Satoshi Kagitani

Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/ salt hypertensive rats

Objective In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats. Methods Sprague–Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-β1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined. Results SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-β1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-β1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast. Conclusion Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.

Fasudil attenuates myocardial fibrosis in association with inhibition of monocyte/macrophage infiltration in the heart of DOCA/salt hypertensive rats.

Objective: To determine the effects of fasudil, a Rho-kinase inhibitor, on mineralocorticoid-induced myocardial remodeling, we investigated whether fasudil would suppress myocardial fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt hypertensive rats. Methods: Sprague-Dawley rats treated with DOCA combined with 1% NaCl and 0.2% KCl in the drinking water after receiving left nephrectomy were given fasudil (10 mg/kg/day; n = 20) or vehicle (n = 20). Systolic blood pressure (SBP) was measured biweekly. Myocardial monocyte/macrophage infiltration and myocardial fibrosis were determined histologically. Expressions of mRNA of procollagen I (PI), procollagen III (PIII), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, type-1 plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-β1, and c-fos were determined. Results: SBP was significantly increased on day 14 after treatment with DOCA/salt. Extent of interstitial and perivascular fibrosis was significantly increased on day 28. Expressions of mRNA of PI, PIII, MCP-1, IL-6, PAI-1, TGF-β1, and c-fos were significantly increased on day 14. Although SBP did not differ between the fasudil and vehicle groups, extent of monocyte/macrophage infiltration and fibrosis was attenuated in the fasudil group. Expressions of mRNA of these factors except TGF-β1 were also attenuated. Conclusion: Fasudil attenuates myocardial fibrosis possibly via suppression of monocyte/macrophage infiltration of the heart in DOCA/salt hypertensive rats.

Different platelet aggregability during mental stress in two stages of essential hypertension

To determine whether platelet response to mental stress is altered in essential hypertension, platelet aggregability and plasma beta-thromboglobulin were determined in 24 patients with essential hypertension (11 patients with World Health Organization (WHO) stage I and 13 patients with stage II) and 14 normotensive controls before and after a 10-min arithmetic stress (serial subtraction of 7 from 1000). In normotensive subjects, arithmetic stress did not affect primary aggregations to 1.0 micromol/L adenosine diphosphate (ADP) and to 2.5 micromol/L 5-hydroxytryptamine (5-HT), ADP threshold for biphasic aggregation and plasma beta-thromboglobulin level. In hypertensive patients with WHO stage I, these parameters were similar to those in normotensives before arithmetic stress, but the arithmetic stress test significantly increased primary aggregation to reagents and beta-thromboglobulin level, and decreased threshold of ADP for biphasic aggregation. In WHO stage II patients, platelet aggregability to reagents and beta-thromboglobulin level were already enhanced as compared with WHO stage I patients and normotensive subjects before arithmetic stress. However, the stress-induced changes in platelet function were less pronounced in WHO stage II patients compared with stage I patients. In conclusion, platelet aggregability and proaggregatory effect of mental stress differed depending on the severity of hypertension in patients with essential hypertension; the transient activation of platelet function during stress with no enhancement under the resting condition in the early phase of hypertension and the continuous activation of platelet function in the advanced phase with hypertensive organ damage.

Increased blood viscosity is associated with reduced renal function and elevated urinary albumin excretion in essential hypertensives without chronic kidney disease

Increased blood viscosity reduces blood flow and elevates vascular resistance in the cardiovascular system. The aim of this study was to elucidate how blood viscosity could affect renal function and eventually contribute to renal damage in essential hypertensives (EHT). In 164 untreated EHT without apparent renal damage (96 men, 56±12 years old, creatinine clearance 123±33 ml min−1 per 1.73 m2 and urinary albumin excretion 19±19 mg per day), blood and plasma viscosity was determined using a falling ball microviscometer. Blood viscosity correlated negatively with creatinine clearance (r=−0.185, P=0.018) and positively with urinary albumin excretion (r=0.253, P=0.001). This indicated that increased blood viscosity is associated with reduced renal function and worsening of albuminuria in EHT. Stepwise multiple regression analysis identified blood viscosity as an independent determinant of creatinine clearance (R2=0.058) and urinary albumin excretion (R2=0.216). In conclusion, increased blood viscosity may be a risk for development of renal disease in EHT.

