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

---

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

Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, functions as a potent vasoconstrictor as well as mitogen. We show here a novel role for ET-1 as an apoptosis survival factor for cultured rat endothelial cells. When we rendered endothelial cells obtained from rat aorta quiescent by serum starvation, significant portions of cultured cells underwent apoptotic death as demonstrated by nucleosomal laddering on agarose gel electrophoresis, flow cytometry analysis with FACS, and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) method. ET-1 dose-dependently (10[-12] to 10[-6] mol/L) suppressed the apoptosis induced by serum starvation. The ET(B) receptor antagonist (BQ788; 10[-6] mol/L) and ET(A/B) receptor antagonists (PD142893 and PD145065; 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-6] mol/L), blocked the apoptosis protective effect of 10[-7] mol/L ET-1. Nonimmune rabbit serum reduced the apoptotic event induced by serum deprivation, whereas neutralization of endogenous ET-1 by polyclonal anti-ET-1 antiserum abrogated this protective effect. The ET(B) receptor antagonist (BQ788; 10[-8] to 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-8] to 10[-6] mol/L), significantly inhibited proliferation of endothelial cells. These data suggest that ET-1, as well as mitogen, functions as an apoptosis survival factor for endothelial cells in an autocrine/paracrine manner via the ET(B) receptor.
Hypertension 1997 Nov
PMID:Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. 936 76

Inhaled nitric oxide (NO) is an important new therapeutic agent used to treat pulmonary arterial hypertension in a variety of disease states. However, the effects of NO on cells in the lung are uncertain. Previously, we have shown that NO gas depresses neutrophil oxidative cell function and increases neutrophil cell death. The purpose of this in vitro study was to determine the mechanism of neutrophil death. We hypothesized that NO hastened cell death by inducing apoptosis. To mimic the clinical environment of patients with respiratory failure, we also studied the effects of hyperoxia on neutrophil cell viability and apoptosis. Isolated human neutrophils were exposed to 80% O2 (O2), NO at 20 ppm in room air (NO/RA), 20 ppm NO blended with 80% O2 (NO/O2), or RA alone (control) for 2 to 24 h. Experiments were repeated with NO concentrations of 5 and 50 ppm and with 20 ppm in the presence of superoxide dismutase (SOD). Neutrophils were also incubated in the absence or presence of neutrophil stimulant fMLP (10 nM). Neutrophil cell viability was measured by fluorescence viability/cytotoxicity assay. Neutrophil apoptosis was assessed by cell death detection ELISA for histone-associated DNA fragments, TdT transferase-mediated fluorescence-labeled dUTP nick end labeling (TUNEL) assay, and DNA fragmentation gel electrophoresis. NO/O2-exposed neutrophils showed decreased viability at 2 h (31.7 +/- 3.7%, mean % viability +/- SD) compared with control (94.7 +/- 4.7%), O2 (75.6 +/- 9.3%), and NO/RA (62.8 +/- 14.9%; P < 0.05 by ANOVA; n = 9). Although control neutrophils demonstrated marked apoptosis at 24 h, there was no significant apoptosis at 2, 4, or 6 h (P < 0.001 by Kruskal-Wallis, n = 20) as assessed by ELISA and TUNEL assays. When compared with RA controls at 2 h, neutrophils exposed to NO/O2 showed significantly more apoptosis (292% of control, range: 106 to 2,488%, P < 0.001 by ANOVA and Kruskal-Wallis) but not with exposure to NO/RA or O2 alone. These findings were confirmed by TUNEL assay (n = 4, P < 0.05). NO/ RA and NO/O2-exposed neutrophils demonstrated both evidence of necrosis and enhanced DNA fragmentation at 2 h by gel electrophoresis (n = 2). Fifty parts per million NO produced similar findings, but exposure to 5 ppm NO did not induce significant DNA fragmentation. Coincubation with SOD inhibited NO/ O2-associated apoptosis, suggesting peroxynitrite contributed to cell death. Stimulation with fMLP did not alter apoptosis induced in neutrophils exposed to NO/RA or NO/O2. We conclude that exogenous NO gas, at clinically relevant concentrations under hyperoxic conditions, induces cell death in neutrophils in part by enhancing DNA fragmentation.
...
PMID:Exogenous nitric oxide enhances neutrophil cell death and DNA fragmentation. 949 Jun 60

