Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous reports have suggested that smooth muscle obtained from the thoracic aorta of spontaneously hypertensive rats is less responsive to vasoconstrictive agents than that obtained from normotensive rats. The present study was undertaken to determine whether the responsiveness of aortic muscles from normotensive and spontaneously hypertensive rats correlates with a difference in the affinity of the adrenergic receptors for norepinephrine and whether antihypertensive therapy alters the affinity of the adrenergic receptors for norepinephrine. The affinity of the adrenergic receptors for norepinephrine was determined by computing the dissociation constant of the norepinephrine-receptor complex (KDR). The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received no antihypertensive therapy were 1.07 X 10(-7)M and 1.17 X 10(-7)M, respectively. The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received antihypertensive therapy were 1.38 X 10(-7)M and 1.29 X 10(-7)M, respectively. The differences in these values for KDR are not significant. These results indicate that the difference in the contractility of aortic muscles from normotensive and spontaneously hypertensive rats is not related to an alteration in the affinity of the adrenergic receptors for norepinephrine and that the affinity of the adrenergic receptors for norepinephrine is not altered by antihypertensive therapy. Thus, it appears that the etiology of hypertension cannot be directly correlated with a difference in the affinity of the adrenergic receptors for norepinephrine.
 ...
PMID:Dissociation constant of the norepinephrine-receptor complex in normotensive and hypertensive rats. 119 63

Preeclampsia is a multisystem disorder characterized by hypertension and proteinuria. There is accumulating evidence that this is a disease of the endothelium, with an as-yet unidentified circulating factor, or factors, causing the observed alteration in vascular function. We previously reported that the function of myometrial vessels is altered on exposure to plasma from women with preeclampsia. Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts via two high-affinity receptors (KDR and Flt-1), and its production is increased in preeclampsia. Here we report that VEGF and its Flt-1 receptor may play a pivotal role in the altered vascular function of preeclampsia. Myometrial resistance vessels were obtained at the time of cesarean section. Using the Mulvany wire myograph, the endothelium-dependent behavior of these vessels was studied. Incubation of vessels from pregnant women with VEGF resulted in a reduction of endothelium-dependent relaxation that mimicked the reduction induced by plasma from women with preeclampsia. The altered function that occurred upon exposure of vessels to VEGF or plasma from women with preeclampsia did not occur when plasma was incubated with antibodies to VEGF before vessel incubation. The presence of an anti-KDR receptor antibody had no effect on VEGF response. However, in the presence of an anti-Flt-1 receptor antibody, VEGF or plasma from women with preeclampsia no longer attenuated the endothelium-dependent relaxation (p < 0.05). The changes observed with VEGF and plasma from women with preeclampsia and their subsequent blockade with anti-VEGF antibody and anti-Flt-1 receptor antibody strongly suggest that VEGF acting through the Flt-1 receptor is pivotal in the pathogenesis of this disease.
 ...
PMID:VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of preeclampsia. 1049 28

