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)

Preeclampsia (gestational hypertension) is accompanied by decreased hPL and increased hCG levels in maternal serum. The expression of these peptides as well as the endocrine mechanisms responsible for their regulation in preeclampsia are unknown. We have demonstrated that regulatory GTP-binding proteins (G proteins) are implicated in the modulation of hPL production by placentas from normal pregnancies. In order to extend our knowledge on placental endocrinology, we analyzed in this study the expression of hPL and beta-hCG mRNAs as well as placental G protein alpha-subunits in pregnancies complicated by gestational hypertension. Western and Northern blot analyses were respectively performed on membrane protein and total mRNA preparations from human placentas of preeclamptic (n = 7) and normal pregnancies (n = 4). The levels of hPL and beta-hCG mRNAs were respectively 108% and 105% of those from normal placentas, suggesting that the altered circulating levels of hPL and beta-hCG are not related to dysfunctional mRNA expression of these peptides. The autoradiographs for G proteins and their mRNAs showed no difference in G protein expression between preeclamptic and normal tissues. Specifically, G alpha i2, G alpha i3, G alpha o, G alpha s, and G alpha q/11 levels reached 87%, 81%, 91%, 99%, and 103% respectively of those from normal placentas. In parallel with the protein levels, their mRNAs expression were respectively 93%, 89%, 113%, 104%, and 94% of normal values for G alpha i2, G alpha i3, G alpha o, G alpha s, and G alpha q/11. These results suggest that neither a change in hPL and beta-hCG expression nor a change in signal transduction machinery is implicated in the altered circulating levels of hPL and beta-hCG in preeclampsia.
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PMID:Expression of G proteins in human placentas from pregnancies complicated by gestational hypertension. 906 Oct 52

The sensitivity of the myofilaments to Ca2+ is increased during agonist-induced contraction of vascular smooth muscle. Given the important contribution of vascular tone to the elevation of peripheral resistance observed in genetic hypertension, we have investigated whether alterations in myofilament Ca2+ sensitivity occur in small arteries from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls during the developmental and established phases of hypertension. Segments of mesenteric, renal, and femoral artery with an average lumen diameter <300 microm from 5- or 20-week-old rats were mounted in a wire myograph. Morphological measurements were made and the vessels permeabilized with Staphylococcus aureus alpha-toxin. Dose-response curves to increasing concentrations of Ca2+ were obtained and the ability of 100 nmol/L endothelin-1 (ET-1) or 10 micromol/L norepinephrine (NE) in the presence of 10 micromol/L GTP to enhance tension in response to low Ca2+ (pCa6.7) was determined. Systolic, diastolic, and mean blood pressures were higher in SHR than in WKY at 5 and 20 weeks. The media thickness:lumen diameter ratio was increased in mesenteric and femoral arteries from SHR compared with WKY at 5 and 20 weeks. There was no difference in media thickness:lumen diameter ratio in renal arteries or between 5- and 20-week animals in any vascular bed. The pCa curves were not different in mesenteric, renal, or femoral arteries from hypertensive compared with normotensive rats or between age groups, except in femoral arteries at 20 weeks, which exhibited a greater sensitivity to Ca2+ in SHR. Tension developed in response to maximal Ca2+ (pCa5.0) was greater in permeabilized mesenteric arteries from SHR compared with WKY at 20 weeks of age only; media stress was again similar in both strains but increased in older animals compared with younger animals in mesenteric arteries from WKY. The submaximal contraction induced by pCa6.7 was greater in femoral and renal than mesenteric arteries. GTP (10 micromol/L) augmented the tension developed to pCa6.7 in mesenteric arteries at 5 and 20 weeks and in renal arteries at 20 weeks. Addition of 100 nmol/L ET-1 or 10 micromol/L NE in the continued presence of GTP markedly increased tension in mesenteric arteries at 5 and 20 weeks. In renal arteries, 10 micromol/L NE enhanced Ca2+ sensitivity in the presence of GTP in SHR at 5 and 20 weeks and WKY at 5 weeks. In femoral arteries, there was a tendency for ET-1 and NE to increase Ca2+ sensitivity, but this increase was significant in WKY at 20 weeks (ET-1) and SHR at 5 weeks (NE) only. We have demonstrated that the sensitivity of the myofilaments to Ca2+ and ET-1- or NE-induced Ca2+ sensitization is not different in permeabilized small mesenteric, renal, or femoral arteries from SHR compared with WKY controls. Only in SHR mesenteric arteries at 20 weeks of age was there evidence of increased active tension in response to maximal Ca2+, despite structural differences, consistent with increased muscle mass in femoral arteries from SHR. We conclude that it is unlikely that a ubiquitous abnormality of the sensitivity of the contractile apparatus to Ca2+ or agonist-induced Ca2+ sensitization in vascular smooth muscle underlies the elevated total peripheral resistance associated with hypertension.
Hypertension 1997 Sep
PMID:Calcium sensitivity and agonist-induced calcium sensitization in small arteries of young and adult spontaneously hypertensive rats. 931 30