Increased apoptosis has been demonstrated in various forms of human and experimental cardiovascular disease. The role of this phenomenon in the vasculature in different models of hypertension is unclear. In hypertension, regression of vessel wall hypertrophy/hyperplasia or remodeling in response to various antihypertensive drugs may be mediated in part by apoptosis. This study examined vascular smooth muscle apoptosis in spontaneously hypertensive rats (SHR), in which it may presumably counterbalance vascular wall growth. Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers induce regression of the vascular wall in hypertension. Therefore, we investigated the effect of the ACE inhibitor enalapril and the dihydropyridine calcium channel blocker amlodipine on apoptosis in blood vessels of SHR to determine whether part of the growth inhibitory effect of these drugs is mediated by apoptosis. This was performed by detection and measurement of DNA fragmentation using DNA laddering and examining aortic histologic sections with in situ end-labeling (terminal deoxynucleotide transferase-mediated dUTP-nick labeling [TUNEL]). Ten-week-old SHR were treated for 12 weeks with 10 mg/kg per day of enalapril and 20 mg/kg per day of amlodipine. Blood pressure was significantly reduced by enalapril and amlodipine (P < .01). Cross-sectional area of aorta was significantly increased (3.34+/-0.15 mm2) in SHR compared to that of Wistar-Kyoto (WKY) control rats (1.17+/-0.07 mm2, P < .01). The cross-sectional area of the aorta was significantly smaller in enalapril-treated SHR (2.42+/-0.12 mm2, P < .05) compared to untreated SHR, and almost normalized by amlodipine (1.65+/-0.31 mm2, P < .01). Apoptosis characterized using terminal deoxynucleotidyl transferase to radiolabel 3'-OH ends of fragmented DNA extracted from aorta, showed presence of fragmented labeled DNA as "DNA laddering," a hallmark of apoptosis. SHR had increased apoptosis (341+/-25 pixels/microg DNA) compared to WKY controls (206+/-13 pixels/microg DNA, P < .01). Apoptosis was six- to eightfold greater in aorta of enalapril and amlodipine-treated SHR (P < .01). These results were confirmed by in situ end-labeling of fragmented DNA in aortic histologic sections. Western blot quantification of Bax and Bcl-2 (pro- and antiapoptotic gene products, respectively) showed higher Bax and lower Bcl-2 expression, and accordingly increased the Bax-to-Bcl-2 ratio in aorta from SHR treated with enalapril or amlodipine in comparison to untreated SHR. In conclusion, enhanced apoptosis is present in aorta of SHR, possibly as a homeostatic mechanism counterbalancing growth. Antihypertensive agents such as the ACE inhibitor enalapril and the calcium antagonist amlodipine may cause regression or inhibition of vascular wall growth in SHR partly through enhanced apoptosis, which may contribute to the antihypertensive effects of these drugs.
...
PMID:Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist. 975 97