Imbalance of Renal Production Between 5-Hydroxytryptamine and Dopamine in Patients With Essential Hypertension Complicated by Microalbuminuria

BACKGROUND In the kidney, 5-hydroxytryptamine (5-HT) and dopamine (DA) are formed by the same enzyme, l-aromatic amino acid decarboxylase, but act on renal function and glomerular structure in an opposite direction. The present study was designed to explore whether rates of renal production of 5-HT relative to that of DA are altered in patients with essential hypertension and microalbuminuria. METHODS We measured urinary levels of 5-HT and DA, reflecting renal production of 5-HT and DA as well as 24-hour ambulatory blood pressure and urinary albumin excretion in 82 consecutive untreated, essential hypertensives without overt proteinuria. RESULTS Urinary 5-HT excretion and the ratio of urinary 5-HT to DA were significantly higher in 22 patients with microalbuminuria than in the remaining patients with normoalbuminuria, although urinary DA levels did not differ between the groups. The 24-hour systolic and diastolic blood pressures were also higher in the microalbuminuric group than in the normoalbuminuric group. Multiple regression analysis revealed that urinary 5-HT excretion and 24-hour systolic blood pressure were independently associated with urinary albumin excretion. Furthermore, urinary 5-HT excretion was positively correlated with creatinine clearance as well as blood pressure but tended to be negatively correlated with fractional excretion of sodium. CONCLUSIONS Renal production of 5-HT is enhanced compared with that of DA in essential hypertensives with microalbuminuria. This imbalance may contribute to the genesis of hypertensive glomerular damage.

Effects of a novel calcium antagonist, benidipine hydrochloride, on platelet responsiveness to mental stress in patients with essential hypertension.

The effects of a novel calcium antagonist, benidipine hydrochloride, on responses of platelets to mental stress were evaluated in nine patients with essential hypertension. Before and 12 weeks after the monotherapy with benidipine (2-4 mg/day), platelet aggregability and plasma beta-thromboglobulin were determined during rest and after a 10-min arithmetic stress. Before the treatment, arithmetic stress significantly increased platelet aggregability in response to adenosine diphosphate (ADP) and plasma beta-thromboglobulin level. Blood pressure, pulse rate, and plasma catecholamines also increased during arithmetic stress. The treatment with benidipine did not affect resting values of platelet functions, but attenuated significantly stress-induced alterations in primary aggregation to 1.0 microM ADP (34 +/- 4% to 40 +/- 3% before treatment vs. 32 +/- 2% to 34 +/- 3% after benidipine), ADP threshold for biphasic aggregation (2.2 +/- 0.4 to 1.8 +/- 0.3 microM before treatment vs. 2.2 +/- 0.3 to 2.2 +/- 0.4 microM after benidipine) and plasma beta-thromboglobulin level (74 +/- 16 to 104 +/- 15 ng/ml before treatment vs. 60 +/- 10 to 52 +/- 8 ng/ml after benidipine; p < 0.05 for Stress x Treatment interactions in all values). The pretreatment elevations in blood pressure and sympathetic activity with stress were not modified by benidipine treatment. In conclusion, the monotherapy with benidipine did not affect platelet function during the resting condition, but significantly suppressed the platelet activation induced by arithmetic stress in patients with essential hypertension.

Situs inversus and cystic kidney disease: Two adult patients with this Heterogeneous syndrome

Summary Background: Situs inversus is a rare complication of cystic kidney diseases. Only three genes, INVS (NPHP2), NPHP3 and PKD2 have been proved to be responsible for some cases, while the responsible genes in many others are still unknown. Case Reports: Here we report two male patients with situs inversus combined with cystic kidney disease without any family history of polycystic kidney disease. Their renal function was normal in childhood but culminated in end stage renal disease in middle age. No pathogenic mutations were found in mutation analysis of INVS, IFT88, PKD2, UMOD or NPHP3 in them. Conclusions: Past reported cases of situs inversus and cystic kidney diseases were divided into three groups, i.e., gestational lethal renal dysplasia group, infantile or juvenile nephronophthisis group and polycystic kidney disease group. The present patients are different from each of these groups. Moreover, the renal lesions of the present two cases are quite different from each other, with one showing mildly atrophic kidneys with small numbers of cysts and the other an enlarged polycystic kidney disease, suggesting very heterogeneous entities.