The effect of parathyroid hormone-related protein on interleukin-1beta-induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1beta time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone-related protein(1-34) alone up to 10(-7) mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid hormone-related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1beta or interleukin-1beta with parathyroid hormone-related protein(1-34) was completely inhibited by coincubation with 3x10(-3) mol/L N(G)-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase, or with 10(-3) mol/L 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin-1 potentiated interleukin-1beta induction of nitric oxide, which might be mediated by endogenous parathyroid hormone-related protein. Neutralization of exogenous or endogenous parathyroid hormone-related protein with antibody attenuated the synergistic effect of parathyroid hormone-related protein, but did not affect interleukin-1beta induction of nitric oxide. These results suggest that locally produced parathyroid hormone-related protein acts as a synergistic regulator upregulating interleukin-1beta-induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.
Hypertension 1997 Oct
PMID:Parathyroid hormone-related protein upregulates interleukin-1beta-induced nitric oxide synthesis. 933 94

Vasoactive peptides such as angiotensin II (AII), atrial natriuretic peptide (ANP) and vasopressin play an important role in the regulation of blood pressure. We have recently shown an augmentation of Gi alpha levels in heart and aorta from genetic and experimentally-induced hypertensive rats, which may be attributed to the increased levels of vasoactive peptides. We have therefore investigated the effect of AII and ANP on the expression of G-proteins (Gi alpha and Gs alpha) in cultured vascular smooth muscle cells (VSMC) and their relationship with adenylyl cyclase activity. Exposure of VSMC with AII resulted in the augmentation of the levels of Gi alpha-2 and Gi alpha-3 proteins and Gi alpha-2 and Gi alpha-3 mRNA and not of Gs alpha as determined by immunoblotting and Northern blotting techniques respectively. However, the stimulatory effects of N-ethylcarboxamide adenosine (NECA) and isoproterenol on adenylyl cyclase was diminished by AII treatment, whereas the inhibitory effects of AII and C-ANP4-23 were completely attenuated. On the other hand, pretreatment of the cells with C-ANP4-23 resulted in the reduction of the levels of Gi alpha-2 and Gi alpha-3 and not of Gs alpha. The inhibitory responses of adenylyl cyclase to C-ANP4-23 and AII were also attenuated and the stimulatory effects of GTP gamma S and other agonists were significantly augmented. These data indicate that AII and ANP modulate the expression of Gia protein in a different manner. It may be suggested that the enhanced levels of Gi alpha protein observed in hypertension may be attributed to the augmented levels of AII and not to ANP.
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PMID:Differential regulation of G-protein expression by vasoactive peptides. 940 40

This study examines the involvement of GTP-binding proteins (Gps) in the regulation of Na+/H+ exchange and Ca2+ influx, which are increased in vascular smooth muscle cells from spontaneously hypertensive rats. Gp activity was modulated by fluoride, GTPgammaS, GDPbetaS, and antisense oligodeoxynucleotides complementary to conserved regions of the alpha- and beta-subunits of Gps (alpha-comm and beta-comm, respectively). Beta-adrenergic-induced Gs-mediated cAMP production was used as a positive control to estimate the efficiency of these compounds. Na+/H+ exchange, measured as ethylisopropyl amiloride-sensitive 22Na influx, was activated by 5- to 6-fold by a 30-minute preincubation of cells with 10 mmol/L NaF with a K0.5 for NaF of approximately 13 mmol/L. In contrast, no activation of 45Ca influx was observed under preincubation of vascular smooth muscle cells with NaF in Ca2+-free medium, whereas at [Ca2+]o >0.5 mmol/L, simultaneous addition of 45Ca and 10 mmol/L NaF led to sharply increased isotope uptake. NaF-induced 45Ca influx did not reach saturation up to 3 mmol/L [Ca2+]o and 20 mmol/L NaF and was correlated with the formation of calcium-fluoride complexes measured by light scattering. GTPgammaS increased basal cAMP production and Na+/H+ exchange, whereas GDPbetaS decreased isoproterenol-induced cAMP production and Na+/H+ exchange. Alpha-comm reduced whereas beta-comm augmented isoproterenol-induced cAMP production by 70%. Both oligodeoxynucleotides decreased basal Na+/H+ exchange by 40% to 50%. NaF-induced Na+/H+ exchange was not sensitive to alpha-comm but was inhibited by 60% in beta-comm-loaded cells. Neither basal nor NaF-induced 45Ca uptake was affected by GTPgammaS, GDPbetaS, and the oligodeoxynucleotides. Our results show that 45Ca uptake is activated by NaF in vascular smooth muscle cells by nonspecific accumulation of calcium-fluoride complexes and is not related to modification of Gps. On the contrary, the Na+/H+ exchanger is controlled by Gps, and Gp beta-subunits are involved in [Ca2+]o-independent activation of this carrier by NaF.
Hypertension 1998 Jan
PMID:Na+/H+ exchange in vascular smooth muscle cells is controlled by GTP-binding proteins. 945 13

