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

Left ventricular hypertrophy is very prevalent among patients with renal insufficiency. Known hypertrophic factors, such as systemic hypertension, do not adequately account for the prevalence of left ventricular hypertrophy in these patients. Circulating growth factors may stimulate cardiomyocyte growth and contribute to the development of left ventricular hypertrophy. The effects of sera from patients with (n = 30) and without (n = 5) chronic renal insufficiency on the growth of cultured adult cardiomyocytes were compared. An adult rat cardiomyocyte primary culture system was established with a high purity of cardiomyocyte population as confirmed by immunocytochemical staining of cardiac contractile proteins. Myocytes responded with increased [3H]thymidine incorporation when treated with angiotensin II, epidermal growth factor, hydrocortisone and insulin, and with increased [3H]phenylalanine incorporation when treated with parathormone, isoproterenol, phenylephrine and insulin. Renal insufficiency serum stimulated [3H]thymidine incorporation was 1.5 times that of the control (P < 0.02) and also tended to increase incorporation of [3H]phenylalanine compared to the control (P = N.S.). Increased [3H]thymidine incorporation by renal insufficiency serum did not correlate with serum insulin, parathormone or glucose in the renal insufficiency patients. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) method was used to measure renal insufficiency serum-induced atrial natriuretic peptide mRNA expression in cultured cardiomyocytes. Atrial natriuretic peptide (ANP) mRNA was increased 1-3-fold in cardiomyocytes treated with renal insufficiency sera in comparison to control sera. These data suggest that circulating growth factor(s) may contribute to the development of cardiac hypertrophy in patients with renal insufficiency.
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PMID:Serum from patients with chronic renal insufficiency alters growth characteristics and ANP mRNA expression of adult rat cardiac myocytes. 900 60

Vascular smooth muscle cells (VSMC) contribute to the pathophysiology of hypertension through cell growth and contraction, and phospholipase C (PLC) is a critical effector enzyme in growth factor and vasoconstrictor signaling. There is indirect evidence that angiotensin II (ANG II) receptors are linked to the PLC-beta isoform signaling pathways. However, recent studies suggest that PLC-beta isoforms may not be expressed in VSMC. Our data demonstrate that in human aortic VSMC, PLC-beta 1 and PLC-gamma 1 proteins were detected by immunoblot analysis, and PLC-beta 1 mRNA was identified by reverse transcriptase-polymerase chain reaction in rat aortic VSMC. Incubation of permeabilized VSMC with anti-PLC-beta 1 or anti-Gq alpha antibodies inhibited ANG II-dependent inositol polyphosphate (IP) formation, while anti-PLC-gamma 1 antibodies did not inhibit ANG II-regulated IP formation. Conversely, anti-PLC-gamma 1 antibodies completely abolished platelet-derived growth factor (PDGF)-dependent IP generation, whereas anti-PLC-beta 1 antibodies had no effect on PDGF-induced PLC activation. Inhibition of tyrosine phosphorylation with genistein or herbimycin A did not diminish ANG II-stimulated IP formation or cytosolic free Ca2+ concentration transients, thereby confirming that ANG II signals via a PLC-gamma 1-independent mechanism. In summary, PLC-beta 1 and PLC-gamma 1 are expressed in human aortic VSMC, and PLC-beta 1 is the isoform that is critical for ANG II-regulated PLC signaling in these cells.
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PMID:Angiotensin II activates the beta 1 isoform of phospholipase C in vascular smooth muscle cells. 917 47

