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)

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
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PMID:Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. 830 Aug 85

The relation between serum lipids, membrane fluidity, insulin, and the activity of the sodium-hydrogen exchanger was investigated in human lymphocytes from 83 subjects. Subjects had a wide range of serum lipids and no concurrent disease. Lymphocyte membrane anisotropy (inversely related to membrane fluidity) was measured with a fluorescence polarization method. Sodium-hydrogen exchange maximal proton efflux rate, affinity for external sodium, and resting pH were determined with the intracellular pH-sensitive fluorochrome 2',5'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Sodium-hydrogen exchange maximal proton efflux rate was negatively correlated with the age of the subject (p = 0.03). Membrane anisotropy correlated with serum triglyceride (p = 0.04). Multiple regression analysis demonstrated that the maximal proton efflux rate in human lymphocytes was significantly related to age (p = 0.005), systolic blood pressure (p = 0.04), membrane anisotropy (p = 0.03), and serum cholesterol (p = 0.03). Incubation of lymphocytes with insulin failed to affect sodium-hydrogen exchange kinetics, intracellular buffering power, or resting intracellular pH. These results suggest that membrane-bound transport proteins may be influenced by serum lipids and the fluidity of the lipid membrane in which they are bound, but they are unlikely to be affected by insulin.
Hypertension 1993 Mar
PMID:Human lymphocyte sodium-hydrogen exchange. The influences of lipids, membrane fluidity, and insulin. 838 1

Chromogranins A and B are major soluble proteins in chromaffin granules. Their adrenomedullary content is increased in the spontaneously (genetic) hypertensive rat. Is augmented catecholamine vesicular storage of the chromogranins a specific feature of genetic hypertension? To explore this question, we measured chromogranin A immunoreactivity, using a novel, synthetic peptide radioimmunoassay, in rat adrenal medullas 4-6 weeks after induction of the two-kidney, one clip Goldblatt model of renovascular hypertension and in unmanipulated control animals. We also measured messenger RNAs of chromogranins A and B and dopamine beta-hydroxylase by Northern blot. Immunoreactive adrenal chromogranin A was 3.3-fold higher (p < 0.01) in clipped rat adrenals. Adrenal catecholamine concentrations and phenylethanolamine-N-methyltransferase activity were also higher in clipped rats. Adrenal dopamine beta-hydroxylase activity (both membrane-bound and soluble forms) and corticosterone (glucocorticoid) concentration did not significantly differ between the groups. Adrenal medullary chromogranin A messenger RNA levels in clipped rats were 3.2-fold higher (p = 0.029) than those in the control group, and chromogranin B messenger RNA levels were 4.6-fold higher (p = 0.05). Dopamine beta-hydroxylase messenger RNA levels were 2.9-fold higher (p = 0.038). Thus, augmented synthesis and storage of adrenomedullary chromogranins A and B, catecholamines, and their biosynthetic enzymes appear to be characteristic of both acquired and genetic hypertension.
Hypertension 1993 May
PMID:Catecholamine secretory vesicles. Augmented chromogranins and amines in secondary hypertension. 849 1

Angiotensin II (Ang II) and arginine vasopressin (AVP) increased intracellular free Ca2+ concentration [Ca2+]i and/or the [Ca2+]i transient rate (CaTR) in cultured neonatal rat cardiomyocytes. These agents increased membrane-bound protein kinase C (PKC) with peak activity at 5 and 10 minutes, respectively. Two-minute exposure to Ang II produced homologous desensitization to a repeated stimulation with Ang II and heterologous desensitization to AVP. Two-minute exposure to AVP also produced homologous desensitization to AVP but not heterologous desensitization to Ang II. When the AVP exposure time was increased from 2 to 10 minutes coincident with maximal AVP-mediated PKC activation, heterologous desensitization to Ang II was also observed. Acute activation (15 minutes) of PKC by phorbol 12-myristate 13-acetate (PMA) blocked responsiveness to both Ang II and AVP. When PKC activation was inhibited by 20 hours of prior exposure to PMA, as confirmed by PKC assay, homologous desensitization of Ang II still occurred, confirming an alternative mechanism(s) for homologous desensitization in the cardiomyocytes. In contrast, 20-hour PMA suppression of PKC markedly diminished the ability of the cardiomyocytes to exhibit AVP-mediated heterologous desensitization for Ang II. These data indicate that PKC activation plays a primary role in mediating vasopressin V1 receptor-induced heterologous desensitization of the Ang II receptor and participates in a hierarchy of two or more kinase systems mediating homologous desensitization of the Ang II receptor in cardiomyocytes.
Hypertension 1996 Feb
PMID:Protein kinase C modulation of cardiomyocyte angiotensin II and vasopressin receptor desensitization. 856 51

