Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Rabbit aortic rings were used to test the possible contractile effects of growth factors and their interaction with other stimuli. A rapid potentiation of kinin-induced contraction by epidermal growth factor (EGF) has been previously observed in this preparation. 2. EGF (5-1500 ng ml-1) and the isoform BB of platelet-derived growth factor (PDGF-BB; 1-126 ng ml-1) exerted modest but sustained contractile effects in rabbit aortic rings. 3. EGF pretreatment (100 ng ml-1) potentiated the contractile responses to des-Arg9-bradykinin (des-Arg9-BK), an agonist of the B1 receptors for kinin found in this preparation, and to human alpha-thrombin but not to several other contractile stimuli. The interaction appeared also relatively selective for the growth factor, because PDGF-BB pretreatment potentiated neither des-Arg9-BK nor alpha-thrombin-induced contraction. 4. EGF, applied on a contraction plateau induced by des-Arg9-BK or alpha-thrombin, exerted a synergistic contractile effect, with a time course and a half-maximal concentration for EGF-induced contraction similar to the ones recorded in resting tissues (between 67 and 220 ng ml-1, depending on the series of experiments). 5. The direct or synergistic contractile effects of EGF were not modified by the removal of the endothelium or by treatment with indomethacin. However, the tyrosine kinase inhibitors, erbstatin or genistein, inhibited the synergistic effect of EGF with des-Arg9-BK. The small direct contractile effect of EGF was significantly reduced by genistein. The synergistic effect of EGF with alpha-thrombin was comparatively more resistant to the tested tyrosine kinase inhibitors.6. An inhibitor of the catalytic activity of alpha-thrombin, D-Phe-Pro-Arg-CH2Cl, prevented the contractile effect of x-thrombin in the aortic rings. In this system, a tetradecapeptide derived from a recently cloned alpha-thrombin receptor was a contractile stimulus at and above 10 microM. Consistent with the hypothesis that this peptide could behave as an alpha-thrombin receptor agonist, its contractile effect was potentiated by EGF pretreatment. Pharmacological evidence was provided to show that the receptors for alpha-thrombin were distinct from the B, receptors for kinins. Together, these findings suggest that a model of a cleavable receptor recently elaborated to account for alpha-thrombin effects on human platelets is valid in blood-free vascular smooth muscle preparations such as the rabbit isolated aorta.7. The synergism between EGF and kinin- or alpha-thrombin-induced contractions constitutes a novel mode of myotropic action for growth factors. The synergism is probably dependent on the tyrosine kinase activity of receptors for EGF. These combinations of stimuli could occur in various types of vascular disease and account for abnormal vascular reactivity often associated with atheroma lesions or vascular wound healing.
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PMID:Synergism between the contractile effect of epidermal growth factor and that of des-Arg9-bradykinin or of alpha-thrombin in rabbit aortic rings. 150 21

G-proteins are transducing proteins that couple a large number of membrane-bound receptors to a variety of intracellular effector systems. Pertussis toxin ADP-ribosylates certain G-proteins causing inhibition of their function. In porcine coronary arteries, pertussis toxin inhibited the endothelium-dependent relaxations evoked by alpha-2-adrenergic or serotonergic receptor stimulation, and by aggregating platelets or thrombin. Relaxations to nitric oxide and endothelium-dependent relaxations to bradykinin, adenosine diphosphate or A23187 were unaffected by the toxin. Therefore, certain endothelium-dependent relaxations are mediated by activation of a pertussis toxin-sensitive G-protein in the endothelial cells, most likely Gi-protein. In porcine coronary arteries with regenerated endothelium (following in vivo denudation), the endothelium-dependent relaxations caused by the pertussis toxin-sensitive stimuli were reduced and were not further affected by pertussis toxin. Relaxations to the other stimuli were not altered by the regeneration process and were still not affected by the toxin. In regenerating endothelial cells there may be a selective impairment of the G-protein-dependent mechanism for releasing EDRF, which may predispose the blood vessel to vasospasm or the initiation of vascular disease.
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PMID:G-proteins and endothelial responses. 212 22

In 42 outpatients of the diabetology division, coagulation and fibrinolysis variables were determined in order to detect typical patterns of results with which it was possible to discriminate between three groups with different diabetic complications (17: no complication, 7: angiopathy alone, 18: neuropathy with or without other complications). There was a statistically significant discriminatory function involving C1-inhibitor concentration, high molecular weight kininogen coagulant activity and fibrinogen as the most decisive variables. The neuropathy group was appropriately separated from the others with an 81% correct reclassification. Heparin cofactor II, histidine-rich glycoprotein, alpha 2-macroglobulin, pre-kallikrein and factor XII had no discriminative power.
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PMID:Patterns of contact phase proteins indicating neuropathy in diabetic patients. 222 44

