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

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

Adrenomedullin (AM), identified from pheochromocytoma and having 52 amino acids, elicits a long-lasting vasodilatation and diuresis. AM is mainly mediated by the intracellular adenylate cyclase coupled with cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) pathway through its specific receptor. The calcitonin receptor-like receptor (CLCR) and receptor-activity modifying protein (RAMP) 2 or RAMP3 models have been proposed as the candidate receptor. AM is produced mainly in cardiovascular tissues in response to stimuli such as shear stress and stretch, hormonal factors and cytokines. Recently established AM knockout mice lines revealed that AM is essential for development of vitelline vessels of embryo. Plasma AM levels elevate in cardiovascular diseases such as heart failure, hypertension and septic shock, where AM may play protective roles through its characteristic biological activities. Human AM gene delivery improves hypertension, renal function, cardiac hypertrophy and nephrosclerosis in the hypertensive rats. AM decreases cardiac preload and afterload and improves cardiac contractility and diuresis in patients with heart failure and hypertension. Advances in gene engineering and receptor studies may contribute to further understandings of biological implication and therapeutic availability of AM.
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PMID:A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. 1175 55

Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N(G)-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure.
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PMID:Nitric oxide reduces blood pressure in the nucleus tractus solitarius: a real time electrochemical study. 1184 23

Preeclampsia (PE) is a leading cause of maternal hypertension in pregnancy, fetal growth restriction, premature birth, and fetal and maternal mortality (1). Activation and dysfunction of the maternal and fetal endothelium in PE may be the consequence of increased oxidative stress associated with circulating lipid peroxides (2-4), and in cases of severe maternal hypertension, uterine and umbilical artery waveforms are abnormal (5). We have investigated PE-associated abnormalities in the regulation of intracellular Ca2+ ([Ca2+]i) and cyclic guanosine monophosphate (cGMP) production (index of nitric oxide [NO]) in human fetal umbilical vein endothelial cells. Basal [Ca2+]i was slightly elevated in PE cells, whereas agonist-stimulated Ca2+ entry was reduced in cells from PE compared with normal term or age-matched preterm pregnancies. Furthermore, PE cells exhibited a decreased permeability to Ba2+ but an increased permeability to Mn2+ and Gd3+, suggesting that PE is associated with phenotypic alterations in fetal endothelial cation channel(s). Basal and histamine-stimulated cGMP levels were elevated in PE compared with preterm or normal cells, implying an increased NO production in PE. However, immunoblots for endothelial NO synthase (eNOS) and soluble guanylyl cyclase (sGC) revealed reduced eNOS expression in PE and preterm cells, with negligible changes in sGC levels. This study provides important and novel insights into abnormalities of fetal endothelial cells isolated from women with PE, reveal ing an altered cation membrane permeability and activity of eNOS-sGC pathway. As these changes are sustained in culture in vitro, this may reflect long-term "programming" of the fetal cardiovascular system.
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PMID:Preeclampsia is associated with altered Ca2+ regulation and NO production in human fetal venous endothelial cells. 1192 25

Inhalation of nitric oxide (NO) is widely employed for the assessment of pulmonary vasoresponsiveness in pulmonary hypertension (PH). However, the reasons for the huge differences in vascular reactivity to NO between patients are unknown, and the role of NO-induced cyclic guanosine monophosphate (cGMP) is unclear. Twenty patients with severe precapillary PH were investigated. Thirty-six Swan-Ganz catheter investigations were performed and the study subjects were tested for responses to NO inhalation. This included an assessment of pulmonary and systemic arterial plasma cGMP and atrial natriuretic peptide (ANP) levels. A significant NO response (pulmonary vascular resistance (PVR) decrease >20%) was noted in nine of 20 patients (45%) during the first catheterization. A highly significant correlation between baseline plasma cGMP and ANP levels with PVR was observed (r=0.62 and r=0.66, respectively; p<0.0001). In response to NO, systemic and mixed venous cGMP levels increased from 13.9 +/- 1.28 nM and 12.75 +/- 0.99 nM to 79.23 +/- 4.99 nM and 55.25 +/- 4.41 nM (p<0.001), respectively, accompanied by the appearance of a marked transpulmonary cGMP gradient. Although in the responder group ANP levels were significantly reduced after NO inhalation, no significant correlation was observed to the extent of PVR reduction. The magnitude of the NO-elicited cGMP response did not discriminate between haemodynamic responders and nonresponders. This study concludes that plasma cyclic guanosine monophosphate levels are significantly correlated with the severity of disease in pulmonary arterial hypertension. Nitric oxide inhalation provokes a prompt increase in cyclic guanosine monophosphate secretion, but the magnitude of this release is not linked with a decrease in pulmonary vascular resistance.
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PMID:Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders. 1199 96

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.
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PMID:Vasoprotection by nitric oxide: mechanisms and therapeutic potential. 1212 64