The serum concentration of lipoprotein(a) [Lp(a)], lipids, lipoproteins, apolipoprotein A-I, and apolipoprotein B were determined in 228 patients with cerebral infarction, composed of 87 cases of asymptomatic lacunar infarction, 99 cases of lacunar infarction, and 42 cases of atherothrombotic infarction, and in a control group of 138 healthy subjects with normal MRI. Observations were made on the distribution of Lp(a), Lp(a) and other risk factors for cerebral infarction and these were statistically analyzed, primarily by multiple logistic regression analysis. The diagnosis of these cases was based on the Classification of Cerebrovascular Diseases III of the National Institute of Neurological Disorders and Stroke. The following results were obtained. 1) Lipoprotein (a) (1) Lp(a) did not show a normal distribution with the curve showing a gradual declining slope to the right. It was therefore considered not appropriate in our analysis to use as a means or standard deviation. (2) The 25th percentile, 50th percentile, and 75th percentile of the control group were 5.0 mg/dl, 11.0 mg/dl, and 22.4 mg/dl, respectively. In studying the distribution in these percentile ranges by subtypes of infarction, an increase in cases showing values greater than the median of the control group was observed in asymptomatic lacunar infarction, lacunar infarction, and atherothrombotic infarction, when compared to the control group. In asymptomatic lacunar infarction and lacunar infarction in particular, Lp(a) showed a significantly higher value compared to the control group. (3) However, by multiple logistic regression analysis to adjust for age and sex, Lp(a) did not show a significant odds ratio for asymptomatic lacunar infarction, lacunar infarction and atherothrombotic infarction. 2) Various serum lipids and other parameters (1) The various serum lipids did not show any involvement in asymptomatic lacunar infarction. However, involvement of HDLC and Apo A-I in lacunar infarction and atherothrombotic infarction was observed with the odds ratios in lacunar infarction being 4.2 with a confidence interval of 2.9-9.4 and 4.7 with a confidence interval of 2.2-10.1, and the odds ratios in atherothrombotic infarction being 3.1 with a confidence interval of 1.1-9.0 and 9.6 with a confidence interval of 3.0-30.5, respectively. (2) Involvement of diabetes mellitus in asymptomatic lacunar infarction and lacunar infarction was small, but a strong involvement in atherothrombotic infarction was observed with the odds ratio being 4.3 with a confidence interval of 1.2-16.2. (3) Involvement of hypertension in asymptomatic lacunar infarction and lacunar infarction was observed with the odds ratios being 2.6 with a confidence interval of 1.4-5.2 and 5.6 with a confidence interval of 2.4-13.0, respectively, but the involvement in atherothrombotic infarction was low. The foregoing results indicated that there was no involvement of Lp(a) as a risk factor for any type of cerebral infarction, unlike its involvement in coronary heart diseases. Only blood pressure was involved as a risk factor for asymptomatic lacunar infarction, but for lacunar infarction not only blood pressure but also HDLC and Apo A-I were involved as risk factors. HDLC, Apo A-I, and diabetes mellitus were involved as risk factors for atherothrombotic infarction, but the involvement of hypertension was minimal.
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PMID:Lipoprotein(a) and other risk factors for cerebral infarction. 856 15

We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.
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PMID:Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. 862 76

