Niere und Kreislauf<sup>1</sup>

Tigerstedt, Robert; Bergman, P. Q.

doi:10.1111/j.1748-1716.1898.tb00272.x

Cited by 789 publications

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“…Although the idea to inhibit renin as a means of blocking the RAAS originated from studies that were conducted over 100 years ago, 2 it is only recently that the effects of inhibiting this enzyme have been studied in depth. There is still much to learn about the mechanism of action of renin inhibition, and how it differs from those of ACEI and AT 1 receptor blockers.…”

Section: Resultsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Resultsmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…The first enzyme is renin which is secreted from the kidney (Tigerstedt & Bergmann, 1898); the second or converting enzymes is located primarily in the lung . Renin acts on a substrate in the plasma protein to produce the relatively inactive angiotensin I (Skeggs et al, 1956) and the converting enzyme in the lung generates from angiotensin I the physiologically active angiotensin II , 1968.…”

Section: Discussionmentioning

confidence: 99%

Fate of angiotensin I in the toad Bufo melanostictus

1973

British J Pharmacology

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Summary1. The effects of angiotensin I and II on the blood pressure of pithed toads and the disappearance of angiotensin I and II in the perfused organs of the toad were studied. 2. Angiotensin I was relatively inactive on the blood pressure of pithed toads; it exhibited less than 3% of the pressor activity of angiotensin II. 3. Angiotensin I was not converted to angiotensin II during passage through the lungs. There was also no evidence of net conversion during passage through the kidney and hind quarters. 4. During passage through the lungs, 33-50% of angiotensin I was removed and 25-50% was removed during passage through the hind quarters. No loss of activity was detected when angiotensin II passed through the kidneys. 5. Angiotensin II passed through the lungs and kidneys without loss but 25-50% disappeared during passage through the hind quarters. 6. The relatively low pressor activity of angiotensin I together with its lack of conversion to angiotensin II in isolated perfused organs suggest that the converting enzyme is absent in the toad, Bufo melanostictus.

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“…Hypertrophy of the heart would be a result of this." 1 No subsequent statement describes the mechanism of vasoconstrictor hypertension any better than the above.…”

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“…We only wish to draw attention to the possible importance of a blood pressureraising substance formed in the kidneys." 1 The authors did suggest that: "under certain circumstances, this substance (renin) could be formed in larger quantities than usual. ...…”

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confidence: 99%

“…In view of the intimate connection between some renal and cardiac diseases, it seemed possible to investigate the presence of such a substance." 1 Ludwig, the pre-eminent teacher of physiology during the 19th century, first interested Tigerstedt in blood circulation. In 1847, Ludwig added a float to Poiseuille's mercury manometer and recorded blood pressure on a revolving kymograph, which remained for the next 100 years the classic method of blood pressure recording in the laboratory.…”

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Tigerstedt and the discovery of renin. An historical note.

Marks¹,

Maxwell²

1979

Hypertension

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Niere und Kreislauf¹

Abstract: Einleitung.

Cited by 789 publications

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New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Fate of angiotensin I in the toad Bufo melanostictus

Tigerstedt and the discovery of renin. An historical note.

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Niere und Kreislauf1

Abstract: Einleitung.

Cited by 789 publications

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New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Fate of angiotensin I in the toad Bufo melanostictus

Tigerstedt and the discovery of renin. An historical note.

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Niere und Kreislauf¹