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

Angiotensin II (Ang II) is one of the most potent vasoconstrictors, and the first specific and orally available Ang II-receptor antagonist, losartan (MK-954, DuP-753), has now come into clinical use. The primary site of insulin resistance, as measured by the glucose clamp technique, is skeletal muscle. Losartan specifically blocks Ang II-induced vasoconstriction, namely causes vasodilation, and may thus increase glucose delivery to skeletal muscle. We used the euglycaemic hyper-insulinaemic glucose clamp technique to assess insulin sensitivity (glucose disposal rate, GDR) or insulin (I) sensitivity index (GDR/I). In 21-year-old men we found negative correlations between GDR/I and blood viscosity (r = -0.69), haematocrit (r = -0.65), fibrinogen (r = -0.50), cholesterol/HDL ratio (r = -0.45), triglycerides (r = -0.46), body mass index (r = -0.64), waist/hip ratio (r = -0.57), resting heart rate (r = -0.46) and diastolic blood pressure (DBP) (r = -0.43), and with DBP (r = -0.62) and plasma adrenaline (r = -0.36) during mental arithmetic stress. In the Losartan Severe Hypertension Study five patients with a record of DBP > or = 115 mm Hg were examined before and on losartan monotherapy for an average of 6 weeks. GDR increased 27% and plasma noradrenaline decreased 40% (P < 0.05 for both) during treatment with losartan. Calculated whole blood viscosity decreased on losartan (P = 0.04) and the changes in GDR correlated with the changes in viscosity (r = 0.89). These results suggest that losartan, possibly by a sympathicolytic effect, lowers blood viscosity, causes vasodilation, and improves insulin sensitivity in essential hypertension.
 ...
PMID:Effects of losartan on insulin sensitivity in severe hypertension: connections through sympathetic nervous system activity? 858 81

On the basis of evidence suggesting the activation of the kallikrein-kinin system in steroid-induced hypertension, we considered the possibility that the angiotensin-converting enzyme inhibitor captopril would lower the arterial blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats through kininase II inhibition. In conscious DOCA-salt hypertensive rats with intact kidneys (n = 6) or uninephrectomized rats (n = 5), the short-term administration of captopril (8 mg/kg IV) decreased mean blood pressure from 141 +/- 3 to 118 +/- 3 mm Hg (P < .05) and from 176 +/- 12 to 158 +/- 15 mm Hg (P < .05), respectively. The maximal effect of captopril was manifested between 40 and 50 minutes after its administration, and blood pressure remained depressed for at least 2 hours. The bradykinin B2 receptor antagonist Hoe 140 (500 micrograms/kg IV) abolished the antihypertensive effect of captopril in the DOCA-salt hypertensive rats, indicating kinin involvement. Losartan, an angiotensin type 1 receptor antagonist, had no effect on blood pressure in another group of DOCA-salt hypertensive rats (n = 9) and did not significantly change the response to captopril. No effect of the angiotensin-converting enzyme inhibitor was seen in normotensive control rats (n = 5), indicating the absence of a nonspecific hypotensive action of the drug. Plasma renin activity was lower in the DOCA-salt hypertensive rats (0.7 +/- 0.2 ng angiotensin I/mL per hour, n = 4) than in normotensive control rats (8.8 +/- 1.7, n = 4). The involvement of kinins in the antihypertensive effect of captopril in DOCA-salt hypertension supports the contention that the kallikrein-kinin system contributes to blood pressure regulation in this hypertension model.
Hypertension 1996 Jan
PMID:Kinin-mediated antihypertensive effect of captopril in deoxycorticosterone acetate-salt hypertension. 859 94

We have reported that the angiotensin II (Ang II) AT1 receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg/kg/d) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9 +/- 0.4 ng Ang I/ mL/h) compared with NNa rats (4.0 +/- 0.3 ng Ang I/mL/h), control arterial pressure was not different between NNa (113 +/- 4 mm Hg) and HNa (113 +/- 2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (-12 +/- 2 mm Hg) but had no effect on arterial pressure in HNa rats (+4 +/- 4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (-32 +/- 2 mm Hg) but remained unchanged compared with control in HNa rats (+5 +/- 6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema-lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95 +/- 3 mm Hg) and APx (96 +/- 2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1 +/- 1.5 versus APx, 5.3 +/- 1.6 mm Hg Ang I/mL/h). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80 +/- 2 mm Hg) compared with APx (90 +/- 3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72.2 +/- 2 mm Hg) was significantly lower than in APx rats (83 +/- 4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72 +/- 2 mm Hg; APx, 84 +/- 2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.
Hypertension 1996 Mar
PMID:Hypotensive response to losartan in normal rats. Role of Ang II and the area postrema. 861 10

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.
 ...
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