1093 THE RELATION OF DIETARY SALT TO INSULIN SENSITIVITY IN PRIMARY ALDOSTERONISM

Objectives: Whether or not the influence of aldosterone on insulin sensitivity is modified by dietary salt is unknown. In this study, the relationship between dietary salt and insulin sensitivity was investigated in primary aldosteronism (PA). Design and Methods: After the measurements of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and urinary sodium excretion (UNaV) during rest, blood sugar (BS) and insulin (IRI) were evaluated before and after glucose loading of 75 g in 20 PA patients. According to dietary salt estimated by UNaV, subjects were divided into patients with 10.3±2.2 (High salt) and 6.2±2.1 g/day (Low salt) (n=10 of each group). Thereafter, in ten patients, the same study was repeated following low-salt diet instruction (6 g/day) for three months. Results: There was no difference in age, blood pressure, PAC and PAC/PRA between the two groups. Before glucose loading, IRI and HOMA-IR index (i.e., index for insulin sensitivity) was higher in High (12.8±6.8 &mgr;U/ml, 3.13±1.86) than in Low group (5.6±2.7, 1.31±0.72) despite no differences in BS among the two groups (96.8±13.1vs 94.0±7.2 mg/dl). After glucose loading, the increase of IRI estimated by AUC of IRI was greater in High (456.5±267.8 U/ml) than in Low group (254.9±177.1), although BS elevated to the similar extent in both groups. Following low-salt diet instruction, both IRI and HOMA-IR decreased (9.87±7.63 to 7.54±5.03 &mgr;U/ml, 2.54±2.08 to 1.88±1.39) without changes in BS. Thus, in PA, salt restriction enhanced insulin sensitivity and reduced blood level of insulin. Conclusions: These results suggest that insulin sensitivity could be salt-sensitive in PA.

294 RELATION OF SMALL DENSE LOW-DENSITY LIPOPROTEIN CHOLESTEROL TO CAROTID ATHEROSCLEROSIS IN ESSENTIAL HYPERTENSIVES WITH NORMAL RENAL FUNCTION

Objectives: Recently, small dense low-density lipoprotein cholesterol (sdLDL-C) has been highlighted as the most atherogenic lipoprotein in cardiovascular disease. In this study, the relations of sdLDL-C and other lipid parameters to surrogate markers of atherosclerosis were investigated in essential hypertensives (EHT) with normal renal function. Design and Methods: In 137 untreated EHT with GFR≥60 mL/min, plasma levels of sdLDL-C (using assay kit supplied by Denka Seiken Co., Ltd., Niigata, Japan), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), adiponectin and norepinephrine, and blood sugar were measured. Intima-media thickness (IMT) and stiffness index &bgr; (&bgr;) of carotid artery (i.e., index for wall thickness and arterial stiffness of large artery, respectively) was also evaluated by B-mode ultrasonography and ultrasonic phase-locked echo-tracking system, respectively. Results: Although LDL, TG and HDL-C did not associate with IMT, sdLDL-C and ratio of sdLDL-C to LDL significantly correlated with IMT (r = 0.226, 0.181, p < 0.05 of each). Multiple regression analysis demonstrated that sdLDL-C was an independent determinant for IMT together with age, blood sugar and plasma levels of adiponectin and norepinephrine (r2 = 0.323, P < 0.05). In contrast, sdLDL-C and the other lipoproteins did not relate to &bgr;. In addition, either blood pressure or pulse rate did not associate with IMT and &bgr;. Conclusions: These results indicate that in EHT with normal renal function, sdLDL was the best marker for large arterial wall thickness among lipid parameters, and suggest that quantitative measurement of sdLDL could give the useful information for atherosclerosis compared with systemic hemodynamics.

226 PROLONGATION OF QT DISPERSION INDUCED BY MENTAL ARITHMETIC STRESS IN ESSENTIAL HYPERTENSIVES COMPLICATED WITH METABOLIC SYNDROME

Objectives: Psychological stress can increase QT dispersion (QTd), thereby increasing risk for arrhythmia and sudden death especially in coronary heart disease. The present study was designed to examine stress-induced alterations of QTd in essential hypertensives (EHT) complicated with metabolic syndrome (Mets), characterized as high risk for cardiovascular disease. Design and methods: Systemic hemodynamics, plasma noradrenaline and QTd (i.e., difference between maximum and minimum QT interval on electrocardiogram) were evaluated during rest and after a 10-min arithmetic stress in 92 consecutive untreated EHT. The data were compared between 42 EHT with Mets and 50 EHT without Mets (non-Mets). Results: Blood pressure, plasma norepinephrine and QTd did not differ between Mets and non-Mets during rest, although pulse rate was higher in Mets compared with non-Mets. Following arithmetic stress, plasma norepinephrine increased in both Mets and non-Mets (228±12 to 299±13 and 217±12 to 261±12 pg/mL), but its increase was greater in Mets than in non-Mets (p<0.05 for group×stress interaction). Concomitantly, QTd increased in Mets (59±5 to 75±5 msec), but it remained unchanged in non-Mets (59±4 to 62±4 msec) (p<0.05 for group×stress interaction). Thus, stress-induced change in QTd was larger in Mets compared with non-Mets. In contrast, blood pressure and pulse rate increased to the similar extent after arithmetic stress in both groups. Conclusion: Mental arithmetic stress induced prolongation of QT dispersion along with exaggerated activation of sympathetic neural activity in EHT with Mets.