In vitro experiments suggest that angiotensin II (Ang II) may cause growth via angiotensin type 1 (AT(1)) receptors and apoptosis via angiotensin type 2 (AT(2)) receptors. To answer the question of whether AT(1) or AT(2) receptor activation could induce apoptosis in the vasculature in vivo, Wistar rats were infused for 7 days with Ang II (120 ng. kg(-1). min(-1) subcutaneously) and treated with the AT(2) receptor antagonist PD 123319 (30 mg. kg(-1). d(-1) subcutaneously) or the AT(1) receptor antagonist losartan (10 mg. kg(-1). d(-1) orally). Apoptosis in thoracic aorta was quantified by radiolabeled DNA laddering and by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling. The expression of p53, bax, bcl-2, and caspase-3, which play critical roles in apoptotic signaling, was examined by Western blot analysis. The mRNA expression of AT(1) and AT(2) receptors was determined by reverse transcription-polymerase chain reaction. The increase in systolic blood pressure and aortic growth induced by Ang II infusion was completely prevented by losartan alone or losartan given with PD 123319, whereas PD 123319 resulted in a greater increase in systolic blood pressure and aortic growth than Ang II alone. Radiolabeled DNA laddering showed that Ang II infusion+/-losartan or PD 123319 significantly increased apoptosis (147+/-8%, 178+/-20%, and 238+/-41%, respectively, P<0.05 compared with control). Expression of bax and active forms of caspase-3 was increased in the Ang II+PD 123319 group, whereas the expression of p53 and bcl-2 was not significantly different in all groups. The expression of AT(1) and AT(2) receptor mRNA was downregulated by losartan and PD 123319, respectively. Thus, when AT(1) or AT(2) receptors are stimulated in vivo, apoptosis is enhanced in the media of blood vessels. In the case of AT(1) receptor stimulation, this may occur secondary to vascular growth and modulate the latter. Both bax and caspase-3 participate in the pathways of apoptosis triggered by in vivo AT(1) receptor stimulation.
Hypertension 1999 Oct
PMID:In vivo study of AT(1) and AT(2) angiotensin receptors in apoptosis in rat blood vessels. 1052 36

Apoptosis (programmed cell death) of smooth muscle cells (SMC) in blood vessels is an essential process involved in the control of vessel wall structure. Several antihypertensive drugs currently used in therapy may exert their pharmacological effects by promoting SMC apoptosis. The biochemical events which regulate SMC apoptosis in the vessel wall are complex, and not well understood. We therefore investigated whether treatment of cultured SMC from normotensive Wistar-Kyoto rats (WKY) and from spontaneously hypertensive rats (SHR) with selected antihypertensive drugs would induce SMC apoptosis. We treated aortic SMC from WKY and SHR in vitro with the L-type Ca2+ channel antagonist, nifedipine; with the nitric oxide donor, sodium nitroprusside (SNAP); with forskolin (an activator of adenylyl cyclase); or with thapsigargin (a selective inhibitor of the sarcoplasmic reticulum (SR), Ca2+-ATPase); and compared their apoptosis-promoting effects in SMC derived from the two strains of rats. SMC were derived from the thoracic aorta of 3-4-week-old WKY and SHR, and were used in passages 7-10. Apoptotic cells were detected by in-situ end labeling using the terminal deoxynucleotide transferase-mediated dUTP-nick end-labeling (TUNEL) method, and by morphological examination. We found that: 1) Treatment of cultured aortic SMC with the L-type Ca2+ channel antagonist, nifedipine (5 X 10(-5) M) for 24 hours induced a significantly higher level of apoptosis in SHR cells than in SMC from WKY. Cells from WKY, following exposure to nifedipine for 72 hours, exhibited a similar response to the cells from SHR treated for 24 hours. This was detectable by both morphological criteria as well as DNA labeling by the TUNEL technique. 2) Similar treatment of these cells with thapsigargin (1 x 10(-7) M) led to morphological alterations characteristic of apoptotic cells in SMC from both WKY and SHR, and cells from SHR but not WKY were labeled by the TUNEL technique at 24 hours. The TUNEL method did however identify cells from both WKY and SHR as apoptotic after 48 and 72 hours of treatment. 3) The addition of SNAP, or forskolin to the cultured SMC induced significant, but low levels of apoptosis in WKY SMC only. This selective apoptosis-promoting effect of nifedipine in SHR SMC may result from differences in the control of intracellular Ca2+ between the two strains of cells, or it may indicate that the signaling pathways which regulate apoptosis are different in SMC from the normotensive and the hypertensive rats. Our findings imply that SMC apoptosis may be a selective target for pharmacological intervention in hypertension.
...
PMID:Nifedipine induces apoptosis in cultured vascular smooth muscle cells from spontaneously hypertensive rats. 1094 49

