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

Nitric oxide (NO) is a major paracrine mediator and important regulatory agent in various female reproductive processes, such as ovulation, implantation, pregnancy maintenance, labor and delivery. Ovulation: Circulating NO-products are increased during follicle development and decreased right after ovulation. INOS-inhibition results in a 50% reduction of ovulation, an effect completely reversed by an NO. Endometrium/Implantation: NO also regulates endometrial functions such as endometrial receptivity, implantation and menstruation. NO-donors may be useful for promoting fertility, while NO-inhibitors might be used for contraception. Uterine contractility: Throughout gestation myometrial NO-production is upregulated thus contributing to achieve uterine quiescence. Close to term, NO-production decreases promoting effective contractions resulting in labor. Clinical trials have demonstrated that NO-donors are effective tocolytics. Cervical ripening: In contrast to the myometrium, NO-production in the cervix is low during gestation and becomes upregulated once pregnancy advances to term. NO-donors are effective and safe cervical ripening agents. This finding from animal studies has been confirmed by several clinical trials. Vasoreactivity: In blood vessels, NO is a potent vasodilator and platelet-aggregation-inhibitor. Lack of NO during gestation was related to the development of pregnancy-induced hypertension and preeclampsia. In conclusion, NO-donors and NOS-inhibitors may provide novel, effective, safe, and inexpensive drugs to regulate and steer various functions in female reproductive life. The benefits reach from contraception to preventing possibly lethal pregnancy complications such as preeclampsia. Introducing NO-donors as tocolytics and cervical ripening agents may contribute to a reduction of fetal and maternal perinatal morbidity and mortality.
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PMID:Nitric oxide and its role during pregnancy: from ovulation to delivery. 1257 Aug 14

Adrenomedullin (AM) inhibits vascular smooth muscle cell proliferation stimulated by fetal calf serum and platelet-derived growth factor in vitro. In this study, an adenovirus expressing AM (AxCAAM) was created to examine the in vivo action of AM. Femoral arteries of Wistar rats were wrapped with a silicone cuff and treated with adenovirus expressing Escherichia coli beta-galactosidase (AxCALacZ) or AxCAAM. Immunoreactivity for endothelial nitric oxide synthase (eNOS) was reduced in the endothelium of cuff-injured arteries and was associated with increased local DNA synthesis. Consequently, the intimal formation measured by the intimal-to-medial ratio was significantly increased at 14 and 28 days after the cuff placement. AxCAAM-infected arteries increased the expression of eNOS in the endothelium and inducible NOS in the media and the adventitia. AxCAAM significantly decreased the intimal-to-medial ratio by 40% at 14 days and 51% at 28 days, whereas AxCALacZ showed no changes compared with cuff-injured control arteries. AM overexpression effectively limits intimal hyperplasia by reducing cell proliferation through a nitric oxide-dependent pathway of eNOS. Our findings suggest the possibility of a therapeutic use of the AM gene for the prevention of vascular proliferative disorders.
Hypertension 2003 Feb
PMID:Adrenomedullin overexpression to inhibit cuff-induced arterial intimal formation. 1257 99

Increased steady shear stress stimulates nitric oxide synthase (eNOS) in part by Akt-dependent phosphorylation. Arteries in vivo are exposed to pulse perfusion (PP) combining phasic shear with stretch. In compliant vessels, enhancing PP lowers vascular tone by stimulating eNOS; whereas in aged, stiff arteries, flow-mediated dilation declines and PP is a prominent risk factor. Here, we tested the hypothesis that reduced wall distensibility alters PP-induced eNOS/Akt mechano-signaling. Bovine aortic endothelial cells cultured within distensible tubes were exposed to physiological nonreversing steady or PP (7 dynes/cm(2) mean shear, pulse pressure 0 or 90 mm Hgx2 hours) in a custom servo-system. In compliant tubes, PP doubled Akt phosphorylation above nonpulsatile flow levels, whereas P-Akt declined to static levels from PP in stiffer tubes. eNOS phosphorylation (S-1179) similarly increased with PP in compliant tubes but was nearly undetectable with increased PP in stiffer tubes. After PP, brief exposure of cells to ultraviolet irradiation (oxidant stress) and subsequent culture revealed cytoprotection in compliant tubes but diffuse cytotoxicity and cell detachment in stiffer tubes. NOS inhibition by L-NAME converted compliant-tube post-UV behavior to that of stiffer tubes. These data provide novel evidence that wall compliance can directionally mediate endothelial Akt/eNOS phosphorylation and mechano-signaling. This may help explain increased vascular risks resulting from artery stiffening.
Hypertension 2003 Feb
PMID:Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. 1257 11

