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)

Endothelin (ET) receptor antagonists have been proposed for the treatment of a variety of disorders where ET may act as a pathogenic mediator. The rationale is very strong in certain diseases, where ET concentrations are increased and where ET receptor antagonists have shown efficacy in experimental conditions. However, clinical studies are needed to prove that this approach is effective in the clinical setting. Because there are still very few ET receptor antagonists in clinical development, proof of concept studies in clinical situations have been performed only in a small number of indications. We describe here the preclinical and clinical results obtained with the first orally active ET receptor antagonist in three therapeutic fields, congestive heart failure, systemic hypertension and cerebral vasospasm. The encouraging clinical results obtained support a further clinical development of ET receptor antagonists in these three indications.
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PMID:Endothelin receptor antagonists: current status and perspectives. 1097 85

Gene transfer to blood vessels is remarkably effective in altering vasomotor function, and has proven to be a useful tool for studying vascular biology. Gene therapy for cardiovascular diseases is an attractive new approach, which will be used initially for diseases in which pharmacologic approaches are not effective. Preliminary data suggest that two possible targets for gene therapy are prevention of cerebral vasospasm after subarachnoid hemorrhage and treatment of pulmonary hypertension. Perhaps, as better vectors are developed, common clinical problems such as hypertension and hypercholesterolemia also may become targets for gene therapy.
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PMID:Gene transfer to blood vessels: a research tool and potential therapy. 1141 62

Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.
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PMID:Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications. 1205 51

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as hypertension, congestive heart failure, and cerebral vasospasm. Bosentan is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). Bosentan has recently moved into Phase III clinical trial. This review will attempt to overview the experimental and clinical effects of bosentan.
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PMID:Endothelin antagonism with bosentan: current status and future perspectives. 1207 May 30

Cerebral vasospasm and related ischemic stroke continue to be significant complicating factors in the course of many patients with subarachnoid hemorrhage from berry aneurysm rupture. The risk of this well-recognized but poorly understood complication can be estimated on the basis of patient medical history, neurologic examination, and head CT findings. Every patient with possible risk needs specialized neurologic intensive care unit care after aneurysm obliteration. Surgical and pharmacologic wash-out of subarachnoid blood around the basal arteries, proper management of intracranial pressure and fluid status, hyponatremia, hypomagnesemia, and fever, as well as use of calcium channel blockers, have been considered helpful in patient management prior to and with the symptomatic vasospasm development. Transcranial Doppler (TCD) ultrasound is important in detecting vasospasm before the patient suffers ischemic neurologic deficit or infarct. Elevated TCD velocities often initiate the use of triple-H (HHH: hypertension, hemodilution, and hypervolemia) therapy and subsequently guide it. Up to the end of the first 3 weeks after subarachnoid hemorrhage and aneurysm obliteration, development of any focal neurologic deficit or mental deterioration, unless convincingly proven otherwise, is assumed to be from cerebral vasospasm. When a hemodynamically significant vasospasm in the arterial segments of clinical concern is suggested, emergency cerebral angiography with balloon dilatation angioplasty or intra-arterial infusion of vasodilating agents may be helpful in relieving ischemic symptoms.
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PMID:Cerebral Vasospasm Following Subarachnoid Hemorrhage. 1219 10

Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
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PMID:Nitric oxide synthase gene therapy for cardiovascular disease. 1223 10

We describe a case of massive hemorrhage in the cerebral ventricles, probably caused by methamphetamine abuse. A 44-year-old male was found dead in a prone position in a hotel room. Old and new injection marks were observed in his right cubital fossa. Petechiae were observed on the conjunctiva of his right eye, laryngeal mucosa, epicardium and under the capsule of the liver (to a slight or moderate degree). The brain, weighing 1.67 kg, was heavily edematous; the lateral and fourth ventricles were filled with hematomas. Subarachnoid, intracerebral hemorrhages were not observed. Cerebral vascular abnormalities were not evident. There were no remarkable changes in other organs, other than congestion. Gas chromatographic-mass spectrometric analysis of the urine disclosed the presence of methamphetamine and amphetamine. The concentration of methamphetamine within the femoral venous blood and intraventricular hematoma was 0.347 microg/ml and 0.189 microg/g, respectively. Amphetamine was not detected in either sample. Urine contained 3.15 microg/ml methamphetamine and 0.063 microg/ml amphetamine. These results indicate that intraventricular hemorrhage might have occurred shortly after intravenous self-administration of methamphetamine. Cerebral arterial spasm and hypertension resulting from the administration of methamphetamine might have resulted in intraventricular hemorrhage.
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PMID:A case of fatal hemorrhage in the cerebral ventricles following intravenous use of methamphetamine. 1224 78

Cerebral vasospasm is a recognised but poorly understood complication for many patients who have aneurysmal subarachnoid haemorrhage and can lead to delayed ischaemic neurological deficit (stroke). Morbidity and mortality rates for vasospasm are high despite improvements in management. Since the middle of the 1970s, much has been written about the treatment of cerebral vasospasm. Hypervolaemia, hypertension, and haemodilution (triple-H) therapy in an intensive-care setting has been shown in some studies to improve outcome and is an accepted means of treatment, although a randomised controlled trial has never been undertaken. In this review, the rationale for this approach will be discussed, alongside new thoughts and future prospects for the management of this complex disorder.
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PMID:Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. 1450 83

Endothelin (ET)-mediated vasoconstriction has been implicated in the pathophysiology of various disorders, e.g. hypertension, chronic heart failure, acute renal failure, pulmonary hypertension, and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. The potential involvement of ETs in cerebral vasospasm following SAH has triggered considerable interest in designing therapeutic strategies to inhibit biological effects of ET. Major approaches include: (a) reducing the levels of circulating ET- 1 by the the specific anti- ET- 1 antibodies, (b) antagonizing the ET receptors, and (c) suppressing the biosynthesis of ET-1. To date, numerous antagonists of ET(A) and/or ET(B) receptors have been discovered, and some are under clinical evaluation. Inhibitors of endothelin-converting enzymes (ECEs), which catalyze the biosynthesis of ET-1, have also been synthesized. Two types of ECE-1 inhibitors have been evaluated in various animal disease models: dual ECE-1/neutral endopeptidase 24.11 (NEP) inhibitors and selective ECE-1 inhibitors. In this article, the effects of ET receptor antagonists and ECE-1 inhibitors on the prevention and reversal of SAH-induced cerebral vasospasm in preclinical animal models are reviewed.
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PMID:Endothelin and subarachnoid hemorrhage-induced cerebral vasospasm: pathogenesis and treatment. 1527 81

A large body of evidence suggests a substantial role of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Recently bosentan, an ET receptor antagonist, has received approval by the Food and Drug Administration (FDA) for use in pulmonary artery hypertension. The ET system may also be involved in cerebrovascular disorders such as stroke and, most notably, development of cerebral vasospasm following subarachnoid hemorrhage. The pathophysiological mechanisms contributing to the development of a cerebral vasospasm after subarachnoid hemorrhage may be taken as a paradigm to explore mechanisms leading to secondary ischemic brain damages in a variety of insults such as stroke and trauma. The present review provides the evidence to evaluate ET receptor antagonists for potential prophylactic and therapeutic use in patients suffering from subarachnoid hemorrhage. The rationale to develop selective ETA receptor antagonists is given with respect to basic and applied studies. This may be useful to better define the desired profile of action of a given compound, and it may also help to design appropriate preclinical and clinical trials, most desirably in close cooperation with pharmaceutical companies and neurosurgical departments.
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PMID:Experimental approaches to evaluate endothelin-A receptor antagonists. 1531 6


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