptor in the present review.
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PMID:Molecular pharmacology and modeling of vasopressin receptors. 1243 35

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.
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PMID:Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. 1243 36

The differential diagnosis of acute loss of vision in children includes acute loss of vision due to retinal or optic nerve disease, and cortical blindness. The retinal disorders which may be mis diagnosed as optic neuritis include Leber neuroretinitis, Leber hereditary optic neuropathy, and Stargardt macular dystrophy. Retinal changes which evolve in neuroretinitis, and the pseudopapilledema in Leber heredity optic neuropathy are helpful in differentiating these disorders from optic neuritis. Stargardt macular dystrophy, a disorder associated with a variety of mutations, may be mis diagnosed as psychogenic visual loss due to the early normal appearance of the retina, and the loss of vision over a period of weeks. The differentiation of optic neuritis from anterior ischemic optic neuropathy (AION), depends upon the initial appearance of the optic disc (in AION either hyperemia due to reperfusion, or swelling and pallor if total infarction has occurred). The authors have described children with abrupt loss of vision during renal dialysis, whose risk factors for AION included systemic hypotension and intra ocular hypertension. Children with vigorous treatment of accelerated hypertension, and children with migraine and pro thrombotic disorders have also incurred AION. Thus, AION should be suspected when acute loss of vision occurs in association with certain ocular and systemic risk factors. In children capable of cooperating for visual field examination, the typical change in AION is an altitudinal defect, while optic neuritis it is a central scotoma. The association of optic neuritis with multiple sclerosis, DeVic disease, and with acute demyelinating1 encephalomyelitis require special consideration in regard to treatment and prognosis. Acute loss of vision due to cerebral cortical insults involves a large differential diagnosis which includes vascular, metabolic and infective disease; as well as disorders causing transitory blindness such as seizures and migraine
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PMID:[Acute loss of vision in children]. 1259 57

Glaucoma is an optic neuropathy in which retinal ganglion cells die probably through an apoptotic process. Apoptosis is known to involve free radicals in several systems including the retina. In this context, the aim of the present work was to analyze retinal oxidative damage in rats with glaucoma induced by the chronic injection of hyaluronic acid in the eye anterior chamber. The results showed a significant decrease in total retinal superoxide dismutase and catalase activities after 6 and 3 weeks of treatment with hyaluronic acid, respectively. Also, although GPX activity increased after 10 weeks of ocular hypertension, GSH levels significantly decreased at 6 weeks of treatment with hyaluronic acid. Moreover, retinal lipid peroxidation significantly increased in a time-of-hypertension-dependent manner. On the other hand, a significant decrease in both diurnal and nocturnal retinal melatonin content was detected at 3, 6, or 10 weeks of treatment with hyaluronic acid. The present results suggest that retinal oxidative stress may be involved in glaucomatous cell death. Thus, manipulation of intracellular redox status using antioxidants may be a new therapeutic tool to prevent glaucomatous neurodegeneration.
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PMID:Retinal oxidative stress induced by high intraocular pressure. 1538 94

The retina and optic nerve are both optically accessible parts of the central nervous system. They represent, therefore, highly valuable tissues for studies of the intrinsic physiological mechanism postulated more than 100 years ago by Roy and Sherrington, by which neural activity is coupled to blood flow and metabolism. This article describes a series of animal and human studies that explored the changes in hemodynamics and oxygenation in the retina and optic nerve in response to increased neural activity, as well as the mechanisms underlying these changes. It starts with a brief review of techniques used to assess changes in neural activity, hemodynamics, metabolism and tissue concentration of various potential mediators and modulators of the coupling. We then review: (a) the characteristics of the flicker-induced hemodynamical response in different regions of the eye, starting with the optic nerve, the region predominantly studied; (b) the effect of varying the stimulus parameters, such as modulation depth, frequency, luminance, color ratio, area of stimulation, site of measurement and others, on this response; (c) data on activity-induced intrinsic reflectance and functional magnetic resonance imaging signals from the optic nerve and retina. The data undeniably demonstrate that visual stimulation is a powerful modulator of retinal and optic nerve blood flow. Exploring the relationship between vasoactivity and metabolic changes on one side and corresponding neural activity changes on the other confirms the existence of a neurovascular/neurometabolic coupling in the neural tissue of the eye fundus and reveals that the mechanism underlying this coupling is complex and multi-factorial. The importance of fully exploiting the potential of the activity-induced vascular changes in the assessment of the pathophysiology of ocular diseases motivated studies aimed at identifying potential mediators and modulators of the functional hyperemia, as well as conditions susceptible to alter this physiological response. Altered hemodynamical responses to flicker were indeed observed during a number of physiological and pharmacological interventions and in a number of clinical conditions, such as essential systemic hypertension, diabetes, ocular hypertension and early open-angle glaucoma. The article concludes with a discussion of key questions that remain to be elucidated to increase our understanding of the physiology of ocular functional hyperemia and establish the importance of assessing the neurovascular coupling in the diagnosis and management of optic nerve and retinal diseases.
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PMID:Visually evoked hemodynamical response and assessment of neurovascular coupling in the optic nerve and retina. 1561 Sep 73