The influence of hypertension on the morphology of hippocampus was assessed in spontaneously hypertensive rats of two, four and six months and in age-matched normotensive Wistar-Kyoto rats. Values of systolic pressure were slightly increased in two-month-old spontaneously hypertensive rats in comparison with age-matched Wistar-Kyoto rats and augmented progressively with age in spontaneously hypertensive rats. No microanatomical changes were observed in the hippocampus of spontaneously hypertensive rats of two months in comparison with age-matched Wistar-Kyoto rats, whereas a decrease of white matter volume was observed in the CA(1) subfield and in the dentate gyrus of four-month-old spontaneously hypertensive rats. In the hippocampus of six-month-old spontaneously hypertensive rats a reduction of grey matter volume both in the CA(1) subfield and in the dentate gyrus, a loss of neurons affecting to a greater extent the CA(1) subfield and an increase of glial fibrillary acid protein-immunoreactive astrocytes was found. The occurrence of apoptosis and/or necrosis identified using the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick end labelling technique was also observed in the CA(1) subfield and to a lesser extent in the dentate gyrus. The only change noticeable in the CA(3) subfield of six-month-old spontaneously hypertensive rats was a slight increase in the number of glial fibrillary acid protein-immunoreactive astrocytes. These findings indicate the occurrence of neuronal loss and of astrocyte changes in the hippocampus of spontaneously hypertensive rats of six months, being the CA(1) subfield the area most affected. The relevance of these neurodegenerative changes in hypertension and the possible occurrence of apoptosis and/or necrosis as expression of hypertensive brain damage is discussed.
...
PMID:The hippocampus in spontaneously hypertensive rats: a quantitative microanatomical study. 1100 65

Vascular remodeling is a key feature of many pathologic states, including atherosclerosis, or hypertension. Vascular smooth muscle cells participate in determining the vessel structure by several mechanisms such as cell migration, cell growth, or cell death (necrosis or apoptosis). Here we report that thapsigargin, an inhibitor of endoplasmic reticulum Ca2+ -adenosine triphosphatase (ATPase), is able to induce apoptosis in human vascular smooth muscle cells (HVSMCs). Apoptosis was assessed by three different methods: differential chromatin binding dye staining. cytoplasmic histone-associated DNA fragments detection by enzyme-linked immunosorbent assay (ELISA) and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). When HVSMCs were treated for 1 h with thapsigargin (100 nM-10 microM), there was a concentration-dependent increase in both parameters 24 h after the thapsigargin pulse. When a time-course experiment was performed, both parameters were significantly enhanced from 3 to 6 h after the exposure to thapsigargin. We conclude that thapsigargin promotes apoptosis in HVSMCs, providing a useful tool for the study of programmed cell death in human vascular smooth muscle.
...
PMID:Thapsigargin induces apoptosis in cultured human aortic smooth muscle cells. 1106 29

This work analyzes the relationship between the number of viable cells and alteration of the cardiomyocytes growth response capacity of the hypertensive rat myocardium. Hypertension was induced in Wistar rats by means of nitric oxide synthesis blockade using NG-nitro-L-arginine methyl ester (L-NAME). L-NAME (12 mg/kg per day) was given to animals in drinking water ad lib for 15 weeks. Proliferating cell nuclear antigen (PCNA) protein expression and the disector method were used to evaluate the proliferation capacity of the cardiomyocytes and its numerical density alteration (Nv[m]), respectively. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and monoclonal antibody to single-stranded DNA were two methods that detected the process of the apoptotic cell death. The association of the p53 expression with the apoptosis was investigated using anti-p53 antibody. The heart weight, body weight, and heart weight/body weight ratio of the control rats increased 114%, 77%, and 22%, respectively, and the Nv[m] decreased 60% (P<0.0001) relative to the L-NAME rats. The cardiomyocytes did not present PCNA labeling, indicating the absence of cellular proliferation. The decline of the Nv[m] was also associated with apoptotic cell death in the myocardium of the hypertensive rats. A p53-dependent pathway seems to mediate the programmed cell death in this model of hypertension.
...
PMID:Influence of the chronic nitric oxide synthesis inhibition on cardiomyocytes number. 1119 80

