The discovery of angiotensin: a foundational step in the history of hypertension

More than 80 years ago, in 1939 two independent teams in Buenos Aires and Indianapolis, headed by Eduardo Braun Menendez and Irving H. Page, identified the polypeptide angiotensin related to the pressor effect of renal hypertension. The interest of the argentine team in hypertension began in 1931 during Taquini’s visit to Volhard´s laboratory as a member of the Houssay (Nobel Prize, 1947) group (the other members were Braun Menéndez, Fasciolo, Leloir (Nobel Prize 1970) and Muñoz). Two years thereafter, Goldblatt´s demostrated that partial occlusion of the renal arteries produces hypertension in dogs and Houssay, in 1936 predicted the presence of a humoral mechanism and with Fasciolo demonstrated that the ischemic kidneys released a pressor substance. Later on, Taquini proved that the rise in blood pressure which follows the re-establishment of circulation in kidneys was also produced by the release of a substance: “hypertensin (from the plasma of venous blood of acute ischemic kidneys). Soon after, they proved that it was the result of an enzymatic reaction in which renin was the enzyme and plasma the substrate. At the same time, in May 1939 Page et al postulated that renin activated by plasma becomes vasoactive (“angiotonin”). Page and his group (Kenneth, Kohlstaedt, Helmer and Corcoran) began in 1937, with the purification of renin, studying its renal hemodynamic effects and measuring the vasoconstriction in dog´s tail perfused with Ringer´s solution. Because of a fortuitous arrangement, a sample of renin was left on Page´s desk for several days. When he finally tested it, a surprising sharp increase in arterial pressure was observed. Later on, Page et al acknowledged in 1943 the enzymatic nature of the system and both groups agreed to fuse the two original names into “angiotensin”.Sociedad Argentina de Fisiologí

The Angiotensin Affair: How Great Minds Thinking Alike Came to a Historical Agreement

In 1934, J. C. Fasciolo had to submit a thesis and Dr. Houssay suggested he investigate about nephrogenic hypertension. E. Braun‐Menéndez showed interest in helping and Drs. L.F. Leloir and J.M. Muñoz from the Institute of Physiology joined them in their attempt to isolate and purify the pressor substance. In 1939, they extracted the substance “hypertension” from the venous blood from the ischemic kidneys. They proposed an enzyme‐substrate reaction. They named hypertensinogen the substrate and hypertensinases the enzymes that break down the hypertension. Two months following the Argentine publication, the team in the United States, formed by I.H. Page and O.M. Helmer, published their findings, which were in agreement with those reported by the Argentine team. By 1940, they isolated angiotonin, the equivalent of hypertension, and called the renin substrate hypertensinogen. In 1957, in the conference held in Ann Arbor, Braun‐Menéndez and Page agreed on a new nomenclature. As a result, the words angiotensinogen and angiotensin were born from the combination of the names originally set by both teams. The discovery of the renin‐angiotensin system is an example that science should follow: Value the progress made by colleagues, collaborate side by side, and pursue the ultimate truth

