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: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A high affinity binding site for 14(R),15(S)-EET, one of the major cytochrome P-450 metabolites of arachidonic acid (AA) in blood vessels, liver, kidney and urine of patients with pregnancy-induced hypertension, has been identified in a membrane preparation from guinea pig mononuclear (GPM) cells. Using a radioligand assay, binding of 14(R),15(S)-[3H]EET to its receptor site was saturable, specific and reversible. Scatchard analysis of saturation binding studies yielded a dissociation constant (Kd) of 5.7 x 10(-9) M, and maximum number of binding sites (Bmax) of 2.4 pmol/mg membrane protein. The specificity of the binding site was determined by competition studies. 14(S),15(R)-EET and 8,9-EET had a Ki of 6.3 and 8.8 nM, respectively, followed by 12(R)-HETE and LTD4. 12(S)-HETE and 5,6-EET were even less effective as a competitive inhibitor of radioligand and binding with Ki values from 2 to 20 microM. Receptor antagonists for TxA2, LTB4, LTD4 and PAF failed to displace 14(R),15(S)-[3H]EET from its binding site on GPM cell membranes. The results correlate well with the reported biological functions of 14,15-EET. In view of its potent biological activities, 14,15-EET may exert its cellular function through the binding and activation of its stereo-specific cell surface binding sites or receptor.
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PMID:14(R),15(S)-epoxyeicosatrienoic acid (14(R),15(S)-EET) receptor in guinea pig mononuclear cell membranes. 839 43

We hypothesized that 5-lipoxygenase and cyclooxygenase products might be mediators of cardiopulmonary and systemic vascular effects induced by a 4 h continuous infusion of platelet-activating factor (PAF, 10 ng/kg/min) in anesthetized pigs. Indomethacin (cyclooxygenase inhibitor) potentiated and CGS 8515 (5-lipoxygenase inhibitor) attenuated PAF-induced increases in total peripheral resistance (TPR) from 2.5 to 4 h. However, the 5-lipoxygenase inhibitor failed to modify pulmonary vasoconstriction and hypertension caused by PAF. Except for a delay in onset (approximately 44 s) and rate of development of pulmonary hypertension during the initial 10 min of PAF infusion, the pulmonary hemodynamic changes were also not attenuated by indomethacin. On the other hand, at 4 h, the PAF-induced pulmonary hypertension and systemic vasoconstriction were completely or partially reversed, respectively, by WEB 2086 (PAF receptor antagonist). The PAF-induced increases in plasma thromboxane B2 (TXB2) were blocked by indomethacin but not by CGS 8515, and at 4 h the 5-lipoxygenase inhibitor potentiated the levels of TXB2 in pigs treated with PAF. The plasma concentrations of 6-keto-PGF1 alpha and leukotriene B4 (LTB4) were not modified by PAF or CGS 8515 + PAF. We conclude that PAF-induced increases in TPR (2.5-4 h) are potentiated by indomethacin and are dependent on 5-lipoxygenase products other than LTB4. Although the early pulmonary vascular response (< 10 min) to PAF is dependent on cyclooxygenase products, the sustained response (after 10 min) cannot be explained by either 5-lipoxygenase or cyclooxygenase products but may be mediated directly by PAF receptors.
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PMID:Effect of 5-lipoxygenase and cyclooxygenase blockade on porcine hemodynamics during continuous infusion of platelet-activating factor. 841 4

1. The objective of the present study was to assess whether inhibition of nitric oxide (NO) production could modulate vascular permeability in the coronary circulation in conscious rats. 2. Intravenous injection of NG-nitro-L-arginine methyl ester (L-NAME, 2 mg kg-1) resulted in a slowly developing hypertension and evoked twofold increases in vascular permeability in the left ventricle and right atrium as measured by the extravasation of Evans blue dye. Maintenance of mean arterial blood pressure at the level observed following L-NAME injection by infusion of noradrenaline (620-820 ng kg-1 min-1) did not induce significant protein extravasation in the coronary circulation. 3. L-NAME treatment markedly enhanced (up to 490%) protein extravasation both in the left ventricle and right atrium in response to platelet-activating factor (PAF, 1.9 nmol kg-1, i.v.) and endothelin-1 (1 nmol kg-1, i.v.). Noradrenaline infusion potentiated (up to 69%) endothelin-1-induced protein extravasation. The permeability effect of PAF was only slightly enhanced by noradrenaline. 4. The present findings indicate that inhibition of endogenous NO synthesis leads to an increase in protein extravasation and to potentiation of the permeability effects of PAF and endothelin-1 in the coronary circulation. These results also suggest that NO may be an important regulator of vascular permeability under physiological and pathological conditions.
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PMID:Nitric oxide modulates vascular permeability in the rat coronary circulation. 844 83

