Reduced expression of endothelial connexin37 and connexin40 in hyperlipidemic mice: recovery of connexin37 after 7-day simvastatin treatment.

Tsai CH.

Mackay Memorial Hospital, Mackay Junior College of Nursing, Taipei Medical University, Taipei, Taiwan.

OBJECTIVE: We sought to clarify the response of endothelial connexins to hyperlipidemia and lipid-lowering therapy. METHODS AND RESULTS: Aortic endothelial gap junctions were analyzed by en face immunoconfocal microscopy and electron microscopy in C57BL/6 mice subjected to the following regimens: (1) normal chow (NC) for 3 months (3 mo), (2) NC for 9 mo, (3) NC for 3 mo, followed by a cholesterol-enriched diet (CED) for 6 mo, (4) NC for 3 mo and CED for 6 mo, with simvastatin in the final week, and (5) (in apoprotein E [apoE]-deficient mice) NC and examined at 3 mo and 7 to 9 mo. In wild-type mice, connexin37 (Cx37) and Cx40 were markedly downregulated in the CED-fed animals compared with those fed NC (CED vs 9-mo NC, 77% reduction in Cx37 and 65% reduction in Cx40; both P<0.01). After simvastatin treatment, Cx40 remained depressed, but Cx37 recovered to 94% of the level found in non-cholesterol-fed animals (P<0.01). Electron microscopy demonstrated that gap junctions were smaller in animals fed the CED compared with those given simvastatin and with controls fed NC (P<0.01). Endothelial connexins were rare in the atherosclerotic plaques of apoE-deficient mice. CONCLUSIONS: Mouse aortic endothelial gap junctions and connexins are downregulated during long-term hyperlipidemia. Short-term treatment with simvastatin leads to recovery of Cx37 expression but not Cx40 expression.

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Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression.

Cimino M.

Istituto di Farmacologia e Farmacognosia, Universita di Urbino, via S. Chiara 27, 61029 Urbino, Italy. balduini uniurb.it

BACKGROUND AND PURPOSE: Prophylactic administration of simvastatin has been shown to protect against brain damage and its long-lasting behavioral consequences in neonatal rats. To establish the drug treatment window, we evaluated the effectiveness of simvastatin administered at different intervals before and after stroke. Furthermore, we determined whether simvastatin affected endothelial nitric oxide synthase (eNOS) or inflammatory cytokines in brain tissue or cholesterol levels in serum. METHODS: On postnatal day 7, male rats were subjected to hypoxia-ischemia (HI). The experiment included sham-operated controls and HI animals receiving daily saline or activated simvastatin (20 mg/kg) injections from postnatal day 1 to day 7 (HI-simvastatin 1-7 group), from postnatal day 4 to day 11 (HI-simvastatin 4-11 group), or from postnatal day 7 to day 14 (HI-simvastatin 7-14 group). The neuroprotective effect of simvastatin was evaluated at adulthood by means of behavioral and histological analyses. Cytokines and eNOS expression were assessed by reverse transcriptase-polymerase chain reaction and Western blotting. RESULTS: Animals in both the HI-simvastatin 1-7 and HI-simvastatin 4-11 groups performed better than HI rats in either the T-maze or the circular water maze and showed significantly attenuated brain damage. Expression of interleukin-1beta and tumor necrosis factor-alpha mRNA in cortex was significantly increased in HI but not in HI-simvastatin 1-7 animals. In the same brain area, simvastatin treatment did not affect the increase of eNOS expression observed after HI. CONCLUSIONS: These findings indicate that prophylactic but not delayed administration of simvastatin improves functional outcome in neonatal rat stroke. The reduced induction of cytokines suggests that the neuroprotective effect of simvastatin may be related to a dampening of the inflammatory response.

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Effects of the combination of an angiotensin II antagonist with an HMG-CoA reductase inhibitor in experimental diabetes.

Cao Z.

Department of Endocrinology, The People's Hospital of Shanxi Province, Taiyuan, Shanxi, People's Republic of China.

