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

Pathophysiological effects of nitric oxide (NO)-deficient hypertension are much better known than are the potential morphological changes. Hearts and main arteries were studied in 15 week old male Wistar rats administered NG-nitro-L-arginine methyl ester (L-NAME) for 4 weeks. A does of 40 mg/kg/day increased systolic arterial pressure by 30%, while heart rate decreased by 20%. Heart/body weight ratios were not significantly changed. Total cardiac RNA and DNA content and [14C]leucine incorporation into myocardial protein were, however, increased by 15%, 228% and 97%, respectively. Light microscopy of hearts showed subendocardial areas of necrosis along with different stages of healing. Morphometric evaluation demonstrated significant increase in myocardial fibrosis. Serum lactate dehydrogenase increased by 91%. Proliferation cell nuclear antigen (PCNA) immunohistochemistry indicated positive cells in areas of postischemic repair. Chronic inhibition of NO synthase (NOS) resulted in periarterial fibrosis and hyperplasia of the media in coronary arteries and aorta. RNA and DNA content, and [14C]leucine incorporation into protein of aorta increased by 255%, 95% and 49%, respectively. PCNA staining showed numerous positive nuclei in the media of coronary arteries and the aorta. It is concluded that inhibition of NOS leads to systemic hypertension with focal myocardial fibrosis reflecting reparative responses associated to ischemic injury. This sequence of alterations involves impaired arterial relaxation, and uncontrolled vascular medial proliferation attributed to the absence of smooth muscle cell proliferation inhibition by NO.
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PMID:Chronic inhibition of NO synthesis produces myocardial fibrosis and arterial media hyperplasia. 922 43

Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1 alpha (220 U/mL [10 ng/mL]), tumor necrosis factor-alpha (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT1) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1 alpha caused a 1.4- to 1.7-fold increase in AT1 binding after 24 hours (P<.01) and a 2.3-fold increase in AT1 mRNA (P<.05). Tumor necrosis factor-alpha and interferon gamma did not cause a significant change in AT1 binding when administered alone but caused a 30% reduction in binding when administered together (P<.05). The maximal decrease in AT1 binding (60%, P<.01) was seen with the combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma. Although the upregulation of AT1 by interleukin-1 alpha was unaffected by pretreatment of cells with N-monomethyl-L-arginine or indomethacin, downregulation of AT1 by interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma was inhibited by N-monomethyl-L-arginine (P<.01). Interleukin-1 alpha treatment enhanced Ang II-induced [3H]uridine incorporation, whereas treatment with interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma attenuated Ang II-induced [3H]uridine and [3H]leucine incorporation. These results demonstrate that interleukin-1 alpha upregulates AT1 receptors and enhances Ang II-stimulated hypertrophic responses. However, a combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma downregulates AT1 receptors by a nitric oxide-dependent mechanism and reduces Ang II-stimulated trophic responses in vascular smooth muscle cells.
Hypertension 1997 Jul
PMID:Regulation of vascular type 1 angiotensin receptors by cytokines. 923 18