Endothelial cells (ECs) are the critical cellular element responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1) in ECs. In addition, transactivation of KDR/Flk-1 by the bradykinin (BK) B2 receptor induces the activation of endothelial nitric oxide synthase (eNOS). These findings indicate that the precise role of BK in angiogenesis is likely to be more complex than initially thought, and it questions the importance of BK in angiogenic processes. Therefore, we examined whether transactivation by BK induced tube formation. We developed an in vitro model of human coronary artery EC (HCEC) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK and VEGF did not separately induce tube formation, the formation was induced by a combination of lower concentrations of BK and VEGF, suggesting that VEGF and BK had a synergistic effect. The effect was blocked by a B2 receptor antagonist (HOE140) and specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NOS. In addition, BK induced tyrosine phosphorylation of the KDR/Flk-1 receptor, as did VEGF itself. The transactivation was also blocked by HOE140 and Tki. Our results showed that, in HCECs, stimulation of the B2 receptor leads to the transactivation of KDR/Flk-1, as well as to eNOS activation, which induces tube formation. To our knowledge, this is a novel mechanism in which transactivation of KDR/Flk-1 by a G protein-coupled receptor, B2 receptor, may be a potent signal for tube formation.
Hypertension 2003 May
PMID:Transactivation of KDR/Flk-1 by the B2 receptor induces tube formation in human coronary endothelial cells. 1265 12

Because zinc (Zn) is an important component for cell protection against certain oxygen species, it has been suggested that Zn deficiency impairs the potent oxidant defense capacity, which is constitutively provided in the vascular system. However, the influence of dietary Zn deficiency on systemic blood pressure and vascular system is controversial and unclear. We therefore examine the effect of dietary Zn deficiency on systemic blood pressure, a potent superoxide scavenger, aortic Cu/Zn superoxide dismutase (SOD) activity, a most representative synthase of the endothelium-derived relaxing factor, and aortic endothelial nitric oxide synthase (eNOS) expression. Furthermore, the direct effects of intravenous administration of NOS inhibitor, Nomega-nitro-L-arginine methyl ester (LNAME), and a SOD mimetic compound, tempol, in normotensives were tested in Wistar-Kyoto (WKY) rats. A Zn-deficient diet (4 wk) contributed to growth retardation, the decrease in thymus weight, and the lower levels of serum Zn compared with the standard diet group. However, no significant difference in conscious systolic and diastolic blood pressure was found in the Zn-deficiency group. The administration of L-NAME caused an increase in the mean arterial pressure (MAP) levels in the two groups of rats and the involvement of the vasodilator nitric oxide (NO) in the regulation of systemic BP in the normotensive state. On the other hand, administration of the superoxide scavenger, tempol, led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in the maintenance of the systemic BP in a normotensive state. There were no significant differences between the Zn-deficient diet group and the standard diet group in the normotensive state. eNOS expression and Cu/Zn SOD activity in the aorta were also intact in Zn-deficient normotensive rats. These findings suggest that the 4 wk of Zn deficiency was inadequate to alter systemic blood pressure and focal NO signaling in the normotensive state. Long-term Zn deficiency affects the neuronal, immune, and hematopoietic systems, which contribute to systemic and/or local circulation. However, Zn deficiency alone does not cause hypertension and local vascular dysfunction in the normotensive state.
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PMID:Dietary Zn deficiency does not influence systemic blood pressure and vascular nitric oxide signaling in normotensive rats. 1271 11

The present study evaluated the potential mechanism involved in the hypotensive effect induced by ET-1 in rats treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water during 7 days. Hypertension developed in the L-NAME-treated rats (164+/-3 versus 112+/-1 mm Hg in untreated control rats), and the hypotensive effect of ET-1 (100 pmol/kg IV) was significantly enhanced compared with control rats (32+/-2% versus 20+/-1% fall in mean arterial pressure). The enhanced ET-1 hypotensive effect in L-NAME-treated rats was abolished by the ETB receptor antagonist BQ-788 but was unaltered by the cyclooxygenase inhibitor diclofenac, the cytochrome P450 inhibitor fluconazole, or the potassium channel blockers apamin, glibenclamide, tetraethylammonium, and 4-aminopyridine. Pretreatment with the cannabinoid CB1 receptor antagonist SR141716A significantly reduced the hypotensive response to ET-1 in L-NAME-treated rats (20+/-1%), although it did not modify the response in untreated control rats (17+/-1%). These findings indicate that in rats under chronic NOS inhibition, the hypotensive effect of ET-1 is unexpectedly enhanced and appears to be mediated by a non-NO/non-prostanoid mechanism and involves an SR141716A-sensitive mechanism triggered by ETB receptor activation.
Hypertension 2003 Oct
PMID:SR141716A-sensitive enhancement of ET-1 hypotensive effect by chronic NOS inhibition. 1291 62

An open, comparative, cross-over 8-week trial of beta-blockers nebivolol and metoprolol in 30 patients with arterial hypertension (AH) studied the office, ambulatory blood pressure and heart rate levels, endothelium-dependent vasorelaxation, endothelial NOS and NO production. It was found that nebivolol activated the system eNOS-NO and improved vasomotor parameters of the endothelium. Metoprolol failed to activate enzyme eNOS activity and NO production to the same level and did not improve the endothelial vasomotor function. The antihypertensive activity of nebivolol was higher than that of metoprolol. Thus, nebivolol can be used in patients with AH and cardiovascular risk factors to correct endothelial dysfunction.
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PMID:[Pharmacological modulation of NO synthesis in patients with arterial hypertension and endothelial dysfunction]. 1293 13

