Renal-protective effect of nondepressor dose of cicletanine in diabetic rats with hypertension

Kohzuki, Masahiro; Wu, Xuemei; Kamimoto, Masahiro; Yoshida, Kazunori; Nagasaka, Makoto; Kanazawa, Masayuki; Yasujima, Minoru; Saito, Takao; Sato, Tokutaro

doi:10.1016/s0895-7061(99)00189-2

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…In this study, we induced diabetes in SHR at 15 weeks of age. This induction of diabetes contributed to the development of cardiac hypertrophy at a younger age, as previously reported (31). Of course we cannot completely exclude that the decrease in the ratio of heart weight to body weight was the consequence of lower body weight in diabetic SHR.…”

Section: Discussionsupporting

confidence: 58%

Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats

Tomita

Yamasaki²,

Izawa³

et al. 2007

Int J Mol Med

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Many clinical trials have demonstrated that angiotensin converting enzyme inhibitors have protective effects on organ damage, suggesting the importance of inhibition of the renin-angiotensin system. In this study, we investigated the effects of a non-depressor dose of imidapril on organ damage induced by diabetes and hypertension. Diabetes was induced by an intravenous injection of streptozotocin (STZ, 40 mg/kg) in 15-week-old male spontaneously hypertensive rats (SHR). Imidapril (2 mg/ kg/day) or vehicle was given orally for 28 days, and then the heart weight, left ventricle mass (LVM), urinary albumin excretion (UAE) and endothelial function were examined, as well as the urinary NOx level and local hepatocyte growth factor (HGF) expression. There were no significant differences between the treated groups in systolic blood pressure and plasma parameters. On the other hand, UAE was significantly suppressed in the imidapril-treated group (450±44 mg/day) compared to the vehicle-treated group (963±182 mg/day) (p<0.01). Moreover, endothelial function assessed by dilative reaction to acetylcholine as well as cardiac hypertrophy assessed by both heart/body weight ratio and LVM were significantly improved in the imidapriltreated group (p<0.05 and p<0.01, respectively). The urinary NOx concentration and local HGF expression in vessel walls were also significantly increased in the imidapril-treated group (p<0.01). A non-depressor dose of imidapril showed protective effects against organ damage in diabetic SHR, which may be partially due to the increase of HGF and NO.

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Section: Discussionsupporting

confidence: 58%

Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats

Tomita

Yamasaki²,

Izawa³

et al. 2007

Int J Mol Med

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“…Previous studies also documented that cicletanine, even at subdepressor doses, exhibited renal-protective effects. 22 The relevance of NKA-and PKC-dependent mechanisms to the renal action of cicletanine remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

et al. 2003

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Abstract-Marinobufagenin (MBG), an endogenous ligand of ␣-1 Na/K-ATPase, becomes elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein kinase C (PKC) phosphorylates ␣-1 Na/K-ATPase and increases its MBG sensitivity. Cicletanine, an antihypertensive compound with PKC-inhibitory activity, reverses MBG-induced Na/K-ATPase inhibition and vasoconstriction. We hypothesized that increased PKC levels in sodium-loaded hypertensive DS would sensitize ␣-1 Na/K-ATPase to MBG and that PKC inhibition by cicletanine would produce an opposite effect. We studied the effects of cicletanine on systolic blood pressure, left ventricular PKC isoforms, cardiac ␣-1 Na/K-ATPase levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg · kg Ϫ1 · d Ϫ1 cicletanine, and 7 DS received vehicle during 4 weeks of an 8% NaCl diet. Vehicle-treated rats exhibited an increase in blood pressure, left ventricular mass, MBG excretion (74Ϯ11 vs 9Ϯ1 pmol/24 h, PϽ0.01), myocardial ␣-1 Na/K-ATPase protein, and PKC ␤2 and ␦. The sensitivity of Na/K-ATPase to MBG was enhanced at the level of high-affinity binding sites (IC 50 , 0.8 vs 4.4 nmol/L, PϽ0.01). Cicletanine-treated rats exhibited a 56-mm Hg reduction in blood pressure (PϽ0.01) and a 30% reduction in left ventricular weight, whereas cardiac ␣-1 Na/K-ATPase protein and MBG levels were unchanged. In cicletanine-treated rats, PKC ␤2 was not increased, the sensitivity of Na/K-ATPase to MBG was decreased (IC 50 ϭ20 mol/L), and phorbol diacetate-induced ␣-1 Na/K-ATPase phosphorylation was reduced versus vehicle-treated rats. In vitro cicletanine treatment of sarcolemma from vehicle-treated rats also desensitized Na/K-ATPase to MBG, indicating that this effect was not solely attributable to a reduction in blood pressure. Thus, PKC-induced phosphorylation of cardiac ␣-1 Na/K-ATPase is a likely target for cicletanine treatment. Key Words: rats, Dahl Ⅲ Na/K-transporting ATPase Ⅲ digitalis-like factor Ⅲ bufanolides Ⅲ hypertrophy Ⅲ protein kinases Ⅲ antihypertensive agents E ndogenous digitalis-like sodium pump ligands (SPLs) increase during states of NaCl retention to induce inhibition of the renal tubular sodium pump and natriuresis. 1,2 Enhanced SPL levels, however, can also inhibit Na/KATPase (NKA) in cardiovascular tissues and raise arterial pressure. 2,3 Recently, we have shown that plasma and urine levels of marinobufagenin (MBG), an endogenous bufadienolide NKA inhibitor, rather than endogenous ouabain, increases and contributes to hypertension in Dahl salt-sensitive rats (DS) maintained on a long-term high-NaCl intake. 4,5 In vitro, MBG acts as a vasoconstrictor 6,7 and exhibits selectivity toward ␣-1 isoform of the sodium pump, ie, the major isoform in renal tubules and adult cardiomyocytes. 4,6 Protein kinase C (PKC) can affect NKA activity by altering its phosphorylation state. 8,9 This modulatory effect of PKC is specific to the NKA ␣-1 isoform. 9,10 In arterial sarcolemma, PKC induces the phosphorylation of ␣-1 NKA and enhances the NKA sensitivity to M...

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Effect of Rat-to-Mouse Bioartificial Pancreas Xenotransplantation on Diabetic Renal Damage and Survival

Sakata¹,

Gu²,

Qi³

et al. 2006

Pancreas

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Renal-protective effect of nondepressor dose of cicletanine in diabetic rats with hypertension

Cited by 3 publications

References 29 publications

Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats

Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

Effect of Rat-to-Mouse Bioartificial Pancreas Xenotransplantation on Diabetic Renal Damage and Survival

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