Angiotensin II (Ang II) has been implicated in stimulating myocyte growth in vitro, but the mechanism for such stimulation is still an open question. To understand the role of Ang II, we studied its effect on protein synthesis in rat neonatal and adult myocytes. Ang II (10(-8) mol/L) stimulated protein synthesis in neonatal myocytes by 43+/-3.5% over control. To prevent the proliferation of fibroblasts, bromodeoxyuridine was added, and protein synthesis in neonatal myocytes was reduced to 21+/-2.2% over control. In adult myocytes (cultured without bromodeoxyuridine), Ang II stimulated [3H]leucine incorporation by 24+/-2.3% over control; with bromodeoxyuridine, that stimulation was reduced significantly (13+/-0.93% over control). These data suggest that the presence of fibroblasts in the cultures may control myocyte growth. When supernatant from pure fibroblast culture was added to myocyte preparations, a significant increase (49.8+/-3.5% over control) in protein synthesis occurred. Pretreatment of these fibroblasts with Ang II (10(-3) mol/L) further stimulated protein synthesis, suggesting that Ang II directly stimulates the production of a factor from fibroblasts. The stimulatory effect of Ang II on the release of the factor can be completely blocked by pretreatment with losartan, an Ang II receptor (AT1) blocker. Our data are the first to demonstrate a paracrine effect of a fibroblast-derived factor that modulates myocyte growth. Fibroblast-derived factor loses its biological activity by (1) tryptic digestion, (2) exposure to pH below 4.0 and above 9.0, and (3) heating to 95 degrees C. The molecular weight of the factor is approximately 65 kD. The antibodies against fibroblast growth factor (both acidic and basic) could not inhibit this factor's stimulatory effect. Furthermore, this factor is heart specific and is produced at least up to the 16th passage of neonatal rat heart fibroblasts. Skin fibroblasts, aortic endothelial cells, and aortic smooth muscle cells do not produce this protein. Our data suggest that the observed myocyte growth by Ang II comes about via fibroblast-derived factor, which is increased by Ang II. Cross talk between fibroblasts and myocytes is an important factor in stimulating myocyte growth by Ang II.
Hypertension 1997 Aug
PMID:Angiotensin II and myocyte growth: role of fibroblasts. 926 Sep 82

Angiotensin II (Ang II), a potent vasoactive peptide with mitogenic potential, influences vascular smooth muscle cell contraction and growth through receptor-linked pathways that increase intracellular free Ca2+ concentration ([Ca2+]i) and pH (pHi). Activation of these second messengers by Ang II may involve tyrosine kinase-dependent signaling pathways. This study determined the role of tyrosine kinases in Ang II-stimulated pHi, and in simultaneously measured contractile and [Ca2+]i responses, as well as growth in cultured vascular smooth muscle cells from mesenteric arteries of Wistar-Kyoto rats. pHi was determined by fluorescent digital imaging using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM). Vascular smooth muscle cell [Ca2+]i and contractile responses were assessed simultaneously by fura 2 methodology and by photomicroscopy in cells grown on rat tail collagen gels. Cell growth was determined by DNA and protein synthesis as measured by [3H]thymidine and [3H]leucine incorporation, respectively. The Ang II receptor subtypes (AT1 or AT2) through which Ang II mediates effects were assessed with [Sar1,Ile8]Ang II (a nonselective subtype antagonist), losartan (a selective AT1 antagonist), and PD 123319 (a selective AT2 antagonist). To determine whether tyrosine kinases influence Ang II-stimulated responses, cells were pretreated with 10(-5) mol/L tyrphostin A-23 (a specific tyrosine kinase inhibitor). Ang II increased pHi in a dose-dependent manner (pD2, 9.2+/-0.2) and significantly increased vascular smooth muscle cell contraction (30%) and [Ca2+]i (pD2, 7.4+/-0.1). Ang II (10(-7) mol/L) increased DNA ([3H]thymidine incorporation) and protein synthesis ([3H]leucine incorporation). [Sar1,Ile8]Ang II and losartan but not PD 123319 abolished Ang II-elicited responses. Tyrphostin A-23 significantly attenuated Ang II-stimulated pHi responses; it also inhibited [Ca2+]i and contractile responses and cell growth. The inactive analogue tyrphostin A-1 did not alter Ang II-stimulated actions. These results provide novel evidence for a role of tyrosine kinases in Ang II-mediated pHi responses in vascular smooth muscle cells and indicate that tyrosine kinases participate in the regulation of signal transduction associated with AT1 receptor subtype-mediated contraction and growth.
Hypertension 1997 Aug
PMID:Angiotensin II regulates vascular smooth muscle cell pH, contraction, and growth via tyrosine kinase-dependent signaling pathways. 926 Sep 84