Many studies employed L-NAME (N(G)-nitro-L-arginine methyl ester), an L-arginine antagonist and nitric oxide (NO) synthase (NOS) inhibitor, to produce hypertension experimentally in male animals. It is not known whether females respond similarly. We thus examined the effect of long-term oral administration of L-NAME on body weight (BW), blood pressure (BP), and heart rate (HR) of both female and male rats. We found that L-NAME induced significant increase in mean BP (MAP) in both genders, however, L-NAME-treated females (F*) exhibited a significantly higher elevation than males (M*) did. This difference persisted for 5 wks and then diminished. L-NAME was thus withdrawn and a rapid decrease of MAP was observed. MAP of F* decreased less and thus remained higher than M* for 5 wks. MAP of control rats (F and M) remained unchanged during the period. Systolic BP (SBP) altered in a similar pattern. We also found that HR decreased immediately after L-NAME administration and that HR of F* was significantly less reduced. These findings indicate that L-NAME induced a more pronounced response in females than males, consistent with the view that females are more dependent on NOS activity for their regulation of BP.
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PMID:Gender-dependent response in blood pressure changes following the inhibition of nitric oxide synthase. 1297

Our laboratory has recently shown increased renal expression of NO synthase 3 (NOS3) in the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension suggesting an up-regulation of the nitric oxide (NO)-cyclic guanosine-3',5'-monophosphate (cGMP) pathway. The present study was designed to determine changes in renal soluble guanylyl cyclase (sGC) activity and expression in the DOCA-salt hypertensive rat. Rats were uninephrectomized and subcutaneously implanted with either a placebo or DOCA-salt pellet. Placebo-treated animals were given tap water ad libitum, while DOCA-treated animals received 0.9% NaCl solution to drink. Each week, rats were placed in metabolic cages for 24 h collection of urine samples. Urine samples were measured for cGMP concentrations using a scintillation proximity method. After 3 weeks, kidneys were removed and dissected into cortex, outer medulla, and inner medulla. Each region of the kidney was further separated into detergent-soluble and detergent-insoluble fractions. DOCA-treated rats exhibited significant increases in urinary cGMP excretion (27.0+/-1.4 fmol/mg creatinine) after 1 week compared to placebo control animals (8.7+/-0.6 fmol/mg creatinine). This was followed by a significant decrease by the second week of treatment (5.4+/-1.0 and 11.4+/-0.6 fmol/mg creatinine in DOCA-salt and placebo, respectively) and a return to placebo values by the third week of treatment (16.2+/-3.1 and 12.9+/-1.0 fmol/mg creatinine in DOCA-salt and placebo, respectively). Western blot analysis of inner medullary detergent-soluble fraction indicated a decrease in the expression of the beta(1)-subunit of sGC in the third week of DOCA-salt-treated animals as compared to placebo controls (n=5 animals per group) while expression of the alpha(1)-subunit was unchanged. Western blot analysis of cortex and outer medullary preparations comparing placebo controls and DOCA-salt-treated animals revealed no difference in alpha(1)- or beta(1)-sGC protein expression. These data suggest an uncoupling of NOS/NO and sGC/cGMP pathways in the renal inner medulla of the DOCA-salt hypertensive rat.
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PMID:Down-regulation of soluble guanylyl cyclase in the inner medulla of DOCA-salt hypertensive rats. 1367 47

This study was designed to determine whether recombinant human erythropoietin (rHuEpo) administration increases vascular nitric oxide (NO) production in healthy rats. We hypothesized that rHuEpo hypertension is associated with increased endothelial expression of nitric oxide synthase and augmented NO-dependent vasodilation. Male rats were instrumented with pulsed Doppler flow probes around their ascending aorta and with arterial and femoral catheters. Rats were treated for 14 days with rHuEpo (2 U/d) or vehicle. rHuEpo elevated hematocrit and increased mean arterial pressure (142 +/- 3 versus 116 +/- 4 mm Hg). Thoracic aorta segments from rHuEpo rats had a modest increase in NO-dependent relaxation assessed by acetylcholine (10(-10) to 10(-5) mol/L) relaxation of phenylephrine (PE) (10(-6) mol/L) contracted arteries. Relaxation to NO-donor, s-nitrosyl acetylpenicillamine, and PE contraction were not different from control arteries. The NO synthase inhibitor, N-omega-nitro-L-arginine, increased blood pressure and total peripheral resistance more in rHuEpo rats at both 10 and 30 mg/kg. NOS expression in rHuEpo aorta and plasma NOx concentrations were increased compared with control. Thus, it appears that vascular eNOS expression is increased and causes basal vasodilation in rHuEpo hypertensive rats.
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PMID:Erythropoietin administration in vivo increases vascular nitric oxide synthase expression. 1450 39


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