Effects of atorvastatin and ezetimibe on endothelial function in dyslipidemic patients with chronic kidney disease.

BACKGROUD: Chronic kidney disease (CKD) is a staple risk factor not only for renal failure but also for cardiovascular diseases. In addition, because dyslipidemia facilitates atherosclerosis and renal dysfunction, antihyperlipidemic treatment is important to prevent cardiac and renal events in CKD patients. METHODS: We compared the effects of a statin and an intestinal cholesterol transporter inhibitor in 20 dyslipidemic patients with CKD presenting with proteinuria and/or glomerular filtration rate <60 mL/min/1.73 m(2). Either 5-10 mg atorvastatin or 10 mg ezetimibe was given for 3 months each in a randomized crossover manner and the parameters of oxidative stress, inflammation and endothelial function were compared. RESULTS: Atorvastatin lowered serum low-density lipoprotein (LDL) cholesterol more prominently than ezetimibe (103 ± 38 vs 130 ± 45 mg/dL, p < 0.001), while serum γ-glutamyl transpeptidase was higher in atorvastatin than in ezetimibe (29 ± 16 vs 25 ± 11 U/L, p = 0.013). On the other hand, serum oxidized LDL and high-sensitivity C-reactive protein were lower in the atorvastatin treatment period than in the ezetimibe treatment period (109 ± 38 vs 146 ± 67 U/L, p = 0.002; 1.02 ± 1.46 vs 1.47 ± 1.77 µg/mL, p = 0.003). Although serum adiponectin was not significantly different between the two drugs, the reactive hyperemia index, an index of endothelial function, was higher in atorvastatin than in ezetimibe (1.94 ± 0.58 vs 1.60 ± 0.44, p = 0.023). CONCLUSION: It is concluded that atorvastatin is more potent than ezetimibe in improving the serum lipid profile, reducing oxidative stress, suppressing inflammation and preserving endothelial function, while ezetimibe may be advantageous in reducing the hepatic lipid load.

Long-term antihypertensive effects of aliskiren, a direct renin inhibitor, in chronic hemodialysis patients.

The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = -0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II.

Combination of angiotensin II receptor antagonist with calcium channel blocker or diuretic as antihypertensive therapy for patients with chronic kidney disease.

We compared treatment with an angiotensin II receptor antagonist (ARB) and a calcium channel blocker (CCB) combination and a fixed-dose ARB and thiazide diuretic in 18 chronic kidney disease (CKD) patients. A randomized crossover study was performed using a fixed-dose combination of losartan-hydrochlorothiazide or losartan combined with controlled-release nifedipine. Both systolic blood pressure (SBP) and diastolic blood pressures (DBPs) were lower during the nifedipine period than during the diuretic period. No significant difference was observed in urinary albumin excretion, but the estimated glomerular filtration rate was higher in the nifedipine than in the diuretic period. Serum uric acid and low-density lipoprotein cholesterol were higher in the diuretic than in the nifedipine period. A significantly low cardio-ankle vascular index, an index of arterial wall stiffness, was observed in the nifedipine period. A combination of ARB and a controlled-release nifedipine at 20-40 mg used showed a superior antihypertensive effect in CKD patients compared to a fixed-dose combination of losartan 50 mg-hydrochlorothiazide 12.5 mg in terms of blood control. The former combination is considered advantageous for maintaining renal function and artery wall elasticity without influencing uric acid or lipid metabolism.

Year-long antihypertensive therapy with candesartan completely prevents development of cardiovascular organ injuries in spontaneously hypertensive rats.

Most previous studies have examined the effects of antihypertensive drugs in hypertensive animals for only a few months, and little information has been provided as to the protective effects of lifetime antihypertensive medication against cardiovascular organ injury. In this study, spontaneously hypertensive rats (SHR) were treated for 1 year with an angiotensin-II receptor antagonist (ARB) and the development of hypertensive organ injury was evaluated. Male 15-week-old SHR (n = 9) were given 25 mg/L candesartan (CS) in their drinking water for 1 year. Twelve SHR and 9 normotensive Wistar-Kyoto rats (WKY) were given normal tap water. Tail-cuff blood pressure was almost normalized by CS throughout 1 year (at 12-months: WKY 132 ± 3, SHR 229 ± 3, CS 137 ± 4 mmHg). After 1 year, cardiac ventricular weight (SHR +33%, CS -2% versus WKY) and aortic thickness (SHR +34%, CS +4% versus WKY) in the CS-treated SHR rats were not different than those of WKY. Echocardiographic midwall fractional shortening (SHR -18%, CS -1% versus WKY) and left ventricular hydroxyproline content (SHR +47%, CS +11% versus WKY) were also improved by CS to the WKY level. With respect to kidney function, GFR (SHR -24%, CS +9% versus WKY) was preserved, proteinuria (SHR +312%, CS +12% versus WKY) was reduced, and the histological glomerular injury rate (SHR +186%, CS +6% versus WKY) was reduced by CS. These results suggest that long-term antihypertensive therapy with CS can completely prevent hypertensive cardiovascular and renal injuries in SHR.

Xenopus neurula left-right asymmetry is respeficied by microinjecting TGF-beta5 protein.

A variety of TGF-beta-related ligands regulate the left-right asymmetry of vertebrates but the involvement of TGF-betas in left-right specification has not been reported. We assessed whether TGF-beta signaling is involved in the left-right specification of Xenopus post-gastrula embryos by microinjecting Xenopus TGF-beta5 protein into the left or right flank of neurula-tailbud embryos. Injection on the right side of neurulae caused left-right reversal of the internal organs in 93% of the embryos, while injection on the left side caused less than 5% left-right reversal. Expression of Xenopus nodal related-1 (Xnr-1 ), Xenopus antivin and Xenopus Pitx2, which are normally expressed on the left, was unaltered by the left-side injection. In contrast, right-side injection into neurulae induced the expression of these genes predominantly on the right side. Right-side injection into tailbud embryos caused bilateral expression of these handed genes. Time course analysis of asymmetric gene expression revealed that Xnr-1 could be induced by TGF-beta5 at late neurula stage, while antivin and Pitx2 could be induced by TGF-beta5 at the latertail bud stage. Injection of the antisense morpholino oligonucleotide against Xenopus TGF-beta5 into the left dorsal blastomere inhibited the normal left-handed expression of Xnr-1 and Pitx2, and caused the organ reversal in the injected embryos. These results suggest that normal left-right balance of endogenous TGF-beta5 signaling in the neurula embryo may be needed to determine the laterality of the asymmetric genes and to generate the correct left-right axis.