We have shown recently that intracisternal administration of endothelin-(ET)1 and ET-3 evokes increases in gastric motor function and arterial blood pressure. The aim of our study was to investigate whether the dorsal vagal complex (DVC) is a medullary site of action for the gastric motor and cardiovascular effects of ET-1 and to identify the ET receptor subtype through which these effects are mediated. ET-1 (0.1-40 pmol/site) and ET-3 (1 and 100 pmol/site) were microinjected into the DVC of alpha-chloralose anesthetized rats, while monitoring intragastric pressure, contractile activity of greater curvature longitudinal and pyloric circular smooth muscle, arterial blood pressure and heart rate. ET-1, at doses of 0.1 to 40 pmol, increased intragastric pressure and, at doses of 10 and 40 pmol, increased pyloric contractile activity and arterial blood pressure. The increases in gastric motor function, but not the hypertension, induced by ET-1 (10 pmol) in the DVC were completely abolished by bilateral vagotomy. Spinal cord transection prevented increases in arterial blood pressure evoked by ET-1 (40 pmol). Because only the highest dose of ET-3 (100 pmol), microinjected into the DVC, increased intragastric pressure and pyloric contractile activity and no consistent changes in cardiovascular functions were noted, we hypothesized that the gastric motor and hypertensive responses to endothelins in the DVC are mediated via ET(A) receptors. This was supported by the observation that a selective ET(A) receptor antagonist, cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123; 400 pmol), microinjected into the DVC 15 min before ET-1 (10 pmol) or ET-3 (100 pmol), completely blocked the gastric motor and cardiovascular responses to endothelins. We conclude that endothelins act in the brainstem at the level of the DVC to increase intragastric pressure and gastric contractile activity via a vagally mediated pathway and that both the gastric motor and hypertensive effects of endothelins in the DVC are mediated through ET(A) receptors.
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PMID:Excitatory gastric motor and cardiovascular effects of endothelins in the dorsal vagal complex are mediated through ET(A) receptors. 926 13

The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL, P<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients' compliance to ACE inhibitor treatment.
Hypertension 1997 Nov
PMID:High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition. 957 37

Long-term administration of NG-nitro-L-arginine methyl ester (L-NAME) induces development of NO-deficient hypertension. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor captopril can prevent hypertension, left ventricular (LV) hypertrophy, changes in nucleic acid concentration, protein synthesis and protein profile of the left ventricle. Four groups of rats were investigated: control, L-NAME 40 mg/kg/day, captopril 100 mg/kg/day, L-NAME 40 mg/kg/day along with captopril 100 mg/kg/day. NO-synthase activity in the left ventricle was found to be decreased by 69% in the L-NAME group. Captopril did not influence this inhibition of NO-synthase activity. However, it completely prevented hypertension and left ventricular hypertrophy development. The increase in left ventricular RNA and DNA concentration and -14C-leucine incorporation observed in the L-NAME group was completely prevented by simultaneous captopril treatment. The protein profile of the left ventricle in the L-NAME group was characterized by higher concentration of metabolic proteins (MP), soluble collagenous proteins (SCP) and of hydroxyproline in insoluble collagenous proteins (ICP). The concentration of hydroxyproline in ICP was significantly decreased by simultaneous captopril treatment. We conclude that captopril prevented the development of hypertension, left ventricular hypertrophy, increase in nucleic acid concentration and diminished collagen concentration by mechanisms different from affecting NO-synthase activity.
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PMID:Protein remodelling of the heart in NO-deficient hypertension: the effect of captopril. 944 42

