Calcification is an undesirable disorder, which frequently occurs in the heart vessels. In general, the formation of calcific vascular lesions involves complex physicochemical and molecular events. Calcification (hydroxyapatite) is initiated by injury and is progressed by promoter factors and/or the deficit of inhibitory signals. Myo-inositol hexakisphosphate (phytate, InsP6) is found in organs, tissues and fluids of all mammals and exhibits an important capacity as a crystallization inhibitor of calcium salts in urine and soft tissues. The levels found clearly depend on the dietary intake but it can also be absorbed topically. In this paper, the capacity of InsP6 as a potential inhibitor of cardiovascular calcifications was assessed in Wistar rats. Three groups were included, a control group, an InsP6 treated group (subjected to calcinosis induction by Vitamin D and nicotine and treated with standard cream with a 2% of InsP6 as potassium salt) and an InsP6 non-treated group (only subjected to calcinosis induction). All rats were fed AIN 76-A diet (a purified diet in which InsP6 is undetectable). Animals were monitorized every 12 hours. After 60 hours of calcinosis treatment, all rats of the InsP6 non-treated group died and the rest were sacrificed. Aortas and hearts were removed. A highly significant increase in the calcium content of aorta and heart tissue was observed in the InsP6 non-treated rats (21 +/- 1 mg calcium/g dry aorta tissue, 10 +/- 1 mg calcium/g dry heart tissue) when compared with controls (1.3 +/- 0.1 mg calcium/g dry aorta tissue, 0.023 +/- 0.004 mg calcium/g heart dry tissue) and InsP6 treated (0.9 +/- 0.2 mg calcium/g dry aorta tissue, 0.30 +/- 0.03 mg calcium/g dry heart tissue) animals. Only InsP6 non-treated rats displayed important mineral deposits in aorta and heart. These findings are consistent with the action of InsP6, as an inhibitor of calcification of cardiovascular system.
The aim of this study was to assess the inhibitory action of phytate in formation of renal calculi. Hypertension (induced by nicotine) combined with hypercalcemia (induced by D vitamin) was used to induce calcification in renal tissue in male Wistar rats that were fed a purified phytate free diet. Phytate non-treated rats developed significant calcium deposits in kidneys and papillae, as well as in kidney tubules and vessels, whereas calcium deposits were absent in control and phytate treated rats. Fragments of hydroxyapatite (HAP) calculi exhibited the capacity to induce the growth of calcium salts on their surfaces. Presence of 1.5 mg/L of phytate in the synthetic urine inhibited the formation of calcium oxalate monohydrate on HAP renal calculi in normocalciuric conditions. The findings show that the action of phytate as a crystallization inhibitor takes place both in the intrapapillary tissue and urine.
End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60–70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.
The high efficacy of phytate in reducing dental calculus formation suggests that this substance may be an effective treatment for preventing the development of calculus deposits.
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