Técnica de inmunoperoxidasa en miocardiopatia chagásica crônica experimental

Chagas'disease has been described as the commonest form of chronic myocarditis. An immunologic pathogenesis has been discribed for this form of the disease. So far, no immunoperoxidase technique has been used for the detection of immunological deposits in chronic experimental Chagas'myocardiopathy. Forty-one Swiss mice, three months old were inoculated intraperitoneally with doses between 10 and 10(5) Tulahuen trypomastigotes. Mice were reinoculated one month after with doses between 10² and 10(5) and sacrificed at 6 (n=21) and 9 months (n=9) after the first inoculation. ECGs were recorded before sacrifice. Immunoperoxidase technique (peroxidase-antiperoxidase method), immunofluorescence (direct and indirect) as well as histological studies were performed in myocardiums and skeletal muscles of the surviving animals. The most sensitive methods for detecting chronic chagasic infection were the routine histologic studies (73%) and the ECGs 83% and 89% on 6 and 9 mo. post-infected mice, respectively. Myocardial involvement varied from interstitial mild focal lymphocyte infiltrates up to replacement of myocytes by loose connective tissue. Atrial myocardiums (21/23, 91%) were more affected than ventricles (9/23, 39%). Typical chagasic nests were rarely found. Skeletal muscle involvement (11/18 and 7/9) varied from mild to extensive lymphocyte and plasmacell infiltrates, and necrotic fibers. The involved antigen were shown in skeletal muscles by the immunoperoxidase technique as diffusely arranged granular intracytoplasmatic deposit for both IgC and total immunoglobulins. The coincidence between this technique and histologic muscle lesions was 11/18 (61(%) in 6 mo. and 6/8 (75%) at 9 mo. post-infection. In heart, delicate granular deposits of total immunoglobulins were seen diffusely arranged within the ventricular myocytes; coincidence between immunoperoxidase technique anl histologic involvement increased from 36 to 66% in animals sacrifeced 6 and 9 mo. post-infection. This strongly stressed the increase of immunologic phenomena with the chronification of infection. Concerning sensitivity, immunoperoxidase and direct immunofluorescence were highly sensitive in skeletal muscle (100%, p < 0.01). Conversely, direct immunofluorescence technique showed poor results in heart while immunoperoxidase increased its sensitivity from 21.4% (at 6 mo.) to 66.6% (at 9 mo.) post-infection (p < 0.001). Considering the necessity of obtaining an adequate vaccine in order to prevent this disease an experimental model like this, rendering immunological reactions as revealed by the immunoperoxidase technique, would be useful.La enfermedad de Chagas ha sido considerada como una de las causas más frecuentes de miocarditis crônica. Siendo descriptas Ias alteraciones inmunológicas, como patogenia para este tipo de enfermedad. Por tal motivo, se empleó la técnica de inmunoperoxidasa para la detección de depósitos de inmunoglobulinas en la miocardiopatía chagásica crônica experimental. Se utilizaron 41 ratones Swiss de 3 meses de vida, los mismos fueron inoculados intraperitonealmente con dosis entre 10 y 10(5); tripomastigotas de la cepa Tulahuen. La reinoculación se realizo 1 mes después con dosis entre 10² y 10(5); siendo sacrificados a los 6 (n=21) y 9 meses (n=9) de la primera inoculación, prévios estúdios elect roçar diográficos. Posteriormente se estudiaron los miocardios y músculos esqueléticos con técnicas histológicas de rutina, inmunoperoxidasa (método peroxidasa anti-peroxidasa) e inmunofluorescencia (directa e indirecta). Los métodos más sensibles para la detección de la enfermedad de Chagas crônica resultaron ser los estúdios histológicos (73%) y la electrocar-diografia (83%) a los 6 meses pi.y (89%) a los 9 meses p.i. (pos-infección). Se observaron diferentes alteraciones miocárdicas, desde infiltrados linfocitarios leves y focales en intersticio hasta reemplazo de miocitos por tejido conectivo. Los miocardio auriculares (21/23,91%) fueron más afectados que los ventrículos (9/23, 39%); mientras que las típicos quistes chagásicos resultaron excepcionales Los músculos esqueléticos (11/18 Y 7/9) presentaron distintos grados de lesión histológica, desdes leves a extensos infiltrados linfoplasmocitarios con presencia de fibras necróticas. Mientras que con la técnioa de inmunoperoxidasa, los antígenos se revelaron como depósitos granulares intracitoplasmáticos difusamente distribuidos, tanto para IgG como para Ig totales. La coincidência entre este método y Ias lesiones musculares histológicas fueron 11/18 (61%) a los 6 meses p.i.y 6/8 (75%) a los 9 meses p.i. Por otra parte, los depósitos de lg totales en corazón se observaron dispuestos difusamente, en forma finamente granular dentro de los miocitos ventriculares La coincidência entre ambas técnicas (inmunoperoxidasa e histología) resultó ser dei 36% y 66% para los animales sacrificados a los 6 y 9 meses p.i. respectivamente. Este fenômeno inmunológico se incremento notablemente con el curso crônico de la enfermedad. Con respecto a la sensibilidad, tanto la inmunoperoxidasa como la inmunofluorescencia directa fueron altamente sensibles en músculo esquelético (100%, p 0,01). Por otra parte, la técnica de inmunofluorescencia directa en corazón, evidencio pobres resultados, mientras que el método peroxidasa anti-peroxidasa incrementó su sensibilidad de 21,4% a los 6 meses pi. al 66.6% a los 9 meses p.i. (p 0.001). Este modelo experimental, en el cual se observan reacciones inmunológicas reveladas por la técnica de inmunoperoxidasa, podría resultar de utilidad, considerando la necesidad de obtener una vacuna adecuada para prevenir la miocardiopatía chagásica