As part of the DREsden CArdiovascular risk and Nutrition study, 2038 participants, selected from a cohort of 3076 workers in the Dresden area, underwent a detailed nutritional analysis of the periods before and after German reunification. Although protein, fat, carbohydrate, and total calorie intake did not change in Dresden after reunification, polyunsaturated fat replaced 17% of the saturated fatty acids, dairy product intake tripled, and fruit intake increased by 70%. Relative to a reference PROCAM 'western' cohort, the 90th percentile of triglycerides was higher in middle-aged men, and the levels of total cholesterol and HDLC were higher in all males. Serum LDLC levels in males and females were similar. Serum lipid concentrations and the prevalence of hyperlipidemia were similar to those of the PROCAM cohort, but smoking was less common. In young males and females, body mass index was higher; hypertension was more frequent. We assume that the differences in nutrition and risk profile before reunification were less substantial than commonly believed.
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PMID:Dietary habits in Eastern Germany: changes after reunification and their relation to CHD risk profiles (DRECAN). 886 23

In the present study, we evaluated the effect of low-dose aspirin (acetylsalicylic acid (ASA); 1.0 mg/kg daily) on blood pressure, albumin excretion, glomerular fibrinogen deposits, and glomerular (basement) membrane-bound adenosine diphosphatase (ecto-ADPase) activity, as well as on glomerular inflammation in pregnant rats infused with low-dose endotoxin (1.0 mg/kg). Rats (day 14 of pregnancy) were infused with endotoxin (ET rats) or saline (control rats) and received ASA in their drinking water. These rats were compared with non-ASA-treated rats. Blood pressure and albumin excretion were measured from day 15 to day 21, and glomerular fibrinogen and ecto-ADPase activity were measured at day 21. Glomerular inflammation was evaluated at various times after the start of the infusion. The results show that treatment with ASA had a significant beneficial effect on hypertension and inflammation induced by endotoxin in pregnant rats, whereas it reduced albumin excretion and glomerular fibrinogen deposits in some of the rats.
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PMID:Aspirin treatment of the low-dose-endotoxin-treated pregnant rat: pathophysiologic and immunohistologic aspects. 939 Jun 37

Both endothelial cells and vascular smooth muscle cells are capable of producing reactive oxygen species from a variety of enzymatic sources. In disease states such as atherosclerosis and hypertension, vascular production of these reactive oxygen metabolites can increase substantially. Increases in the production of superoxide anion can lead to decreases in ambient levels of nitric oxide via a facile radical/radical reaction that occurs more rapidly than the reaction of superoxide anion with superoxide dismutase. This phenomenon alters endothelial regulation of vasomotion in a variety of disease conditions. Recent evidence suggests that the major source of vascular superoxide ion and hydrogen peroxide is a membrane-bound, reduced nicotinamide-adenine dinucleotide (NADH)-dependent oxidase. The activity of this enzyme system is regulated by angiotensin II and is elevated following prolonged exposure to nitroglycerin. Alterations of vascular oxidant state caused by angiotensin II may contribute substantially to vascular pathology and may also provide a link between hypertension and atherosclerosis.
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PMID:Endothelial function and oxidant stress. 942 47

Hypertension and kidney dysfunction in sodium transport observed in the Milan hypertensive strain (MHS) of rats are genetically associated with point mutations of adducin, an actin- and spectrin-binding protein of the membrane cytoskeleton. Polymorphism in the adducin locus has been reported to occur also in cases of human primary hypertension. In this study we show by immunostaining that adducin is localized along the basolateral epithelial membrane surface of the entire proximal and distal tubule with no detectable differences between MHS rats and the normotensive control strain (MNS). However, the total amount of adducin in kidney homogenates is reduced by about 45% in MHS rats as determined by quantitative immunoblotting. In erythrocyte membranes of MHS rats, adducin is reduced approximately 10%. The reduction of renal adducin in MHS rats is mainly caused by a reduction of the adducin pool that is loosely associated with kidney membranes and can be released by the non-ionic detergent, Triton X-100. The Triton-resistant, tightly membrane-bound pool of renal adducin differed by approximately 10% between MHS and MNS rats. Since several ion transporters have been shown to be tethered to the membrane cytoskeleton, we suppose that the reduction of the dynamic, loosely bound pool of adducin in MHS rats might interfere with the normal turnover and incorporation of yet unknown transporters involved in kidney sodium transport. However, the Na+,K+-ATPase appears to be not involved, as indicated by normal distribution and amounts of NA+,K+-ATPase in the kidney of MHS rats revealed by immunostaining and immunoblotting.
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PMID:Localization and quantification of the cytoskeleton-associated protein adducin in the kidneys of normal and Milan hypertensive rats. 950 78


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