Central autonomic dysfunctions can be due to primary (degenerative) or secondary disorders. Autonomic failure (AF) may be a major manifestation of multiple system atrophy (MSA) and idiopathic Parkinson's disease (IPD). In both MSA and IPD, AF is almost invariably associated with neuronal loss in the intermediolateral cell columns. Dysautonomia in MSA is early, severe, and progressive, including marked orthostatic hypotension and urinary incontinence and is complicated by respiratory disturbances, such as laryngeal stridor and sleep apnea. MSA/AF can be differentiated from primary (or pure) autonomic failure (PAF) without central nervous system involvement. PAF is mainly a disorder of the postganglionic neurons. In contrast to PAF, MSA/AF has preserved basal sympathetic activity, decreased cerebrospinal fluid (CSF) neurotransmitter markers, impaired vasopressin response to hypotension, and impaired adrenocorticotrophic hormone/beta endorphin response to hypoglycemia. AF in IPD is generally less severe than in MSA. Poor response to L-Dopa, abnormal urethral sphincter electromyography, and CSF markers may distinguish MSA from IPD. Secondary autonomic disorders may result from traumatic, vascular, inflammatory, demyelinating, or neoplastic lesions involving corticolimbic, hypothalamic, brainstem, or spinal autonomic network. These disorders can cause AF or autonomic hyperactivity, such as arrhythmia, hypertension, and hyperthermia. However, many disorders may only produce subclinical abnormalities.
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PMID:Central autonomic disorders. 845 95

An unresolved question of many medical nephropathies is the progression of chronic renal failure to end-stage renal insufficiency: every year many patients must be submitted to extracorporeal haemodialysis with a high cost for society. The control of so-called risk factors of progression, such as arterial hypertension, persistent proteinuria, renal infection etc. is not sufficient to prevent the progression to end-stage renal failure. The hypoproteic diet may retard this progression So currently the ability of physicians to alter the inexorable course of the disease is limited. In recent years medical research has shown that many mediators of phlogosis may play an important role in renal glomerular pathology. PAF seems to have a preeminent role. The aim of this study is to present the actual knowledge about the role played by PAF in renal physiology and pathophysiology with future perspectives on renal insufficiency progression.
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PMID:[Progression of renal insufficiency and platelet activating factor (PAF)]. 870 Mar 58

The reactivity and the structure as well as the growth of the vascular wall depend on a variety of locally synthetised factors in a process of a permanent structure-function adaptation. These substances exert their inhibitory or stimulatory growth effects by paracrine or autocrine mechanisms. These factors command the reorganisation of the structure of existing blood vessel or the creation of new vessels. They are synthetised and secreted form either endothelial and smooth muscle cells or circulating cells (in particular macrophages, platelets). The growth factors are multiple and interactive insuring a role of physiological vascular modeling in normal conditions but they may participate and even induce dramatic structural dysfunctions that are observed in pathologies such as venous diseases, atherosclerosis or hypertension. Among them, the polypeptides PDGF (platelet derived growth factor), FGF (fibroblast growth factor) and TGF beta (transforming growth factor beta) play a major role. Other factors like cytokines, IGFs (insulin like growth factors), PAF (platelet activating factor) endothelins or nitric oxide have also to be considered. Thus, the vascular wall structure is under the influence of a complex group of growth factors which become to be identified and may be the targets of new therapies of the vessels.
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PMID:Growth factors and vascular wall. 880 32

