Angiotensin Synthesis in the Brain and Increased Turnover in Hypertensive Rats

Ganten, Detlev; Hermann, K.; Bayer, Carolyn L.; Unger, Th.; Lang, R.

doi:10.1126/science.6879184

Cited by 310 publications

(128 citation statements)

References 15 publications

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“…In this regard, estimates of cross-reactivity using either RIA ( 5 ) or immunoblots (35) indicate that the ANG I1 antisera cross-react primarily with ANG I1 and, to a lesser extent, with angiotensin I and angiotensin 111. The latter is only present in low concentrations in the mammalian brain (4). In the present study, immunoreactivity to ANG I1 could be completely abolished by preabsorption of a working dilution of the antibody with 15 pg of purified Ile5-ANG 11.…”

Section: Circurnvrntriculur Organs-sites Without a Blood-bruin Burriersupporting

confidence: 50%

“…Ganten et al (4) isolated angiotensin I and A N G II from the rat brain and demonstrated the central nature of ANG I1 production by the intracerebroventricular administration of an inhibitor of angiotensin-converting enzyme which caused a reduction in local ANG 11. Furthermore, the presence of each of the components of the renin angiotensin system (RAS) has been demonstrated immunocytochemically (5)(6)(7)(8) and the likelihood of local production supported by the identification of mRNA for renin and angiotensinogen (9,10).…”

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An Ultrastructural Analysis of the Distribution of Angiotensin II in the Rat Brain

Oldfield

Ganten

1989

J Neuroendocrinology

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Abstractlmmunopositive angiotensin I1 nerve fibres and terminals are widely distributed throughout the rat brain, including areas of the brain with and without a blood-brain barrier. Ultrastructural examination indicates that in the circumventricular organs (areas which lack a blood-brain barrier), many angiotensin Il-positive nerve terminals are closely aligned with fenestrated blood vessels and do not have synaptic specializations. This appearance is in contrast to that of angiotensin II terminals in regions with a blood-brain barrier where there exists a more typical synaptic configuration. In both cases, angiotensin II is contained within large (100 to 125 nm) vesicles which coexist with smaller, lucent, non-immunoreactive vesicles. These observations suggest a possible duality of function such that angiotensin II in circumventricular organs may be secreted into the circulation, whereas angiotensin I I in the remainder of the brain is more likely to be acting as a neurotransmitter or neuromodulator.The octapeptide, angiotensin 11 (ANG II), when administered into the CNS, causes a number of well-defined physiological and behavioural responses including thirst, vasopressin secretion, natriuresis, increased blood pressure and salt appetite (1-3).One of the major questions central to understanding the actions of ANG I1 in the brain has been the source of its production. Ganten et al. (4) isolated angiotensin I and A N G II from the rat brain and demonstrated the central nature of ANG I1 production by the intracerebroventricular administration of an inhibitor of angiotensin-converting enzyme which caused a reduction in local ANG 11. Furthermore, the presence of each of the components of the renin angiotensin system (RAS) has been demonstrated immunocytochemically (5-8) and the likelihood of local production supported by the identification of mRNA for renin and angiotensinogen (9, 10). However, the cellular disposition of each of the components of the RAS still remains unclear, as does the nature of their interaction and the degree of their anatomical overlap. Immunocytochemically-identified A N G I1 is contained in a network of neural pathways connecting areas of the forebrain and brainstem which are largely concerned with autonomic or homeostatic functions (11). It is on the basis of these studies and the good correlation of A N G 11-positive terminal fields with A N G II receptors (12-15) that ANG I1 is suggested to act as a neurotransmitter/neuromodulator in the CNS.The present study has sought to further elucidate the action of ANG 11 in the CNS by examining its ultrastructural distribution. In particular, we have focused on the nature of morphological interactions between A N G 11-positive elements and other neural and non-neural structures in a range of brain areas.Previous studies at the light microscopic (LM) level have shown ANG 11-positive structures, presumed to be terminals, to be aggregated both in circumventricular organs (CVOs) and in regions behind the blood-brain barrier. Because the function of ...

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Section: Circurnvrntriculur Organs-sites Without a Blood-bruin Burriersupporting

confidence: 50%

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An Ultrastructural Analysis of the Distribution of Angiotensin II in the Rat Brain

Oldfield

Ganten

1989

J Neuroendocrinology

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“…Young SHR have been reported to have elevated turnover and levels of Ang II in the brain. 4,45 SHR have also been reported to be hyperresponsive to the effects of intracerebroventricular Ang II and Ang III. 46 In membrane preparations from SHR and WKY brains, Ang II is metabolized more rapidly by SHR than by WKY but Ang III metabolism is similar.…”

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Kidney Aminopeptidase A and Hypertension, Part I