The isolated amyloid substance in hereditary cystatin C amyloid angiopathy (HCCAA) is mainly composed of a cystatin C variant devoid of the 10 amino terminal amino acid residues of extracellular cystatin C from healthy individuals. We have developed a procedure for protein sequencing directly from agarose gel electropherograms and used this in conjunction with isoelectric focusing to investigate the amino terminal sequence of cerebrospinal fluid (CSF) cystatin C in HCCAA patients. The amino-terminal sequence determined for cystatin C from a HCCAA patient CSF sample, Xaa-Ser-Pro-Gly-Lys-Pro-Pro-Xaa-Leu-Val-Gly-Gly-Pro-Met-Xaa-Ala-Xaa-Val, showed that the protein was not amino-terminally truncated. CSF cystatin C from all nine HCCAA patients investigated was found to have an isoelectric point identical to that of native cystatin C, and the truncated form of cystatin C isolated from amyloid deposits was shown to contribute to less than 1% of the total amount of cystatin C in CSF. The total cysteine proteinase inhibitory capacity of CSF from HCCAA patients was lower than that of CSF from other patients. This decreased CSF inhibitory capacity in HCCAA patients was caused by decreased levels of cystatin C, since the levels of the other two cysteine proteinase inhibitors found in CSF, alpha 2-macroglobulin and kininogen, were significantly higher than in CSF from non-HCCAA patients.
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PMID:The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from agarose gel electropherograms. 231 47

The isolation and characterization of six human cysteine proteinase inhibitors is reported. Their distribution in human biological fluids is also described and discussed with respect to physiological function. Studies on kininogen and cystatin C with respect to structure-function relationships and, as a result of the cystatin C studies, a general model for the mechanism of cysteine proteinase inhibition by cystatins are presented. The model was used for the construction of synthetic inhibitors which showed good inhibitory properties against papain and the streptococcal cysteine proteinase. Structures of cDNA and gene for normal human cystatin C are accounted for, as well as studies on the cystatin C gene in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA). As a result of this an RFLP that showed total co-segregation with the disease was found. It was concluded that the disease is caused by a point mutation in the cystatin C structural gene and that the RFLP will be a most useful tool for diagnosis of HCCAA. The production of recombinant cystatin C in E. coli is also reported and its possible use for treatment of HCCAA is discussed.
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PMID:Human cysteine proteinase inhibitors. Isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. 307 20

Acetylsalicylic acid (aspirin) inhibits prostanoid synthesis by irreversible acetylation of fatty acid cyclooxygenase (EC 1.14.99.1). It thereby inhibits synthesis of pro-aggregatory thromboxane A2 (TXA2) by platelets and is widely used in the treatment and prophylaxis of vascular disease. Its efficacy, however, may be reduced since it also inhibits formation of prostacyclin (PGI2) which is a vasodilator and anti-aggregatory agent. There is uncertainty over the optimum dose regimen for aspirin since although it inhibits platelet thromboxane production for many days, the magnitude and duration of its effect on PGI2 production by vascular endothelium in vivo is unknown. Resting plasma concentrations of PGI2 (measured as the stable hydrolysis product 6-oxo-PGF1 alpha) are at or below the limit of sensitivity of the most sensitive assays and cannot therefore be used to demonstrate a reduction in production. Bradykinin stimulates PGI2 synthesis by cultured human vascular endothelial cells and we have shown that it stimulates PGI2 production by man in vivo. We report here that an oral dose of aspirin (600 mg) causes rapid and substantial inhibition of bradykinin-stimulated PGI2 production, but recovery occurs within 6 hours; this implies that endothelial PGI2 synthesis would be spared most of the time during dosing once daily with even this relatively large dose of aspirin.
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PMID:Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man. 390 19

Pyrrolizidine monocrotaline (MCT) from plant seed produces pulmonary endothelial cell injury, pulmonary hypertension, and inflammation in rats, providing a useful animal model for studying progressive pulmonary vascular disease. Kininogen is the precursor of proinflammatory kinins and may also exert anti-inflammatory actions by inhibiting cysteine proteinases. Given the potential roles of kininogen in vascular injury and inflammation, we have investigated the regulation of kininogen gene expression in the MCT-induced pulmonary hypertensive rat model. Sprague-Dawley rats, in groups of six, were given a single subcutaneous injection of monocrotatine (60 mg/kg body wt) and sacrificed 10 and 20 days later. Northern blot hybridization using a kininogen cDNA probe showed kininogen gene expression in the liver, lung, and kidney. MCT treatment induced a time-dependent increase in kininogen mRNA levels, whereas it reduced rat alpha 1-antitrypsin and kallikrein-binding protein mRNA levels in the liver. Similarly, kininogen mRNA levels were low in the normal lung and were increased 7.5- and 13.7-fold, respectively, after MCT injection for 10 and 20 days. Immunoreactive kininogen levels in perfused liver and lung extracts of rats receiving MCT injection increased up to 20-fold, as measured by a T-kininogen radioimmunoassay. Western blot analyses showed that a 68-kilodalton immunoreactive kininogen increased in the serum and lung extracts of MCT-treated rats compared to those in the control rats. In control rats, immunostaining for kininogen in the lung was most marked in venous endothelial cells and alveolar macrophages. After MCT treatment, staining for kininogen increased dramatically throughout the lung tissues, often covering the epithelial surfaces of alveoli and bronchi. The present studies have shown that the toxin MCT altered the synthesis and distribution of pulmonary kininogen and suggest that the kininogen/kinin system may be associated with the pulmonary vascular injury, remodeling, and inflammation seen in this animal model.
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PMID:Regulation of kininogen gene expression and localization in the lung after monocrotaline-induced pulmonary hypertension in rats. 850 64