BACKGROUND: Angiotensin II type 1 (AT1) receptor antagonists and 3-hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors have been shown to confer renoprotection. However, the renal effects of the combination of an AT1 receptor antagonist and an HMG-CoA reductase inhibitor in experimental diabetes are unknown. METHODS: Diabetes was induced by injection of streptozotocin in Wistar rats. Diabetic rats were randomly treated with losartan, an AT1 receptor antagonist, or simvastatin, an HMG-CoA reductase inhibitor, as well as the combination of both for eight weeks. Albumin excretion rate (AER) and plasma concentrations of blood urea nitrogen (BUN), creatinine, cholesterol, and triglycerides were measured. Renal injury was evaluated. Immunohistochemical staining of transforming growth factor beta1 (TGF beta 1) and vascular endothelial growth factor (VEGF) were performed. RESULTS: Increased AER in diabetic rats was attenuated by treatment with either losartan or simvastatin and further reduced by the combination of the two. Elevated plasma concentrations of BUN and creatinine were only reduced by the combination. There was no significant difference in plasma concentrations of cholesterol and triglycerides between control and diabetic rats and neither was influenced by losartan or simvastatin. Kidney pathologic injury was attenuated by losartan, but not simvastatin, compared to diabetic animals. Overexpression of TGF beta 1 and VEGF was observed in the glomeruli of diabetic rats and was attenuated by losartan, simvastatin, or the combination of both to a similar level. CONCLUSION: The combination of an angiotensin antagonist with an HMG-CoA reductase inhibitor confers superiority over monotherapies on renal function, as assessed by prevention of albuminuria and rise in plasma BUN and creatinine. However, no advantage of combination therapy was seen with respect to attenuating renal structural injury and renal expression of TGF beta and VEGF in experimental diabetes.

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Effect of pitavastatin on sterol and bile acid excretion in guinea pigs.

Saito Y.

Tokyo New Drug Research Laboratories I, Atherosclerosis Research Department, Pharmacology Group, Kowa Company, Ltd., Tokyo, Japan. t-aoki kowa.co.jp

The influence of pitavastatin (CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, exerted on fecal and biliary excretion of sterols and bile acids was investigated using guinea pigs. The cumulative amount of [3H] bile acid in bile 0 to 6 h after the injection of high density lipoprotein (HDL), which was labeled with [3H] cholesteryl ester (CE), was slightly decreased with atorvastatin (30 mg/kg, CAS 134523-00-5) and simvastatin (30 mg/kg, CAS 79902-63-9), and the same level as the control was maintained with pitavastatin (3 mg/kg). The amount of excretion of [3H] sterol into bile was significantly increased with atorvastatin and simvastatin, and exhibited a tendency to decline with pitavastatin. The [3H] bile acid/[3H] sterol ratios were significantly lowered with atorvastatin and simvastatin by 41% and 29%, respectively, as compared to the control, and exhibited an upward tendency with pitavastatin (22%). The total amounts of fecal [3H] bile acid from 0 to 7 days were significantly decreased with atorvastatin and simvastatin by 30% and 32%, respectively, and slightly increased with pitavastatin by 8% Furthermore, mRNA expression of the hepatic microsomal cytochrome P-450 enzyme, cholesterol-NADPH: oxygen oxidoreductase (cholesterol 7 alpha-hydroxylase; CYP7A), which is a late limiting enzyme with a bile acid composition, was also decreased with atorvastatin and simvastatin by 54% and 38%, respectively, and slightly increased with pitavastatin (14%). The change in CYP7A mRNA expression was well correlated with the amount of the fecal [3H] bile acid. The bile acid excreting efficacy of pitavastatin was relatively high as compared with atorvastatin or simvastatin. It is suggested that this action may contribute to the powerful cholesterol lowering action of pitavastatin.

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Effects of simvastatin on the development of osteopenia caused by ovariectomy in rats.

Gubala I.