Healy

Song

1999

Hypertension

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Abstract-Tissue and plasma levels of aminopeptidase A (APA), the principal enzyme that hydrolyzes angiotensin II (Ang II) to angiotensin III, were measured in spontaneously hypertensive rats (SHR) and their normotensive control strain at 3 different ages corresponding to prehypertensive (4 weeks), developing (8 weeks), and established (16 weeks) phases of hypertension. Plasma APA activity was significantly but modestly elevated in SHR at all 3 ages compared with normotensive Wistar-Kyoto rats. Likewise, levels of APA in brain, heart, and adrenal gland were generally, but again only moderately, elevated in SHR at all ages. However, a large increase in APA activity was seen within the kidney in which APA levels were elevated 41%, 51%, and 68% in SHR at 4, 8, and 16 weeks of age, respectively. Kidney APA levels were also significantly increased in immunoblots from 8-and 16-week-old SHR. Glomeruli isolated from 16-week-old SHR had 57% higher APA activity and increased immunoreactivity compared with Wistar-Kyoto rats. To determine whether the increase in kidney APA activity in SHR was related to Ang II levels, SHR were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril. Captopril treatment reduced blood pressure to normotensive values and resulted in a 25% reduction in kidney APA activity. These results suggest that APA expression in the kidney may be regulated by activity of the renin-angiotensin system. If so, this would further suggest that upregulation of APA during conditions in which Ang II levels were elevated would have a protective effect against Ang II-mediated cardiovascular diseases, whereas a decrease in APA expression or a failure to upregulate would exacerbate such conditions. (Hypertension. 1999;33:740-745.)

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“…The research in Detlev Ganten's laboratory was stimulating. The role for a renin-aniotensin system in the brain conducting cardiovascular regulation, salt-and-water appetite, and even controlling energy metabolism is now well established [3,4]. Natriuretic peptides had been discovered, but developing an assay to measure natriuretic peptides brought this line of research into the clinical arena [5].…”

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A visionary scientist selects clinicians for clinical research

Luft

2016

J Mol Med

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We celebrate Detlev Ganten's 75th birthday late this March (Fig. 1); we hope he is celebrating too. Detlev Ganten is not only founding editor of the Journal of Molecular Medicine and still active in this capacity, he is also the initial director of the Max-Delbrück Center for Molecular Medicine (MDC) Berlin-Buch. The MDC traces its heritage to the KaiserWilhelm Institute für Hirnforschung, officially founded 1931. The collaboration between Nikolai TimofejewRessovsky, Karl Zimmer, and Max Delbrück that resulted in placing genetics on a molecular footing has been told many times. When the institute was reconstituted after German reunification, Detlev Ganten was given the task of resurrecting the MDC to world-class. And so he did; for 13 years, he was at the helm. Since its founding, 25 years have passed and the MDC has performed even beyond Detlev Ganten's expectations. Of course, since his first two publications appeared in Nature [1] and in Science [2], he probably believes that such publications are easy, as they were for him.Detlev Ganten gave the MDC a unique mission, namely pursuing the highest caliber of disease-oriented (clinical) biological research focusing on the basic mechanisms and molecules of relevance in health and disease and emphasizing the most advanced methodologies in cell biology, genetics, and genomics. He was less interested in the topic and wisely supported the idea that the MDC should pursue a broad spectrum of problems comprising the current chronic scourges, namely cardiovascular disease, cancer, and neurodegenerative disorders. Similarly circumspect, the MDC has maintained this broad base until the present day.Another unique decision Detlev Ganten made was to include clinicians in the field of MDC senior scientists. As the institute had a tradition of encompassing clinical departments since the time of Oskar and Cécile Vogt, the decision was made easier. The institute had continued that tradition and before German reunification had worked intensively with a clinic dedicated to cancer and a clinic for cardiovascular diseases in the framework of the BAcademy of the Sciences^. However, although the clinics were still there, the framework was gone and to continue the concept in conjunction with the two medical schools Berlin had in 1991 was difficult. Furthermore, the mission Detlev Ganten espoused was not necessarily commensurate with the usual department chairmanships in academic medicine. Clinical excellence, teaching, and research were the appropriate criteria of the time; however, Detlev Ganten wanted the order and emphasis revised and reversed. Research at an internationally competitive level was to receive priority, yet the clinical departments also had to work; the patient care had to be excellent, and the teaching mission was not to be ignored. He found his clinicians and the search also underscores the value of personal relationships when making personnel decisions.

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Angiotensin Synthesis in the Brain and Increased Turnover in Hypertensive Rats

Cited by 310 publications

References 15 publications

An Ultrastructural Analysis of the Distribution of Angiotensin II in the Rat Brain

An Ultrastructural Analysis of the Distribution of Angiotensin II in the Rat Brain

Kidney Aminopeptidase A and Hypertension, Part I

A visionary scientist selects clinicians for clinical research

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