A significant body of evidence suggests that the development and maintenance of elevated blood pressure in the spontaneously hypertensive rat (SHR), a genetic model for essential hypertension, is due at least partly to a central hyper-cholinergic state. For example, this strain responds with an exaggerated pressor response to pharmacological stimulation of central muscarinic receptors in certain brain regions compared to normotensive Wistar Kyoto rats (WKY). At least part of the enhanced response to central muscarinic receptor stimulation in SHR is due to the altered expression of post-synaptic receptors. In the present study, the reverse transcriptase-polymerase chain reaction and autoradiographic techniques were used to estimate the relative levels of mRNA and density of receptor binding sites for the five subtypes of muscarinic receptors within the rostral ventrolateral medulla (RVL) of SHR and WKY. Adult (12-week-old) SHR exhibited an increase in the levels of both M2 muscarinic mRNA, and M2 receptor binding sites in RVL compared to age-matched normotensive WKY. Similarly, 4-week-old pre-hypertensive SHR exhibited increased levels of M2 mRNA in whole medulla oblongata, and an increase in the number of binding sites for M2 receptors in the RVL. Since the RVL is known to integrate tonic cholinergic sympathoexcitatory input, these results suggest that the increased expression of M2 muscarinic receptors in this region represents one neurochemical correlate for the maintenance of excessive central efferent sympathetic nervous activity in the SHR. Since the neurochemical change precedes the development of hypertension, the altered medullary M2 receptor expression may play a role as an initiating or predisposing factor for the development of hypertension in SHR.
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PMID:Increased expression of M2 muscarinic receptor mRNA and binding sites in the rostral ventrolateral medulla of spontaneously hypertensive rats. 918 22

The molecular and cellular mechanisms by which hypertension enhances atherosclerosis are poorly understood. Angiotensin II (Ang II) has been implicated in the regulation of cellular lipoxygenases (LO), which are thought to play a role in atherogenesis by inducing oxidative modification of low density lipoprotein (LDL). We sought to test the hypothesis that Ang II would stimulate murine macrophage LO activity (which has both 12- and 15-LO activity). Competitive binding studies revealed the presence of Ang II AT1 receptors on mouse peritoneal macrophages (MPM) and J-774 cells, but not on the RAW cell line. Valsartan, a specific AT1 receptor antagonist inhibited Ang II binding, whereas PD 123319, an AT2 receptor antagonist did not. Incubation of MPM or J-774 cells with Ang II (10 pM to 1 microM) for 24 h led to a 2.5-3.5-fold increase in LO activity, measured as generated 13-HODE or 12(S)-HETE. This stimulation was inhibited by valsartan, but not by PD 123319. In contrast, Ang II did not stimulate LO activity in RAW macrophages. Semiquantitative reverse transcriptase-polymerase chain reaction showed a 2-3-fold increase in LO mRNA in MPM, but not in RAW cells after treatment with Ang II. Ang II also induced an increase in 12-LO protein. In addition, pretreatment of J-774 cells with Ang II increased in a dose-dependent manner the ability of the cells to modify LDL, resulting in greater chemotactic activity for monocytes, typical of minimally modified LDL. This stimulation was inhibited by AT1 receptor blockade. In summary, these data suggest that Ang II increases macrophage LO activity via AT1 receptor-mediated mechanisms and this further increases the ability of the cells to generate minimally oxidized LDL. These studies provide a link between hypertension and the associated increased atherosclerosis observed in hypertensive patients.
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PMID:Angiotensin II increases macrophage-mediated modification of low density lipoprotein via a lipoxygenase-dependent pathway. 926 Nov 83

In the present study, the angiotensin II receptor subtype I-a (AT1a) and I-b (AT1b) mRNA levels in aortic smooth muscle (ASM), ventricular myocardium (VM) and adrenal from 12-week-old stroke-prone spontaneously hypertensive rats (SHRsp) and age-matched Wistar-Kyoto (WKY) rats with normal diet (control) and high salt-loading were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that: (1) The AT1a and AT1b mRNA levels in ASM and VM from SHRsp were lower than those from WKY rats (in ASM, 10% and 23%, while in VM, 23% and 40% lower, respectively). In contrast, both AT1a and AT1b mRNA levels in adrenal from SHRsp were higher (176% and 157%, respectively). (2) In the WKY rats with high salt-loading, the AT1a and AT1b mRNA levels in adrenal, as well as AT1b mRNA level in VM, increased significantly, as compared with the control (in adrenal, 167% and 401%, while in VM, 62%). However, the AT1a and AT1b mRNA levels in ASM, as well as AT1a mRNA level in VM, showed no obvious change. (3) In SHRsp with high salt-loading, the AT1b mRNA level in ASM, as well as AT1a and AT1b mRNA levels in VM, increased markedly (in ASM, 90%, while in VM, 590% and 200%); whereas the AT1a mRNA level in adrenal decreased significantly (58%). There was little influence on the regulation of AT1a (in ASM) and AT1b (in adrenal) receptor gene expression after high salt-loading. The results suggest that AT1a and AT1b receptors may be involved in the pathogenesis of salt-induced hypertension. The up-regulation of AT1b receptors in ASM may induce the remodeling of arterial wall, while that of AT1a and AT1b receptors in VM might contribute to ventricular hypertrophy in hypertension. Furthermore, there are certain differences between SHRsp and WKY rats with respect to the regulation of AT1a and AT1b receptor gene expression with or without external stimulation.
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PMID:[Effects of high salt-loading on the regulation of angiotensin II receptor mRNA expression]. 938 99

Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1A receptors stimulate changes in cytosolic calcium concentration ([Ca2+]i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT1A/AT1B receptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1B receptor mRNA but not that for the AT1A receptor. In wild-type cells with AT1A present, Ang II (10(-7) mol/L) produces a characteristic rapid peak increase in [Ca2+]i of 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca2+]i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca2+]i changes produced by Ang II were similar in cells that lacked AT1A receptors but possessed AT1B receptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT1A receptors suggests that non-AT1A receptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT1A and non-AT1A receptors share common signal transduction pathways. The AT2 receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2 receptors and/or an absence of their linkage to [Ca2+]i pathways. The nonpeptide AT1 receptor blocker losartan antagonizes Ang II-induced [Ca2+]i increases in both cell groups, supporting mediation by native AT1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT1A-deficient VSMCs that is mediated by an endogenous losartan-sensitive AT1B receptor.
Hypertension 1998 May
PMID:Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice. 957 31

The development of hypertension in spontaneously hypertensive rats (SHR) and hyperactive voiding in rats with urethral obstruction are characterized by abnormal smooth muscle growth, increased tissue levels of nerve growth factor (NGF) and altered patterns of innervation. The present study was undertaken to determine if bladder smooth muscle from SHRs contains and secretes elevated levels of NGF, and if so, whether the augmented NGF contributes to changes in bladder innervation and function without tissue hypertrophy. Voiding behavior was monitored using specially designed metabolic cages. NGF levels in tissue homogenates and conditioned cell culture media were measured by ELISA. NGF mRNA in cultured bladder smooth muscle cells (BSMCs) was quantified using reverse transcriptase PCR. Noradrenergic innervation was assessed by staining with glyoxylic acid and assaying norepinephrine (NE) content in bladders with high performance liquid chromatography. SHRs voided more frequently than WKY rats. NGF content was higher in bladders from adult SHRs when compared to Wistar-Kyoto normotensive rats (WKYs). No significant difference in NGF mRNA content was observed between SHR and WKY BSMCs. However, SHR BSMCs secreted NGF at a higher rate and amount per unit mRNA than did WKY BSMCs. SHR bladders contained more NE and were more densely stained for catecholaminergic fibers than bladders from WKY rats. The results support the hypothesis that elevated NGF secretion by bladder smooth muscle is associated with hyperinnervation of bladder and hyperactive voiding in SHRs. Thus, the SHR strain may represent a genetic model to study changes in bladder function resulting from altered patterns of innervation.
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PMID:Neurally mediated hyperactive voiding in spontaneously hypertensive rats. 959 70

To assess the chronic in vivo effects of OPC-21268, a vasopressin-V1 receptor antagonist, on renal injury, we investigated the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta1 and proliferating cell nuclear antigen (PCNA) in the glomeruli of spontaneously hypertensive rats (SHR) treated with OPC-21268 for 3 weeks. SHR aged 10 weeks were given 2% NaCl in drinking water for 3 weeks. The OPC group was fed a 0.5% OPC-21268-containing diet for 3 weeks and the control group was given a normal diet. There were no significant changes in the time course of systolic blood pressure, heart rate, urine volume, or urinary sodium, protein and N-acetyl-beta-glucosaminidase (NAG) excretion between the two groups. Serum electrolytes, protein and creatinine levels also did not differ between the groups. The mRNA expressions of PDGF B-chain, TGF-beta1 and PCNA in the glomerulus were examined using reverse transcriptase-polymerase chain reaction (RT-PCR) methods. The mRNA expressions of PDGF B-chain and PCNA among these were significantly suppressed in the OPC group. No significant differences in renal histology including the organ weights were found between the two groups; however, the glomerular size tended to be enlarged in the OPC group. These findings suggest that chronic V1-receptor blockade directly inhibits the glomerular proliferative injury of salt-loaded SHR at the established hypertension stage.
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PMID:Effects of OPC-21268, a vasopressin V1-receptor antagonist, on expression of growth factors from glomeruli in spontaneously hypertensive rats. 965 81