Hypertension is an important cardiovascular risk factor. High blood pressure per se is not a disease but a hemodynamic alteration associated with vascular disease. Two classes of drugs are especially effective in lowering blood pressure and preventing cardiovascular complications, angiotensin converting enzyme (ACE) inhibitors and calcium antagonists. The hemodynamic effects of ACE inhibitors and calcium antagonists are complementary. While ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Certain calcium antagonists, such as verapamil, lower heart rate. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are also complementary. While ACE inhibitors inhibit activation of angiotensin I into angiotensin II and prevent the breakdown of bradykinin (which stimulates nitric oxide and prostacyclin formation), calcium antagonists inhibit the effects of vasoconstrictor hormones such as angiotensin II at the level of vascular smooth muscle by reducing calcium inflow and facilitating the vasodilator effects of nitric oxide. Calcium antagonists reduce smooth muscle cell proliferation and atherosclerosis. In hypertensive animals, verapamil and trandolapril normalize endothelial dysfunction. In large angiographic trials, nifedipine and nicardipine reduced the development of new atherosclerotic plaques. After myocardial infarction, verapamil reduces mortality and cardiac events in patients without heart failure. In contrast, ACE inhibitors are effective after myocardial infarction in patients with impaired left ventricular function. Urinary albumin excretion rate decreases during ACE inhibitor therapy or with a calcium antagonist such as verapamil; combination of the two drugs has an additive effect. In resistance arteries, hypertension is associated with an increased media/lumen ratio. ACE inhibitors, but not beta-blockers, markedly improve these structural changes. In summary, ACE inhibitors and calcium antagonists have a complementary profile, both in their hemodynamic and local vascular action. Hence, combination therapy with these two classes of drugs appears particularly useful in patients with hypertension, not only to lower blood pressure, but hopefully to achieve improved cardiovascular protection.
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PMID:Vascular protective effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination therapy in hypertension and other cardiovascular diseases. 856 68

The ability of the vasculature to modify its geometry in accordance with conditions of its microenvironment--the process of vascular remodeling--is an important pathobiologic process common to vascular disorders such as atherosclerosis, restenosis after angioplasty, and hypertension. Vascular remodeling characterizes the natural history of atherosclerosis, contributes to increased vascular resistance, and may contribute to the clinical complications of hypertension. A growing body of evidence indicates that locally generated vasoactive substances such as angiotensin II and nitric oxide are important determinants of the natural history of vascular disease. In particular, angiotensin II may promote vascular lesion formation by increasing vascular cell population via increased cell growth and decreased programmed cell death, and it may also alter extracellular matrix composition. Thus, angiotensin II is a pleiotropic local mediator capable of modulating cell growth, programmed cell death, migration of vascular smooth muscle cells, and extracellular matrix modulation, all of which are biologic mechanisms of vascular remodeling and intimal formation. This is proposed to occur via a local tissue angiotensin system. Angiotensin II may also promote chronic hypertension by modulating the vascular redox state and promoting the catabolism of the endothelium-derived nitric oxide, an endogenous inhibitory vasodilator. Because angiotensin-converting enzyme (ACE) is strategically positioned to influence the activity of at least three local vasoactive systems--angiotensin II, nitric oxide, and bradykinin--blocking ACE with ACE inhibition may have profound effects on ventricular and vascular structure and function, and have particular efficacy in preventing the morbidity and mortality of vascular diseases such as hypertension and atherosclerosis.
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PMID:Vasculoprotective and cardioprotective mechanisms of angiotensin-converting enzyme inhibition: the homeostatic balance between angiotensin II and nitric oxide. 942 48

Endothelial cells control the tone of the underlying vascular smooth muscle by secreting vasodilator substances (prostacyclin, nitric oxide and endothelium-derived hyperpolarizing factor). These vasodilator substances also contribute to the antithrombogenicity of the normal endothelium, and inhibit cellular growth. In coronary vascular disease, the ability of the endothelium to secrete vasodilator substances is reduced, while the propensity to release endothelium-derived contracting factors is increased. In particular, the reduced release of nitric oxide in response to aggregating platelets, thrombin and circulating catecholamines favours the occurrence of thrombosis and vasospasm, and plays a key role in the initiation of the atherosclerotic process. From the therapeutic point of view, the best available way to enhance the release of endothelium-derived nitric oxide and hyperpolarizing factor is to inhibit converting enzyme. This will protect endogenous bradykinin from breakdown and prolong its action on endothelial receptors.
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PMID:Endothelial dysfunction and inhibition of converting enzyme. 979 35


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