Department of Pharmacology, Silesian Medial University, Jagiellonska 4, PL 41-200 Sosnowiec, Poland.

Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-determining enzyme for cholesterol synthesis which is used in the treatment of hypercholesterolemias, particularly in type IIa and IIb hyperlipoproteinemias, frequently in postmenopausal women. Inhibition of cholesterol synthesis by simvastatin may cause disorders of bone remodelling. The aim of the present study was to investigate the effects of simvastatin (3 mg and 6 mg/kg/day per os) administered for 4 weeks on the development of ovariectomy-induced osteopenia in 3-month-old female Wistar rats. The experiments were carried out on six groups of animals: I (C)--sham operated rats, II (S-3)--sham operated rats + simvastatin 3 mg/kg/day p.o., III (S-6)--sham operated rats + simvastatin 6 mg/kg/day p.o., IV (OVX)--ovariectomized rats, V (OVX + S-3)--ovariectomized rats + simvastatin 3 mg/kg/day p.o., VI (OVX + S-6)--ovariectomized rats + simvastatin 6 mg/kg/day p.o. In all the groups, we examined body weight gain, and macrometrical, histomorphometrical and mechanical parameters. Bilateral ovariectomy induced osteopenic skeletal changes in mature female rats. In cortical bone, ovariectomy intensified resorption processes at the marrow cavity, as indicated by a decrease in endosteal transverse growth and an increase in transverse cross-section surface area of the marrow cavity in the tibia. Intensification of resorption processes was observed in cancellous bone (a statistically significant decrease in the width of trabeculae in the epiphysis and metaphysis of the femur). Structural changes in the long bones resulting from bilateral ovariectomy were manifested by deterioration of mechanical properties of the shaft and neck of the femur. The force needed to fracture the neck and shaft of the femur was significantly smaller than that in sham operated rats. Simvastatin (3 and 6 mg/kg/day p.o.) slightly influenced bone remodelling in sham operated rats. Simvastatin (3 and 6 mg/kg p.o. daily) administered to ovariectomized rats intensified bone formation processes and decreased bone resorption processes induced by bilateral ovariectomy, showing stronger activity at 6 mg/kg.

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Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME.

Marhuenda E.

Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/Profesor Garcia-Gonzalez s/n, 41014 Seville, Spain.

Blood pressure, plasma NO(2) and NO(3) level, heart weight index, antioxidant enzyme activity, and vascular reactivity in rat intact aortic rings were assessed to investigate the effects of 8-week treatment with the hydroxy-methyl-glutaryl coenzyme A reductase inhibitor simvastatin (1 mg/kg per day) on endothelial dysfunction induced by chronic Nomega-nitro-l-arginine methyl ester (l-NAME 70 mg/kg per day). Results were compared with those obtained in rats receiving l-NAME, simvastatin or control animals. Coadministration of simvastatin did not restore l-NAME-increased blood pressure but normalized heart weight index (P < 0.05), endothelium-dependent relaxation to acetylcholine (P < 0.001), and plasma NO(2) and NO(3) concentration (P < 0.001) without affecting relaxation to sodium nitroprusside. Endothelium-dependent relaxation in these animals was abolished by acute incubation with l-NAME, unaffected by thromboxane synthetase inhibitor and TXA(2)/PGH(2) receptor antagonist, ridogrel, and decreased by indomethacin. Simvastatin treatment also increased plasma NO(2)+NO(3) without affecting endothelial function, heart weight index, and blood pressure of control rats. The presence of superoxide dismutase (SOD) and catalase improved endothelial relaxation only in l-NAME-treated rats, but O(2)- generated by hypoxanthine and xanthine oxidase inhibited the relaxant effect in both l-NAME and simvastatin plus l-NAME-treated rats. SOD activity was increased in all groups receiving simvastatin. Long-term treatment with simvastatin restored l-NAME-induced endothelial dysfunction, probably by preventing nitric oxide decrease. Other effects of simvastatin, including release of compensating vasodilatory cyclo-oxygenase products and increased SOD activity, could also be involved.

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