Superoxide radical (O2-) is ubiquitously critical to the bioactivity of endothelial nitric oxide. In angiotensin-dependent hypertension, vascular O2- levels rise and impede endothelium/nitric oxide-dependent vascular relaxation. We have reported that the major O2- source in the rabbit aorta is adventitial fibroblast phagocyte-like NADPH oxidase and shown that angiotensin (Ang) II treatment of adventitial fibroblasts causes a concentration-dependent increase in particulate NADPH-dependent O2-. From cultured rabbit aortic adventitial fibroblasts treated or not treated with Ang II, we prepared particulate fractions and measured lucigenin-enhanced chemiluminescence. Because [Sar1,Thr8]-Ang II, a generalized antagonist of Ang II and plausible inhibitor of the conversion of Ang II, reversed Ang II (10 nmol/L)-induced NADH- and NADPH-dependent O2- to basal levels, we tested the effect of the inhibitor of aminopeptidase N, amastatin (10 micromol/L), and found no effect on Ang II-stimulated O2-. Ang(1-7), Ang III, and Ang IV also were not effective in stimulating O2- levels at concentrations similar to those of Ang II. Kinetic analysis showed a rise in NADPH oxidase O2- production in response to Ang II, which peaks at 3 hours and returns to basal levels by 16 hours. p67phox, a cytosolic factor, appears to be affected at both the level of transcription and protein synthesis because actinomycin and cycloheximide individually inhibited the observed effect. A partial sequence of p67phox was recovered by reverse transcriptase from mRNA harvested from cultured rabbit aortic adventitial fibroblasts. Furthermore, the p67phox mRNA transcript in aortic fibroblasts is induced by Ang II before the peak of NADPH oxidase by Northern analysis and ribonuclease protection assays. These data suggest that Ang II stimulates NAD(P)H oxidase O2- generation in fibroblasts of aortic adventitia via transcriptional activation of p67phox. These data also provide preliminary evidence for the regulation of factors of the NADPH oxidase and potentially provide a novel means by which to abrogate the development of O2(-)-dependent hypertension.
Hypertension 1998 Aug
PMID:Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. 971 63

Estrogen replacement therapy is cardioprotective in postmenopausal women; however, the precise molecular mechanisms for this modulation are not fully elucidated. We previously showed that chronic estrogen replacement therapy reduced angiotensin-converting enzyme (ACE) activity in tissue extracts and serum with an associated reduction in plasma angiotensin II. A reverse transcriptase-polymerase chain reaction assay was developed to determine whether estrogen treatment regulates tissue ACE mRNA concentration. Total RNA was isolated from kidney cortex, kidney medulla, lung, and aorta of ovariectomized Sprague-Dawley rats after 21 days of chronic 17beta-estradiol replacement therapy (5 mg pellet per rat SC) or placebo. A marked decrease in densitometric intensity ratios of amplified ACE cDNA to elongation factor-1alpha control cDNA was observed in all tissues from placebo-treated rats compared with the estradiol-treated rats (renal cortex: 0.29+/-0.04 versus 0.14+/-0.02; renal medulla: 0. 37+/-0.04 versus 0.24+/-0.03; lung: 4.49+/-0.37 versus 2.49+/-0.59; and aorta: 0.41+/-0.04 versus 0.29+/-0.02; all P<0.05). A comparable reduction in ACE activity was detected in tissue extracts from kidney cortex, kidney medulla, and lung of hormone-treated animals. Incubation of purified rat lung ACE with 1 or 10 micromol/L 17beta-estradiol had no effect on enzyme activity. These results suggest that estrogen treatment regulates tissue ACE activity by reducing ACE mRNA concentrations. Thus, the beneficial cardiovascular effects of estrogen may be mediated in part by downregulation of ACE with a consequent reduction in the circulating levels of the vasoconstrictor angiotensin II, a decrease in the metabolism of the vasodilator bradykinin, and an increase in the production of the vasorelaxant angiotensin-(1-7).
Hypertension 1999 Jan
PMID:Estrogen regulation of angiotensin-converting enzyme mRNA. 993 Nov 24


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