Systemic hypertension exacerbates diabetic retinopathy and other coexisting ocular disorders through mechanisms that remain largely unknown. Increased vascular permeability and intraocular neovascularization characterize these conditions and are complications primarily mediated by vascular endothelial growth factor (VEGF). Because systemic hypertension increases vascular stretch, we evaluated the expression of VEGF, VEGF-R2 (kinase insert domain-containing receptor [KDR]), and VEGF-R1 (fms-like tyrosine kinase [Flt]) in bovine retinal endothelial cells (BRECs) undergoing clinically relevant cyclic stretch and in spontaneously hypertensive rat (SHR) retina. A single exposure to 20% symmetric static stretch increased KDR mRNA expression 3.9 +/- 1.1-fold after 3 h (P = 0.002), with a gradual return to baseline within 9 h. In contrast, BRECs exposed to cardiac-profile cyclic stretch at 60 cpm continuously accumulated KDR mRNA in a transcriptionally mediated, time-dependent and stretch-magnitude-dependent manner. Exposure to 9% cyclic stretch increased KDR mRNA expression 8.7 +/- 2.9-fold (P = 0.011) after 9 h and KDR protein concentration 1.8 +/- 0.3-fold (P = 0.005) after 12 h. Stretched-induced VEGF responses were similar. Scatchard binding analysis demonstrated a 180 +/- 40% (P = 0.032) increase in high-affinity VEGF receptor number with no change in affinity. Cyclic stretch increased basal thymidine uptake 60 +/- 10% (P < 0.001) and VEGF-stimulated thymidine uptake by 2.6 +/- 0.2-fold (P = 0.005). VEGF-NAb reduced cyclic stretch-induced thymidine uptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan. Hypertension increased retinal KDR expression 67 +/- 42% (P < 0.05) in SHR rats compared with normotensive WKY control animals. When hypertension was reduced using captopril or candesartan, retinal KDR expression returned to baseline levels. VEGF reacted similarly, but Flt expression did not change. These data suggest a novel molecular mechanism that would account for the exacerbation of diabetic retinopathy by concomitant hypertension, and may partially explain the principal clinical manifestations of hypertensive retinopathy itself. Furthermore, these data imply that anti-VEGF therapies may prove therapeutically effective for hypertensive retinopathy and/or ameliorating the deleterious effects of coexistent hypertension on VEGF-associated disorders such as diabetic retinopathy.
 ...
PMID:Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2: potential mechanisms for exacerbation of diabetic retinopathy by hypertension. 1127 59

Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1-selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1- selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P<0.01) but was greater than that to Flt-selective mutant (P<0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P<0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
Hypertension 2002 Jun
PMID:KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF. 1205 48

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

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
 ...
PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. 1280 93

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
 ...
PMID:A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. 1545 12

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
 ...
PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

Angiogenesis is important in the growth and progression of solid tumours. The main pro-angiogenic factor, namely vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells. The soluble isoform of VEGF is a dimeric glycoprotein of 36-46 kDa, induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine-kinase receptors: VEGF-1 (flt-1) and VEGF-2 (KDR/flk1). An increase in VEGF expression in tumour tissue or some blood compartments (i.e. serum or plasma) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis. Bevacizumab, a recombinant humanised monoclonal antibody developed against VEGF, binds to soluble VEGF, preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation. Pre-clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression. Bevacizumab is the first anti-angiogenetic treatment approved by the American Food and Drug Administration in the first-line treatment of metastatic colorectal cancer. It has shown preliminary evidence of efficacy for breast, non-small-cell lung, pancreatic, prostate, head and neck and renal cancer as well as haematological malignancies. Common toxicities associated with bevacizumab include hypertension, proteinuria, bleeding episodes and thrombotic events. This review summarises the critical role of VEGF and discusses the data available on bevacizumab, from the humanisation of its parent murine monoclonal antibody (mAb) A.4.6.1 to its use in cancer clinical trials.
 ...
PMID:Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. 1684 97

Endothelial dysfunction, a well recognized marker of cardiovascular risk, is an early event in arteriosclerosis process. Diabetes mellitus, hypertension and dyslipidemia, known risk factors for coronary disease have been associated with endothelial dysfunction, which improves after the control of these factors. Statins have additional benefits on endothelial function not related to decreasing cholesterol levels, known as pleiotropic effects. Most recently it has been reported the effect of statins promoting bone marrow-derived mononuclear cells. These cells are positive for CD34 and KDR superficial markers of endothelial cellular lineage, which is consistent with the hypothesis that they constitute the endothelial progenitor cells. Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina and other stressful situations. Recent studies have demonstrated an inverse relationship between the EPC count in peripheral blood and risk of developing a cardiovascular event. In addition, circulating EPC correlates with the presence of endothelial dysfunction and could play a role as a surrogate biologic marker in vascular function. The effect of statins on endothelial progenitor cells might contribute to improve endothelial function leading to a decrease in vascular risk, independently of their impact on LDL cholesterol. In this paper, we review the role of statins in EPC mobilization, its effect in endothelial function restoration and the relevance of this finding in cardiovascular risk. We also review future therapeutic implications.
 ...
PMID:The role of endothelial progenitor cells and statins in endothelial function: a review. 1797 88


1 2 3 Next >>