Angiotensin tachyphylaxis and vascular angiotensinase activity

Zusammenfassung Die Auffassung, dass die Gewebsangiotensinase-Aktivität entscheidend sei, ob sich eine Gewebs-Tachiphylaxie gegenüber Angiotensin entwickelt oder nicht, konnte durch Versuche an verschiedenartigen Geweben keine Bestätigung finden.

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Supported by grants from the John A. Hartford Foundation, Inc., and the U.S. Army R and D Command No. DA-49-193-MD 2497.     

Pyrogallol and vasopressin tachyphylaxis

Résumé Le pyrogallol empêche le développement d'une tachyphylaxie à la vasopressine. Il restitue la réaction pressorique après l'apparition d'une tachyphylaxie. Cet effet ne semble pas être lié à l'action inhibitrice de cette substance sur l'enzyme transférase o-méthyl.     

Antihypertensive effect of purified enzyme showing angiotensinase activity from rabbit red cells in rats

Zusammenfassung In der akuten Phase der Goldblatt-Hypertonie der Ratte verhinderte die Injektion von reiner Angiotensinase ein Aussteigen des Blutdruckes. Die Behandlung war unwirksam bei chronischem Hochdruck.     

Plasma angiotensin,serum ‘angiotensinase activity’, and blood pressure response during angiotensin II amide infusions in normal volunteers

Résumé Des doses croissantes d'angiotensine II amide furent injectées à des volontaires normaux. La réponse de la pression artérielle fut en relation directe avec le log de la dose de peptide injectée, avec la concentration sérique en sodium et avec l'activité sérique «angiotensinase», mais en relation inverse avec l'augmentation de la concentration plasmatique en angiotensine. Ces résultats suggèrent que la réponse de pression est déterminée, au moins en partie, par le «turnover» du peptide au niveau des récepteurs et qu'à ce niveau angiotensinase influence le «turnover» et la concentration plasmatique du peptide.

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A preliminary report of this work was presented at the Eastern Section Meeting of the American Federation for Clinical Research, Washington, D.C., December 13, 1969.

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Supported by U.S.P.H.S. Grant No. HE 11691-02, NIH; the American and Maryland Heart Associations; and the Kidney Foundation of Maryland. Thanks are due Dr.J. R. Hebel for statistical analyses and MissD. S. Baker for secretarial assistance.

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Supported by the Fulbright-Hays Program and the Italian National Research Council.     

Angiotensin I converting enzyme activity in pulmonary tissue of fetal and newborn rabbits

Summary Angiotensin I converting enzyme in pulmonary tissue of fetal and newborn rabbits was measured using Hip-His-Leu as substrate. Enzyme activity was detected in the late fetal period, increased gradually until birth and increased markedly after birth. Enzyme activity reached adult levels on the 2nd and 3rd day after birth. This observations suggests that the metabolic activity of the lung for angiotensin develops suddenly at the time of derivery.This work was supported in part by grant No. 187032 from Ministry of Education.     

Increased vascular prostacyclin activity in rats after endotoxin administration

Summary Endotoxin did not interact in vitro with prostacyclin activity but stimulated its release from vascular tissues when administered in single doses to rats 30 min before testing.Acknowledgments. This work was performed with the partial support of the Italian National Research Council (contract CNR 80-01086-83, Medicina Preventiva-Arteriosclerosi).     

Normal liver actually possesses a high vascular plasminogen activator activity

Summary Blood vessels isolated from the liver of the rat, guinea-pig, rabbit, dog and pig showed histochemically a more or less high plasminogen activator activity. In whole liver sections, the abundant release and diffusion of inhibitors of fibrinolysis from the liver parenchyma during the histochemical procedure, partially or totally mask this high vascular activity.     

Normal liver actually possesses a high vascular plasminogen activator activity.

Blood vessels isolated from the liver of the rat, guinea-pig, rabbit, dog and pig showed histochemically a more or less high plasminogen activator activity. In whole liver sections, the abundant release and diffusion of inhibitors of fibrinolysis from the liver parenchyma during the histochemical procedure, partially or totally mask this high vascular activity.     

Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA

Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients’ serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a “gatekeeper” in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.     

Angiotensin II in the hippocampus. A histochemical and electrophysiological study

Summary The presence of the renin angiotensin system in the hippocampus is shown by immunohistochemistry. Intra- and extra-cellular recordings revealed that angiotensin II and III excite CA 1 pyramidal cells by disinhibition. The effect is antagonized by [Sar¹, Thr⁸]-A II.This work was supported by grant Nos 3.271.78 and 3.396.78 of the Swiss National Science Foundation and research grant HL-24112 from NIH. T. Inagami was a visiting scientist of the Roche Medical Research Foundation.     

Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining ‘increased angiogenesis’ as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.Received 24 November 2004; received after revision 21 January 2005; accepted 2 March 2005     

Endothelium-derived nitric oxide and vascular physiology and pathology

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca²⁺. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.     

Aging and endothelin-1 induced vascular contractions

Contractions produced by endothelin-1 (0.3-30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC50 values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC50 value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Aging and endothelin-1 induced vascular contractions

Summary Contractions produced by endothelin-1 (0.3–30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC₅₀ values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC₅₀ value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.     

Chromatin-remodeling complex specificity and embryonic vascular development

Vascular development is a dynamic process that relies on the coordinated expression of numerous genes, but the factors that regulate gene expression during blood vessel development are not well defined. ATP-dependent chromatin-remodeling complexes are gaining attention for their specific temporal and spatial effects on gene expression during vascular development. Genetic mutations in chromatin-remodeling complex subunits are revealing roles for the complexes in vascular signaling pathways at discrete developmental time points. Phenotypic analysis of these models at various stages of vascular development will continue to expand our understanding of how chromatin remodeling impacts new blood vessel growth. Such research could also provide novel therapeutic targets for the treatment of vascular pathologies.