Angiotensin II (AII) receptor antagonists, a new class of antihypertensive agents, recently became available for the treatment of clinical hypertension. These agents have a unique mechanism of action: they selectively block the AII receptor type I thereby blocking all known physiological actions of AII that are relevant to hypertension. Controlled clinical trials have shown losartan potassium, the first of the AII receptor type I antagonists approved for clinical use, to be effective, providing long-term control of blood pressure in once daily oral doses in patients who have mild to moderate essential hypertension. Losartan is as efficacious as enalapril maleate and atenolol in these patients. Its antihypertensive effect is enhanced when used in combination with a thiazide diuretic. Losartan is well tolerated and generally free of the side effects that are commonly associated with angiotensin converting enzyme inhibitors and other currently available antihypertensive drugs. Thus, AII receptor blockers represent an important therapeutic advance in treating hypertension and provide a targeted treatment approach to block activation of the renin-angiotensin system.
 ...
PMID:Angiotensin II receptor blockers. A new class of antihypertensive drugs. 864 Mar 26

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.
 ...
PMID:Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. 865 89

In previous studies, we showed that in vivo infusion of angiotensin II (Ang II) to adult rats induced vascular changes in gene expression, and this effect did not depend solely on blood pressure elevation. To determine whether nitric oxide can influence the effects of Ang II on the vessel wall, we administered to rats Ang II separately or in combination with the arginine analogue N omega-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase chronically when given in vivo. We measured changes in aortic medial thickness, the association of macrophages with the endothelial surface of the aorta, the presence of proliferating cell nuclear antigen in the intima and adventitia as an index of aortic cell cycle changes, and the expression of immunodetectable fibronectin as an index of changes in the extra-cellular matrix. After 18 days of nitric oxide inhibition, the major changes were increased medial thickness and a 3.5-fold increase in the number of adherent macrophages. Rats treated with two different doses of Ang II for 3 days had a fivefold and threefold increase in the number of proliferating cells from the intimal and adventitial regions, respectively. Combined treatment resulted in increased medial thickness, intimal and adventitial cell proliferation, and macrophage adherence. An increased and altered pattern of fibronectin distribution was found in all treatment groups. Losartan administration prevented the effects of Ang II but not of nitric oxide inhibition, whereas administration of L-arginine, prevented both intimal macrophage adherence and increased adventitial proliferation in rats given combined treatment. The data suggest that nitric oxide selectively influences macrophage association with the arterial wall, whereas Ang II and nitric oxide may have opposing effects on arterial cell proliferation.
Hypertension 1996 Aug
PMID:Effects of angiotensin II infusion and inhibition of nitric oxide synthase on the rat aorta. 870 75

We studied the effect of chronic (7 days) angiotensin II (Ang II) infusion in nonpressor and pressor doses on cardiovascular mass and expression of alpha- and beta-myosin heavy chain genes in the left ventricle in normotensive Wistar rats. An increased left ventricular mass was observed in rats receiving non-pressor and pressor doses of Ang II, but only high doses increased arterial pressure. Normalization of arterial pressure during Ang II infusion by losartan, a specific Ang II receptor antagonist, or hydralazine had different effects on left ventricular mass. Losartan prevented the increased left ventricular mass, and hydralazine did not affect left ventricular mass. Northern blot analysis showed that the switch in left ventricular myosin isoform mRNA from the adult to the fetal pattern occurred only in rats given the pressor Ang II dose. Both losartan and hydralazine, in parallel with the normalization of arterial pressure, prevented this myosin isoform switch. Thus, these data suggest that the Ang II-induced increase in left ventricular mass was not dependent on pressure overload, but the switch in myosin isoform mRNA from the adult to the fetal pattern was dependent on pressure overload.
Hypertension 1996 Aug
PMID:Angiotensin II increases left ventricular mass without affecting myosin isoform mRNAs. 870 92

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.
 ...
PMID:Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. 876 77

Fibrosis makes an important contribution to the pathophysiological events leading to the development of heart failure in ischemic and hypertensive heart disease. Since cardiac fibroblasts are mainly responsible for the synthesis and deposition of the extracellular matrix, we have established a method for isolating and cultivating human cardiac fibroblasts from explanted human hearts. The cell yield was 2.14+/-0.25x10(6 )cells in five independent isolations and the cell purity was 95-97%, contaminating cells being vascular smooth muscle cells and pericytes. Cultured cells were studied with respect to growth properties, morphology and deposition of components of the extracellular matrix. Isolated cells displayed a differentiated phenotype, including the second passage in culture; they synthesised collagen I, III, IV, fibronectin, vitronectin, tenascin and chondroitin sulphate and expressed an atypical angiotensin receptor. This atypical angiotensin receptor internalised angiotensins II and III but not angiotensin IV in a time-dependent manner. Stimulation of the cells with angiotensins II and III but not with angiotensin IV resulted in a dose-dependent stimulation of DNA synthesis. Co-incubation with the subtype-specific receptor antagonists Losartan and PD 123317 did not prevent the stimulation of DNA synthesis. The further characterisation of this receptor should provide insights into the pathobiochemical events leading to heart failure in hypertension and ischemic heart disease.
 ...
PMID:Isolation and characterisation of human cardiac fibroblasts from explanted adult hearts. 878 Dec 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>