To determine whether angiotensin type 2 (AT(2)) receptor stimulation induces apoptosis in cardiomyocytes in vivo, we developed transgenic mice overexpressing the AT(2) receptor in a cardiac-specific manner, using the alpha-myosin heavy-chain promoter. Ten- to 12-week-old male homozygous transgenic mice (n=44) and wild-type mice (n=44) were used. Both transgenic and wild-type mice were given either saline (control), a subpressor dose of angiotensin II (100 ng. kg(-1). min(-1)), a pressor dose of angiotensin II (1000 ng. kg(-1). min(-1)) for 14 days, a pressor dose of angiotensin II for 28 days to investigate the effects of stimulation on both angiotensin type 1 (AT(1)) and AT(2) receptors, the AT(1) antagonist L158809 alone, or a combination of angiotensin II (1000 ng. kg(-1). min(-1)) and L158809 for 14 days to investigate the effects of selective AT(2) receptor stimulation. Apoptosis was analyzed in paraffin-embedded ventricular sections by the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) technique. In both transgenic and wild-type mice, administration of a subpressor dose of angiotensin II, L158809, or a combination of angiotensin II and L158809 did not significantly affect the tail-cuff blood pressure or heart-to-body weight ratio, whereas administration of a pressor dose of angiotensin II for 14 or 28 days significantly increased blood pressure and the heart-to-body weight ratio. However, there was no statistical difference between the effects of angiotensin II in transgenic and wild-type mice. The number of TUNEL-positive nuclei was approximately 0 to 10 per 100 000 cardiomyocytes, with no difference between transgenic and wild-type mice, regardless of saline infusion or any stimulation. In infarcted canine myocardial tissue sections for positive control, the number of TUNEL-positive nuclei was increased by 13.8 to 19.1 times compared with those in the noninfarcted myocardium. In conclusion, angiotensin II infusion for a period of 28 days failed to induce cardiomyocyte apoptosis regardless of the presence or absence of cardiac AT(2) receptor overexpression. It is unlikely that in mice the AT(2) receptor is a strong signal to induce cardiomyocyte apoptosis in vivo.
Hypertension 2001 Jun
PMID:Apoptosis is not increased in myocardium overexpressing type 2 angiotensin II receptor in transgenic mice. 1140 83

In proteinuric nephropathies tubular atrophy leads to glomerular-tubule disconnection through an unknown mechanism. Here we studied whether proteinuria promoted glomerular-tubule disconnection in individual nephrons and whether this phenomenon was prevented by an angiotensin-converting enzyme (ACE) inhibitor. Passive Heymann nephritis (PHN) and control rats were studied at 4 and 8 months. Two additional groups of PHN rats received lisinopril (40 mg/L) or a calcium channel blocker (lacidipine, 3 mg/kg) from day 7 after surgery to 8 months. At sacrifice, kidneys were serially sectioned to identify glomerular- tubule abnormalities in individual nephrons and changes in interstitial volume. In PHN rats, the time-dependent increase in proteinuria was paralleled by tubular atrophy leading to glomerular-tubule disconnection and interstitial volume enlargement. Marked apoptosis was invariably found in atrophic tubules in contrast to the absent or very mild terminal dUTP nick-end labeling staining in tubules normally connected to glomeruli in PHN animals. Treatment with an ACE inhibitor prevented hypertension, proteinuria, the formation of atrophic tubuli, glomerular-tubule disconnection and limited the fractional interstitial volume expansion. Although lacidipine limited hypertension, it did not reduce proteinuria or prevent tubular atrophy and disconnection. Multivariate analysis showed that the appearance of atubular glomeruli and the increase in interstitial volume were better predicted by proteinuria than blood pressure. This study suggests that ACE inhibitors effectively prevent glomerular-tubule disconnection possibly by their ability of reducing proteinuria, which in turn favors proximal tubular cell apoptosis. Agents that only reduced hypertension but not proteinuria do not affect tubular behavior.
...
PMID:Angiotensin-converting enzyme inhibition prevents glomerular-tubule disconnection and atrophy in passive Heymann nephritis, an effect not observed with a calcium antagonist. 1169 35


1 2 3 4 5 Next >>

---