Ocular hypertension (OHT) is defined as intraocular pressure (IOP) elevated above normal levels which occurs without detectable damage to the papilla or visual field. It is considered to be the most important risk factor for developing primary open-angle glaucoma (POAG). The "Ocular hypertension treatment study" (OHTS) addresses the issue of whether lowering IOC before damage to the papilla or visual field occurs can hinder their development and whether OHT can be treated categorically. This randomized, prospective, nonmasked and non-placebo-controlled, multicenter study documents the protective effect of prophylactic lowering of IOC and identifies and explains the risk factors for developing POAG. These include advancing age, reduced corneal thickness, increased pattern standard deviations in white-on-white perimetry, and elevated vertical or horizontal cup to disc ratio. Due to the large individual differences in risk distribution and the very high costs of treating OHT, the question of whether OHT should be treated on principle remains open in the OHTS. This decision must be made on an individual basis after each patient's risk has been assessed.
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PMID:[Results of the "Ocular hypertension treatment study"]. 1570 19

Glutamate-induced excitotoxicity has been proposed to mediate the death of retinal ganglion cells in glaucoma. The metabolic dependence of glutamatergic neurons upon glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. Thus, the aim of the present work was to study the retinal glutamate/glutamine activity in eyes with hypertension induced by intracameral injections of hyaluronic acid (HA). For this purpose, weekly injections of HA were performed unilaterally in the rat anterior chamber, whereas the contralateral eye was injected with saline solution. At 3 or 10 weeks of treatment, glutamate and glutamine uptake and release were assessed using [3H]-glutamate and [3H]-glutamine as radioligands, respectively. In addition, glutamine synthetase activity was assessed by a spectrophotometric assay, whereas glutaminase activity was measured through the conversion of [3H]-glutamine to [3H]-glutamate. At 3 weeks of treatment with HA, a significant decrease (P<0.01) in glutamate uptake and glutamine synthetase activity was observed. Glutamine uptake and release, as well as glutaminase activity, were significantly increased (P<0.01) in eyes injected with HA for 3 weeks compared with vehicle-injected eyes, whereas [3H]-glutamate release did not change in hypertensive eyes. Only the changes in glutamine synthetase activity persisted at 10 weeks of treatment with HA. These results indicate a significant alteration in the retinal glutamate/glutamine cycle activity in hypertensive eyes. Since these changes preceded both functional and histological alterations induced by ocular hypertension, these results support the involvement of glutamate in glaucomatous neuropathy.
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PMID:Effect of glaucoma on the retinal glutamate/glutamine cycle activity. 1587 62

In cases of high intraocular pressure, the patient's hypertension must first be confirmed and its characteristics delineated with a diurnal IOP curve or at least several different measures. Central corneal thickness should be measured, since a thin cornea is a risk factor of progression toward glaucomatous neuropathy. Later, the optic nerve head and retinal nerve fibers should be tested (HRT, GDx, and OCT), to determine whether the ocular hypertension is associated with other findings, and visual field analysis should be carried out (standard automated perimetry, blue-yellow perimetry, FDT), completed by a search for associated risk factors. Therapeutic decisions will be based on this workup, keeping in mind that in the majority of cases, monitoring and information are sufficient but necessary; treatment should, however, be initiated in cases of ocular hypertension with a high risk of progression.
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PMID:[Practical assessment. Ocular hypertension]. 1620 35


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