Beta-adrenoceptors are members of a large family of hormone and neurotransmitter receptors that initiate their biological function by coupling to GTP-binding regulatory proteins. beta-Adrenoceptors can be subdivided into two main subgroups, designated beta1 and beta2. Atypical beta-adrenoceptors or beta3-adrenoceptors, which are present on adipocytes, have been demonstrated pharmacologically. Their function in adipose tissue is currently being investigated. Beta2-adrenoceptor agonists have played a key role in the treatment of asthma for some 30 years, being used for the relief and prophylaxis of symptoms. There is, however, no evidence that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. In neuropsychiatry, beta-adrenoceptor antagonists have been used for the treatment of acute stress reactions and generalised anxiety, essential tremor and prophylaxis of migraine. In general, they are effective in anxiety disorders if the somatic symptoms are not extreme. For prophylactic treatment of migraine, beta-adrenoceptor antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs of first choice. In cardiology, beta-adrenoceptor antagonists are an important class for the treatment of high blood pressure, arrhythmias and angina pectoris, and for prevention of myocardial infarction. With chronic treatment, they reduce mortality in hypertension and prolong survival in patients with coronary heart disease.
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PMID:Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. 955 98

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal regulated kinase (ERK) activity in a pertussis toxin insensitive manner. This ERK activation was abolished by the Gq-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or TMB-8 abolished Ang II induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21(Ras), which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21(Ras). These findings demonstrate that in cardiac fibroblasts, Ang II induced Ras/ERK activation is dominantly regulated by Gq-coupled Ca2+/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II induced Ras/ERK pathway.
Hypertension 1998 Oct
PMID:Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. 977 61

In 32 published reports in surgical patients, the preponderance of evidence from standard clinical measures of renal function (BUN and Cr) indicates the absence of renal toxicity following sevoflurane anesthesia. Studies of surgical patients receiving intermediate-duration sevoflurane with high or low fresh gas flow and long-duration sevoflurane with high fresh gas flow included sensitive measures of renal function and/or injury, which also indicate the absence of renal toxicity following sevoflurane anesthesia. Studies of surgical patients receiving long-duration sevoflurane with low fresh gas flow did not include sensitive measures. Seven studies in volunteers are not directly relevant to clinical practice but do raise the issue of whether it is important to apply sensitive measures of renal function and/or injury such as urine concentrations and/or excretion of NAG, beta 2M, alpha 1M, AAP, alpha GST, pi GST, gamma GTP, albumin, protein, and glucose and Cr clearance. Two studies of volunteers receiving prolonged sevoflurane anesthesia with fresh gas flow no greater than 2 L/min concluded that the potential for adverse renal effects of sevoflurane may exist. The other studies of volunteers did not. In 14 published reports of surgical patients in special conditions, the preponderance of evidence from standard clinical measures of renal function indicates the absence of renal toxicity. Studies with sensitive measures have been reported for some conditions where the kidney may be at increased risk (e.g., sevoflurane-induced hypotension, advanced age, and renal insufficiency and failure), are incomplete in others (e.g., hypertension and ischemic heart disease), and are missing in others (e.g., morbid obesity). Studies with sensitive measures of renal function and/or injury are also missing in an important group where the kidney may not be at increased risk--pediatric patients. Studies of other risk conditions, such as temporary ischemia, hemorrhagic hypotension, nephrotoxic antibiotics, kidney transplantation, and diabetes may provide additional information about the renal effects of sevoflurane.
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PMID:Renal effects of sevoflurane during conditions of possible increased risk. 980 93

-Natriuretic peptides suppress adrenergic neurotransmission by a mechanism sensitive to pertussis toxin, suggesting that GTP-binding proteins are involved in the response. The major GTP-binding proteins present in the pheochromocytoma (PC12) cells used in this report are Goalpha and Gialpha2. We tested the hypothesis that the more abundant GTP-binding protein, Goalpha, mediates natriuretic peptide effects in PC12 cells by selectively ablating Goalpha from the cells with antisense oligodeoxynucleotides. The results indicate that a selective ablation of Goalpha with this technique eliminated C-type natriuretic peptide (CNP) effects and suppressed dopamine efflux evoked by a depolarizing stimulus. However, the activation of guanylyl cyclase (GC) by CNP was sustained after the Goalpha ablation. Further, Nomega-nitro-L-arginine methyl ester suppressed evoked dopamine efflux equally in the presence and absence of Goalpha. These results suggest that CNP attenuates evoked catecholamine efflux from PC12 cells by a mechanism requiring Goalpha but independent of GC activation.
Hypertension 1999 Jan
PMID:C-type natriuretic peptide attenuates evoked dopamine efflux by influencing Goalpha. 993 Oct 92


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