Spironolactone-induced inhibition of aldosterone biosynthesis in primary aldosteronism: Morphological and functional studies

Twenty-five patients harboring aldosterone-producing adenomas were treated with spironolactone for 2-170 days immediately preoperatively. In the early period of administration of the drug (up to 27 days), plasma and urinary aldosterone decreased sharply while plasma renin activity (PRA) and serum potassium were rising. During this period of time, spironolactone bodies (SB), which form exclusively in cells actively producing aldosterone, were forming rapidly in the tumor cells but not in the inactive glomerulosa cells proper. The SB appear to be a morphological expression of a block in aldosterone biosynthesis. Since SB do not occur in normal fasciculata cells, which, like glomerulosa cells, also synthesize corticosterone, it is concluded that spironolactone inhibition of aldosterone biosynthesis occurs between corticosterone and aldosterone. Recent studies in vitro by others have suggested that the inhibition occurs at the corticosterone-methyl oxidase step, I (Ulick's nomenclature). The great diuresis of sodium and retention of potassium resulting from continued administration of the drug sharply activates aldosterone stimulatory factors. Aldosterone production may return to baseline levels in several weeks but it is inappropriately low in relation to the levels of PRA and serum potassium. With the further passage of time (average 4-6 wk), aldosterone production may increase 50%-100% above baseline levels, suggesting that the block has disappeared or is receding. At this time SB are diminishing in number and by 170 days of the drug they have virtually disappeared. We have hypothesized, among other possibilities, that recovery of the ability to convert corticosterone to aldosterone occurs by virtue of a mechanism activated by sodium deficiency, independent of angiotensin, which stimulates step 1 of the corticosterone-methyl oxidase system. As the block in the final step(s) of the biosynthetic pathway recedes, the existing elevated levels of angiotensin become much more effective in stimulating the production of aldosterone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22806/1/0000363.pd

The effects of biomaterial components on bone cells

Biomaterialien können als Alternative zur Transplantation von menschlichem oder tierischem Knochengewebe in der Therapie von diversen Knochendefekten vielseitig eingesetzt werden. Die 2-Photonen-Polymerisation bietet eine Möglichkeit zur innovativen Produktion von beliebigen dreidimensionalen Strukturen aus photosensitiven Materialien, bestehend aus Monomeren und Photoinitiatoren. In dieser Arbeit wurde der Einfluss von drei ausgewählten Photoinitiatoren (Irgacure 2959, Irgacure 369 und Ini1) sowie der zwei Monomere Polyethylenglycoldiacrylat (PEGDA) und Polyethylenglycoldimethacrylat (PEGDMA) auf verschiedene Zelltypen getestet, um deren Zytotoxizität zu ermitteln. Die Substanzen wurden im entsprechenden Zellkulturmedium gelöst und für 72 h mit den Zellen inkubiert. Um die Beeinträchtigung von Wachstum und Viabiliät der Zellen durch verschiedene Konzentrationen der Photoinitiatoren oder Monomere zu ermitteln, wurde danach die Zellzahl von Osteoblasten, NIH 3T3 und RAW 264.7 Zellen mittels CASY Zellzählgerät bestimmt, wohingegen Osteoklasten TRAP-gefärbt und im Mikroskop gezählt wurden. Im Vergleich mit Irgacure 2959 und Irgacure 369 weist der experimentelle Photoinitiator Ini1 die höchste Wasserlöslichkeit gepaart mit niedriger Zytotoxizität auf und erscheint daher am geeignetsten. PEGDMA erwies sich als weniger zytotoxisch im Vergleich mit PEGDA. Allerdings ist es unumgänglich, Struktur und Freisetzungscharakteristik von Abbauprodukten der Biomaterialien zu untersuchen, um Vorhersagen bezüglich der Biokompatibilität in vivo treffen zu können.Biomaterial scaffolds are used in bone grafting as alternatives to naturally derived tissue. A possible way to fabricate arbitrary three-dimensional structures is the two photon polymerization of photosensitive materials consisting of monomers and photoinitiators. In this work, the three photoinitiators Irgacure 2959, Irgacure 369 and Ini1 as well as the two monomers poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) dimethacrylate (PEGDMA) were tested with different cell types to assess their cytotoxicity. The substances were dissolved in the appropriate cell culture medium and incubated with the cells for 72 hours. To assess the impairment of cell viability and growth by different concentrations of the monomers or photoinitiators, cell number of osteoblasts, NIH 3T3 and RAW 264.7 was determined with a CASY cell counter at the end of the experiments, while osteoclasts were TRAP-stained and counted using a microscope. The experimental photoinitiator Ini1 appeared to be the most favourable compared to Irgacure 2959 and Irgacure 369. It exhibited highest water solubility and lowest cytotoxicity. PEGDMA generally showed lower cytotoxicity than PEGDA, but it is important to also determine structure and release profile of degradation products to predict biocompatibility of a biomaterial scaffold in vivo