Norio Komai

Association of Hypoadiponectinemia With Impaired Vasoreactivity

Abstract—Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total (r =0.257, P <0.001) and no-medication (r =0.296, P =0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout (KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.

Comparison of Arterial Functional Evaluations as a Predictor of Cardiovascular Events in Hypertensive Patients : The Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) Study

Increased arterial stiffness and impaired vasodilator response have been associated with cardiovascular events in high-risk patients. However, whether arterial changes predict the occurrence of hypertensive complications is still unclear. Therefore, we designed a hospital-based cohort study to examine the prognostic impact of arterial functional changes on stroke and cardiovascular diseases in hypertensive patients. The study employed 676 patients with essential hypertension. At baseline, we evaluated second-derived photoplethysmography, carotid-femoral pulse wave velocity (PWV), and forearm reactive hyperemia. We classified subjects into quartile groups according to the baseline measurements of these evaluations and assessed the ability of each measure to predict stroke and cardiovascular diseases (CVD). During a mean follow-up period of 57 months, 52 strokes, 40 CVD, and 22 deaths were recorded. Kaplan-Meier analysis revealed that patients in the highest quartile of PWV showed a higher frequency of stroke and CVD (p<0.0001) and total mortality (p=0.0016), and those in the highest quartile of reactive hyperemia showed a lower frequency of stroke and CVD (p=0.0415). A Cox hazard model identified that classification in the highest quartile of PWV (relative risk=2.717) and reactive hyperemia (0.416) were predictive of stroke and CVD after adjustment for other risk factors. In subjects who did not experience stroke or CVD before the study period (n=558), only PWV was related with the occurrence of stroke and CVD based on the Cox hazard model. In conclusion, increased aortic stiffness evaluated by PWV is more prognostic of cardiovascular events in hypertensive patients than several non-invasive atherosclerotic evaluations.

Isohumulones Derived from Hops Ameliorate Renal Injury via an Anti-Oxidative Effect in Dahl Salt-Sensitive Rats

Previous studies have reported that isohumulones, the bitter compounds in beer, improve insulin resistance and hyperlipidemia in several animal models. In this study, we examined whether isohumulones ameliorate renal injury. Dahl salt-sensitive hypertensive rats were fed a low-salt diet (LS), a high-salt diet (HS) or a high-salt diet containing 0.3% isohumulones (HS+IH) for 4 weeks. Urinary nitrite/nitrate (NOx) excretion was measured at 4 weeks along with blood pressure and urinary protein excretion. Renal injury was evaluated histologically and reactive oxygen species (ROS) and nitric oxide (NO) production in the renal cortex was visualized. Oxidative stress and NO synthase (NOS) expression were evaluated by immunohistochemical staining and Western blot analysis. Mean blood pressure was significantly decreased in the HS+IH group compared with the HS group at 4 weeks (158.1±8.7 vs. 177.5±3.7 mmHg; p<0.05). Isohumulones prevented the development of proteinuria in the HS+IH group compared with the HS group at 2 weeks (61.7±26.8 vs. 117.2±9.8 mg/day; p<0.05). Glomerulosclerosis and interstitial fibrosis scores were significantly decreased in the HS+IH group compared with the HS group (0.61±0.11 vs. 1.55±0.23, 23.7±6.8 vs. 36.1±3.5%; p<0.05 for both). In the HS group, increased ROS and decreased NO were observed in glomeruli in vivo. Isohumulones reduced the ROS production, leading to the restoration of bioavailable NO. Urinary NOx excretion was significantly increased in the HS+IH group compared with the HS group. Furthermore, renal nitrotyrosine was increased in the HS group compared with the LS group, and this effect was prevented by isohumulones. Renal NOS expression did not differ among the three groups. These results suggest that isohumulones may prevent the progression of renal injury caused by hypertension via an anti-oxidative effect.

Serum hepatocyte growth factor concentration is correlated with the forearm vasodilator response in hypertensive patients

To evaluate the clinical importance of serum hepatocyte growth factor (HGF) concentration, we designed two clinical investigations. The first study analyzed the correlation between serum HGF concentration and clinical arterial stiffness or the vasodilator response to reactive hyperemia in hypertensive patients. The second study investigated the correlation between changes in serum HGF concentration and clinical arterial stiffness or reactive hyperemia during treatment with cilazapril or atenolol. A total of 210 hypertensive patients were analyzed in the first study, and 25 patients with essential hypertension were evaluated in the second study. Pulse wave velocity (PWV), strain gauge plethysmography, and serum HGF concentration were measured in the first study. We also evaluated these factors before and after treatment with either cilazapril (2.0 mg/day) or atenolol (25 mg/day) for 6 months in the second study. Serum HGF concentration was negatively correlated to reactive hyperemia in overall (r = 0.434, P < .0001) and nontreatment (r = 0.452, P < .0001) hypertensive patients. Arterial stiffness was weakly related to serum HGF concentration (P < .05) after adjusting for age and mean blood pressure (BP). By multiple regression analysis, only serum HGF concentration showed a strong independent correlation with reactive hyperemia, age and mean BP with PWV. Moreover, a relationship between endothelium-dependent vasodilation and serum HGF concentration was observed during treatment with cilazapril or atenolol (r = 0.406, P < .005). These results suggest that in evaluation of serum HGF concentration, the forearm vasodilator response to reactive hyperemia and PWV might be useful for managing hypertension in patients who are receiving antihypertensive therapy.

Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy

BackgroundSerotonin (5-HT) is involved in vascular inflammation and atherosclerogenesis. Serum 5-HT concentrations are elevated in diabetes, and 5-HT is involved in diabetic vasculopathies. Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, has renoprotective effects, but its effect in diabetic nephropathy is not elucidated. The aim of this study was to examine the effects of sarpogrelate on endothelial dysfunction in rats with streptozotocin (STZ)-induced diabetes.MethodsRats with STZ-induced diabetes were either untreated or treated with sarpogrelate (30 mg/kg P.O.) for 8 weeks. At the end of the experiment, we measured urinary albumin excretion, serum adiponectin concentration and platelet-derived microparticles. Intraglomerular coagulation was detected by immunostaining for platelets. Production of renal reactive oxygen species (ROS) and nitric oxide (NO) was investigated by confocal laser microscopy and used as an index of glomerular endothelial dysfunction.ResultsDiabetic nephropathy was associated with enhanced production of ROS and diminished bioavailable NO in the glomeruli. Treatment with sarpogrelate improved ROS/NO imbalance in glomeruli, suppressed platelet aggregation in glomeruli, reduced platelet-derived microparticles, increased serum adiponectin level and reduced the level of albuminuria, compared with non-treated diabetic rats.ConclusionsOur results indicate that sarpogrelate improves endothelial function in rats with STZ-induced diabetes through a reduction of glomerular platelet activation and an increase in serum adiponectin concentrations and suggest that sarpogrelate is potentially useful for the treatment of diabetic nephropathy.

Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin.

OBJECTIVES We examined whether patients with ischemic heart disease (IHD) should be treated with nicorandil, an adenosine triphosphate-sensitive potassium channel opener, in addition to the regular use of nitrates. BACKGROUND It has been reported that nicorandil possibly has additive effects on nitroglycerin (NTG) treatment for angina, but the mechanism is not clear. METHODS We directly measured anterograde coronary blood flow (CBF) with a Doppler guide wire to examine the effects of intravenous administration of NTG (0.3 mg) and nicorandil (6 mg) during continuous administration of NTG at a sufficient dose (25 microg/min) in subjects with normal and stenotic coronary arteries. RESULTS Additional systemic administration of NTG decreased anterograde CBF (normal -19.7%; stenotic -21.2%). In contrast, nicorandil increased anterograde CBF in both normal (54.6%) and stenotic (89.6%) coronary arteries, without the coronary steal phenomenon. There was a tendency toward nicorandil-dilated diameters in the patients with stenotic arteries (p = 0.06). There were no effects of additional administration on pulmonary artery wedge pressure. There was no difference in changes in heart rate and mean aortic blood pressure between NTG and nicorandil therapy. CONCLUSIONS These results suggest that in patients treated with nitrates, additional administration of nicorandil is more useful, in terms of increasing CBF, than additional administration of nitrates. Adjunctive use of nicorandil with nitrates may provide the further benefit of myocardial protection and may improve the prognosis of patients with IHD.

Mitogenic Activity of Oxidized Lipoprotein (a) on Human Vascular Smooth Muscle Cells

Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P <0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.

Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study

BACKGROUND Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). METHODS We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. RESULTS SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. CONCLUSION Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.

Pioglitazone Enhances the Antihypertensive and Renoprotective Effects of Candesartan in Zucker Obese Rats Fed a High-Protein Diet

The metabolic syndrome is a risk factor for the development of chronic kidney disease. Angiotensin II type 1 receptor blockers (ARBs) and thiazolidinediones (TZDs) provide renovascular protection, probably in the metabolic syndrome. However, the effect of both agents administered together in patients with metabolic syndrome remains to be determined. The aim of this study was to assess the effects of ARB plus TZD combination therapy in Zucker obese rats fed a high-protein diet, an animal model of metabolic syndrome and renal injury. Zucker obese rats were fed a high-protein diet (OHP; n=6), a high-protein diet containing candesartan, an ARB (OHP+C; n=6), or a high-protein diet containing both candesartan and pioglitazone (OHP+CP; n=6) for 12 weeks. Systolic blood pressure and urinary protein excretion were measured throughout the study, and renal histology and immunohistochemistry were assessed at 12 weeks. OHP rats developed hypertension (157±4 mmHg) and proteinuria (178±44 mg/d), and these conditions were significantly ameliorated by candesartan (to 143±3 mmHg and 84±25 mg/d, respectively). Pioglitazone enhanced the antihypertensive and anti-proteinuric effects of candesartan (121±3 mmHg, 16±8 mg/d, respectively). Histologically, candesartan ameliorated glomerulosclerosis, podocyte injury, interstitial fibrosis and monocyte/macrophage infiltration into the tubulointerstitium in the kidneys of OHP rats. Pioglitazone abrogated residual interstitial fibrosis in the kidneys of OHP+C rats. Our results suggested that pioglitazone augmented the antihypertensive, anti-proteinuric and possibly renal anti-fibrotic actions of candesartan in Zucker obese rats fed a high-protein diet. The combination therapy of ARB and TZD may protect against renal injury in patients with metabolic syndrome.

Arterial stiffness index: A new evaluation for arterial stiffness in elderly patients with essential hypertension

Background:  Arterial stiffness is one of the predictors of cardiovascular event. Arterial stiffness is commonly measured by pulse wave velocity between the carotid and femoral arteries. Recently the arterial stiffness index which is measured by computerized oscillometry at the upper arm was developed. As this procedure is a convenient means of measuring pulse wave velocity, we considered it suitable to evaluate arterial stiffness in elderly patients. We evaluated this arterial stiffness index and compared it with other methods of evaluating arterial stiffness in hypertensive patients, including the elderly.