A number of risk factors for cardiovascular disease, including hypertension, are associated with the insulin resistance syndrome. The hallmark of this syndrome is an impairment in insulin action which provokes a compensatory increase in pancreatic beta-cell insulin secretion leading to chronic hyperinsulinemia. Indirect studies show that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine, PAF), a potent antihypertensive lipid produced by the kidney, may be decreased by hyperinsulinemia. The present study was designed to evaluate the effect of chronic hyperinsulinemia on renal PAF metabolism, arterial blood pressure and whole body insulin sensitivity. Chronic catheterized, unstressed rats were infused with saline or insulin plus glucose to create a chronic condition of sustained euglycemic (approximately 130 mg/dl) hyperinsulinemia (approximately 90 mU 1. or 3-fold over basal levels). PAF is a metabolically unstable compound being susceptible to rapid degradation to the biologically inactive lyso-PAF, a metabolite which also serves as a precursor for PAF synthesis. PAF synthesis and counter-regulatory prostaglandins may be derived from the same arachidonate precursor. The enzymes which catalyze these reactions were measured in plasma and in the subcellular fractions of the kidneys. Compared to saline-treated rats, sustained physiologic hyperinsulinemia for 7 days: (i) decreased insulin-mediated glucose disposal by 30%; (ii) caused an increased plasma PAF:acetylhydrolase, which degrades PAF to lyso-PAF, without any change in cytosolic PAF:acetylhydrolase activity; and (iii) completely inhibited microsomal lyso-PAF:acetyl CoA acetyltransferase activity which catalyzes the conversion of lyso-PAF back to bioactive PAF. The increased catabolism of PAF in plasma, combined with decreased renal PAF biosynthesis, would be expected to decrease circulating PAF levels leading to a rise in blood pressure. However, blood pressure remained unchanged. The sustained hyperinsulinemia stimulated plasma membrane CoA-independent transacylase activity, which is responsible for the mobilization of arachidonates into lyso-PAF, to form l-alkylarchidonoyl-glycerophosphocholine. The latter is the stored precursor for the synthesis of PAF and vasodilatory prostaglandins, which may have offset the effect of decreased PAF. We hypothesize that hyperinsulinemia may alter the blood pressure only if the balance between the synthesis/catabolism of PAF and vasodilatory prostaglandins is disrupted.
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PMID:Chronic hyperinsulinemia inhibits platelet-activating factor (PAF) biosynthesis in the rat kidney. 910 20

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.
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PMID:[Nitrates and coronary vascular endothelium dysfunction]. 945 72

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic beta-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothesized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 +/- 3.1 and 24.2 +/- 2.2 for the lean controls, 52 +/- 2.5 and 28.7 +/- 0.9 for the NIDDM subjects and 60 +/- 2 and 27.6 +/- 2.1 for the obese, non-diabetic subjects (mean +/- S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme. A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91 +/- 11, 96 +/- 3 and 146 +/- 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 +/- 0.92, 10.83 +/- 2.03 and 14.68 +/- 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 +/- 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 +/- 7, 164 +/- 7 and 179 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 +/- 7, 87 +/- 6 and 86 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome: hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.
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PMID:Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment. 945 36

In health, the vascular endothelium forms a multifunctional interface between the circulating blood and various tissues and organs of the body. It constitutes a selectively permeable barrier for macromolecules, as well as a nonthrombogenic and nonadhesive container that actively maintains the fluidity of blood. It is a metabolically active endocrine organ, serving as the source of multiple factors and mediators that are critical for normal homeostasis. These include vasodilators (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor), vasoconstrictors (endothelin-1, thromboxane A2, prostaglandin H2 and components of the renin angiotensin system), various pro- and antithrombotic factors (e.g. tissue factor, platelet activating factor--PAF, von Willebrand factor), fibrinolytic activators and inhibitors (e.g. tissue plasminogen activator, plasminogen activator inhibitor-1), potent arachidonate metabolites (prostanoids), leukocyte adhesion molecules (e.g. E-selectin, P-selectin, intercellular adhesion molecule-1--ICAM-1, vascular cell adhesion molecule-1--VCAM-1), and multiple cytokines with activities of growth stimulators and inhibitors, transforming growth factors, proinflammatory and antiinflammatory mediators, tumour necrosis factors and chemotactic factors (chemokines). Besides these essential activities controlling the cardiovascular system, the endothelial cells represent an important part of the immune system as well. They have a pivotal role in the initiation and development of defensive and damaging inflammatory responses. Therefore endothelium can be considered as being the central equipment for the mutual exchange of life important information between the cardiovascular and immune systems. This in turn is leading to rapid advances in understanding the pathogenesis of some of the most serious and most common diseases, including inflammation, atherosclerosis and hypertension. (Tab. 7, Ref. 89.)
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PMID:[Vascular endothelium as a factor in information transfer between the cardiovascular and immune systems]. 958 73


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