Vascular smooth muscle cell (VSMC) proliferation still remains a poorly understood process, although it is believed to play a critical role in pathological states, including atherosclerosis and hypertension. Several reports have suggested that proteases may be directly involved in this process; however, it was still unclear which protease is responsible for VSMC proliferation. In this study, by use of a cell-permeable calpain inhibitor (calpeptin; benzyloxycarbonyl-Leu-nLeu-H), its analogue (benzyloxycarbonyl-Leu-Met-H), the cell-impermeable serine protease inhibitor leupeptin, and antisense oligonucleotide against m-calpain to inhibit proliferation of primarily cultured human VSMCs, we investigated whether calcium-activated neutral protease (calpain) is involved in VSMC proliferation. Calpeptin and its analogue, more specific for m-calpain, equally inhibited the proliferation of VSMCs in a dose-related manner, whereas a more limited antiproliferative effect was observed in leupeptin-treated VSMCs. Antisense oligonucleotide against m-calpain, but not scrambled antisense, dose-dependently inhibited m-calpain expression and proliferation of VSMCs. Maximal inhibition was an approximately 50% reduction of cell number and m-calpain antigen observed at 50 micromol/L of antisense oligonucleotide. Calpeptin or antisense oligonucleotide against m-calpain increased the expression of the endogenous calpain substrate pp125FAK (focal adhesion kinase), whereas the expression of the endogenous calpain inhibitor calpastatin was not affected. These results suggest that the proliferation of VSMCs requires protease activity, some of which is due to m-calpain.
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PMID:Possible involvement of m-calpain in vascular smooth muscle cell proliferation. 951 20

The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [3H]proline and [3H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [3H]proline and [3H]leucine incorporation. These effects were blocked by KF17837 (selective A2 antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A1/A2 receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A1 antagonist), thus excluding the participation of A1 receptors. The lack of effect of CGS21680 (selective A2A agonist) excluded involvement of A2A receptors, thus suggesting a major role for A2B receptors. Comparisons of the inhibitory potencies of N6-cyclopentyladenosine (selective A1 agonist), 5'-N-ethylcarboxamidoadenosine (A1/A2 agonist), and 5'-N-methylcarboxamidoadenosine (A1/A2 agonist) were consistent with that of an A2B receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A2B receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.
Hypertension 1998 Apr
PMID:Adenosine inhibits collagen and protein synthesis in cardiac fibroblasts: role of A2B receptors. 953 19

The mechanisms of sodium-induced myocardial hypertrophy and vascular hypertrophy are poorly understood. We tested the hypothesis that a high sodium concentration can directly induce cellular hypertrophy. Neonatal rat myocardial myoblasts (MMbs) and vascular smooth muscle cells (VSMCs) were cultured in a 50:50 mixture of DMEM and M199 supplemented with 10% fetal bovine serum. When the monolayers reached approximately 80% confluence, normal sodium medium (146 mmol/L) was replaced with high sodium media (152 mmol/L, 160 mmol/L, and 182 mmol/L) for up to 5 days. Increasing sodium from a baseline concentration of 146 mmol/L to the higher concentrations for 5 days caused dose-related increases in cell mean diameter, cell volume, and cellular protein content in both MMbs and VSMCs. Increasing the sodium concentration by only 4% (from 146 mmol/L to 152 mmol/L) caused the following respective changes in MMbs and VSMCs: 8.5% and 8.7% increase in cell mean diameter, 27.6% and 27.0% increase in cell volume, and 55.7% and 46.7% increase in cellular protein content. The rate of protein synthesis, expressed as [3H]leucine incorporation, increased by 87% and 99% in MMbs after exposure to 152 mmol/L and 160 mmol/L sodium, respectively, compared with the 146-mmol/L sodium control group. Exposure of MMbs to medium with a sodium concentration of 10% above normal, ie, 160 mmol/L, caused a significant decrease (range, 26% to 44%) in the rate of protein degradation at multiple time points over a 48-hour period compared with normal sodium control cells. The increase in cellular protein content caused by 160 mmol/L sodium returned to normal within 3 days after MMbs were returned to a normal sodium medium. These findings support the hypothesis that sodium has a direct effect to induce cellular hypertrophy and may therefore be an important determinant in causing myocardial and/or vascular hypertrophy in subjects with increased sodium concentration in the extracellular fluid.
Hypertension 1998 May
PMID:Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells. 957 18


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