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Both carbon monoxide (CO), the product of heme oxygenase (HO), and nitric oxide (NO) elevate cyclic guanosine monophosphate levels in smooth muscle cells, leading to relaxation of the vessels. We examined the hypothesis that the effect of CO in regulating blood pressure could be augmented in hypertension where the function and/or production of NO is impaired. We used two hypertensive models, a spontaneously hypertensive rat (SHR), and a Wistar Kyoto rat (WKY) which was given the NO synthase (NOS) inhibitor N(omega)-nitro- L-arginine (L-NNA). In these hypertensive rats, we examined HO gene expression with Northern blot analysis, guanosine 3',5'-monophosphate (cGMP) levels with enzyme-linked immunosorbent assay of each organ, and the response of blood pressure to treatment with an HO substrate (hemin, 23 micromol/kg body weight, i.p.) or HO inhibitor (zinc or tin protoporphyrin-IX; ZnPP or SnPP, 50 micromol/kg body weight i.p. or s.c.), for 4 or 8 consecutive days with plethysmography. Northern blot analysis showed that HO-1 and -2 mRNA levels in the left ventricle, aorta, kidney, and soleus muscle in the hypertensive rats were 2-5 times higher than those in control normotensive WKYrats. In contrast, both HO mRNA levels in the gastrocnemius muscle in the hypertensive rats were similar to those in control WKYrats. As to whether the HO/CO system contributes to the regulation of blood pressure, ZnPP or SnPP increased and hemin decreased systolic blood pressure (SBP), respectively, in the hypertensive rats (P < 0.01), but not in WKYrats, accompanied with changes in cGMP in each organ of the hypertensive rats. The effect of CO in the regulation of blood pressure is augmented, resulting in increased expression of HO gene when the function and/or production of NO is impaired.
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PMID:Carbon monoxide regulates blood pressure cooperatively with nitric oxide in hypertensive rats. 1218 92

Abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. Recently, there has been an indication that leptin, the product of the human obesity gene, actively participates not only in the metabolic regulations but also in the control of cardiovascular functions. In the present study, to assess the role of leptin in the regulation of membrane properties, the effects of leptin on membrane fluidity of erythrocytes in humans are examined. The membrane fluidity of erythrocytes in healthy volunteers by means of an electron paramagnetic resonance (EPR) and spin-labeling method is determined. In an in vitro study, leptin decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS obtained from EPR spectra of erythrocyte membranes in a dose-dependent manner in healthy volunteers. The finding indicated that leptin increased the membrane fluidity and improved the microviscosity of erythrocytes. The effect of leptin on the membrane fluidity was significantly potentiated by the nitric oxide (NO) donors, L-arginine and S-nitroso-N-acetylpenicillamine (SNAP), and a cyclic guanosine monophosphate (cGMP) analog, 8-bromo-cGMP. In contrast, the change evoked by leptin was significantly attenuated in the presence of the NO synthase inhibitors, N(G)-nitro-L-arginine-methyl-ester (L-NAME) and asymmetric dimethyl-L-arginine (ADMA). The results of the present study showed that leptin increased the membrane fluidity and improved the rigidity of cell membranes to some extent via an NO- and cGMP-dependent mechanism. Furthermore, the data also suggest that leptin might have a crucial role in the regulation of rheological behavior of erythrocytes and microcirculation in humans.
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PMID:Leptin improves membrane fluidity of erythrocytes in humans via a nitric oxide-dependent mechanism--an electron paramagnetic resonance investigation. 1227 Jan 47

The incidence of erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, increases with age and with risk factors for vascular disease, including smoking, diabetes and hypertension. Penile erection results from an arousal-induced synthesis of nitric oxide (NO) in nonadrenergic-noncholinergic nerves (NANC), endothelial cells and cavernosal smooth muscle cells (SMCs). Vasodilation and relaxation of cavernosal SMCs engorges the corpora cavernosa with blood at arterial pressure. The subcellular mechanism by which tumescence occurs involves NO-induced activation of soluble guanylate cyclase, increased cyclic guanosine monophosphate (cGMP) levels and activation of cGMP-dependent protein kinase (PKG). PKG phosphorylates numerous ion channels and pumps, each promoting a reduction in cytosolic calcium. In particular, PKG activates high-conductance Ca2+(-)sensitive K+ (BKCa) channels, which hyperpolarize the arterial and cavernosal SMC membranes, causing relaxation. This mechanism appears to be compromised with age and with vascular disease, leading to ED. Thus, increasing cavernosal nitric oxide synthase (NOS) expression, cGMP levels and/or BKCa channel expression is an effective therapy for experimental ED. Future therapies may involve augmenting K+ channel expression by gene transfer or increasing channel function through the use of Type 5 phosphodiesterase (Type 5 PDE) inhibitors or phosphatase inhibitors.
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PMID:Potassium channels and erectile dysfunction. 1237 24

Nitroglycerin-mediated vasorelaxation is chiefly attributed to the cyclic guanosine monophosphate (cGMP)-dependent pathway, and partly to the cGMP-independent pathway via calcium-activated K(+) channels (K(Ca)). To investigate whether chronic hypertension alters responses of vascular smooth muscle to vasoactive agonists, we determined nitroglycerin-mediated relaxation of aortic rings from coarctation hypertensive rats. Banding the abdominal aorta above the renal arteries for 4 weeks elevated blood pressure and caused cardiac hypertrophy by 49%. In response to nitroglycerin, the relaxation of aortic rings precontracted with 10(-7) M norepinephrine was lower in the banded group than in the sham-operated group. Methylene blue, a guanylate cyclase inhibitor, suppressed a greater part of nitroglycerin-mediated relaxation and reached similar levels of relaxation in the two groups. Charybdotoxin, a specific K(Ca) channel blocker, also suppressed the relaxation by about 40% in the aortic rings from sham-operated animals, but not in those from the banded group. The response to charybdotoxin was markedly diminished or virtually eliminated in the banded group in the presence or absence of methylene blue. The combination of charybdotoxin and methylene blue nearly abolished nitroglycerin-mediated relaxation in the sham-operated group, whereas nitroglycerin-mediated relaxation was seen to remain in the banded group. These results indicate that the involvement of cGMP-independent K(Ca) channels in nitroglycerin-mediated relaxation disappeared after the development of hypertension produced by aortic coarctation.
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PMID:Relaxant properties mediated by nitroglycerin in aortic coarctation hypertensive rats. 1254 Oct 97


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